Critical Reviews in Food Science and Nutrition

ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/bfsn20

Nutraceuticals: unlocking newer paradigms in the

mitigation of inflammatory lung diseases

Yinghan Chan, Venkata Sita Rama Raju Allam, Keshav Raj Paudel, Sachin K.
Singh, Monica Gulati, Muralikrishnan Dhanasekaran, Piyush Kumar Gupta,
Niraj Kumar Jha, Hari Prasad Devkota, Gaurav Gupta, Philip M Hansbro,
Brian Gregory George Oliver, Dinesh Kumar Chellappan & Kamal Dua

To cite this article: Yinghan Chan, Venkata Sita Rama Raju Allam, Keshav Raj Paudel, Sachin
K. Singh, Monica Gulati, Muralikrishnan Dhanasekaran, Piyush Kumar Gupta, Niraj Kumar Jha,
Hari Prasad Devkota, Gaurav Gupta, Philip M Hansbro, Brian Gregory George Oliver, Dinesh
Kumar Chellappan & Kamal Dua (2021): Nutraceuticals: unlocking newer paradigms in the
mitigation of inflammatory lung diseases, Critical Reviews in Food Science and Nutrition, DOI:
10.1080/10408398.2021.1986467

To link to this article: https://doi.org/10.1080/10408398.2021.1986467

Published online: 06 Oct 2021.

Submit your article to this journal

View related articles

View Crossmark data

Full Terms & Conditions of access and use can be found at

https://www.tandfonline.com/action/journalInformation?journalCode=bfsn20
Critical Reviews in Food Science and Nutrition
https://doi.org/10.1080/10408398.2021.1986467

Review

Nutraceuticals: unlocking newer paradigms in the mitigation of

inflammatory lung diseases
Yinghan Chana, Venkata Sita Rama Raju Allamb, Keshav Raj Paudelc,d, Sachin K. Singhe , Monica
Gulatie, Muralikrishnan Dhanasekaranf, Piyush Kumar Guptag , Niraj Kumar Jhah , Hari Prasad
Devkotai , Gaurav Guptaj, Philip M Hansbroc,d , Brian Gregory George Oliverd,k, Dinesh Kumar
Chellappanl and Kamal Duac,m,n
a
School of Pharmacy, International Medical University (IMU), Kuala Lumpur, Malaysia; bDepartment of Medical Biochemistry and
Microbiology, Uppsala University, Uppsala, Sweden; cCentre for Inflammation, Centenary Institute, Sydney, NSW, Australia; dSchool of Life
Sciences, Faculty of Science, University of Technology Sydney, Ultimo, NSW, Australia; eSchool of Pharmaceutical Sciences, Lovely
Professional University, Phagwara, Punjab, India; fDepartment of Drug Discovery and Development, Harrison School of Pharmacy, Auburn
University, Auburn, Alabama, USA; gDepartment of Life Sciences, School of Basic Sciences and Research (SBSR), Sharda University, Greater
Noida, Uttar Pradesh, India; hDepartment of Biotechnology, School of Engineering & Technology (SET), Sharda University, Greater Noida,
Uttar Pradesh, India; iGraduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto City, Kumamoto, Japan; jSchool of
Pharmacy, Suresh Gyan Vihar University, Jagatpura, Jaipur, India; kWoolcock Institute of Medical Research, University of Sydney, Sydney,
NSW, Australia; lDepartment of Life Sciences, School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia; mDiscipline of
Pharmacy, Graduate School of Health, University of Technology Sydney, Ultimo, NSW, Australia; nFaculty of Health, Australian Research
Centre in Complementary and Integrative Medicine, University of Technology Sydney, Ultimo, NSW, Australia

ABSTRACT KEYWORDS
Persistent respiratory tract inflammation contributes to the pathogenesis of various chronic Dietary supplements;
respiratory diseases, such as asthma, chronic obstructive pulmonary disease, and pulmonary fibrosis. inflammation;
These inflammatory respiratory diseases have been a major public health concern as they are the nutraceuticals;
leading causes of worldwide mortality and morbidity, resulting in heavy burden on socioeconomic phytoconstituents;
plant extracts;
growth throughout these years. Although various therapeutic agents are currently available, the
respiratory disease
clinical applications of these agents are found to be futile due to their adverse effects, and most
patients remained poorly controlled with a low quality of life. These drawbacks have necessitated
the development of novel, alternative therapeutic agents that can effectively improve therapeutic
outcomes. Recently, nutraceuticals such as probiotics, vitamins, and phytochemicals have gained
increasing attention due to their nutritional properties and therapeutic potential in modulating
the pathological mechanisms underlying inflammatory respiratory diseases, which could ultimately
result in improved disease control and overall health outcomes. As such, nutraceuticals have been
held in high regard as the possible alternatives to address the limitations of conventional
therapeutics, where intensive research are being performed to identify novel nutraceuticals that
can positively impact various inflammatory respiratory diseases. This review provides an insight
into the utilization of nutraceuticals with respect to their molecular mechanisms targeting multiple
signaling pathways involved in the pathogenesis of inflammatory respiratory diseases.

GRAPHICAL ABSTRACT

CONTACT Dinesh Kumar Chellappan dinesh_kumar@imu.edu.my; Kamal Dua Kamal.Dua@uts.edu.au

© 2021 Taylor & Francis Group, LLC
2 Y. CHAN ET AL.
Introduction
Chronic respiratory diseases such as asthma, chronic
obstructive pulmonary disease (COPD), and interstitial lung
disease are the most common inflammatory diseases of the
lungs. These diseases represent the most notable causes of
worldwide deaths, imparting remarkable socioeconomic bur-
den associated with the high healthcare costs incurred with
treatment, prolonged hospitalization, as well as reduced
productivity. The burden brought upon by these diseases
have also negatively impacted the livelihood of suffering
individuals (Prasher et  al. 2020; Shukla et  al. 2020).
According to the World Health Organization (WHO), there
are approximately 235 million individuals who are suffering
from mild to moderate conditions of asthma, whereas COPD
alone has claimed more than three million lives every year,
which corresponds to an estimated figure of 6% global
deaths (Chronic respiratory diseases, World Health
Organization n.d.). To make matters worse, the prevalence
of inflammatory respiratory diseases is still rapidly rising
each year, sounding the alarm that a large number of world-
wide populations will be shredded in the future as a result
of these diseases. Moreover, inflammatory respiratory dis-
eases are further aggravated by various prime mediators
including worsening air pollution, growing smokers’ popu-
lation, as well as increased exposure to occupational aller-
gens (Hatipoglu 2018; Burney 2017; Duncan 2016). As such,
the rising threat of inflammatory respiratory diseases to
public health has necessitated the prompt management of
these diseases using a safe and effective approach with
regards to the present scenario.
As the lungs constantly interacts with the external envi-
ronment, they are swamped by multiple environmental stim-
uli, such as pollen, dust, chemicals, or foreign antigens that
may result in the development of respiratory tract infections
(Chan et  al. 2021b). Therefore, inflammation is an important
cellular response and a host defence mechanism that will
be initiated to protect against these external threats in the
lungs. However, chronic and persistent inflammatory
response may lead to damage of the lungs as observed in
various inflammatory respiratory diseases (Hatipoglu 2018;
Santana et  al. 2016). During lung inflammation, inflamma-
tory cells such as lymphocytes, macrophages, eosinophils,
and neutrophils will be activated, which subsequently results
in the release of various inflammatory mediators such as
interleukins (IL)-5, IL-6, IL-1β, IL-13, tumor necrosis factor
(TNF)-α, leukotrienes, prostaglandins, and histamines. These
inflammatory mediators are often closely associated with
the pathophysiological features of chronic respiratory dis-
eases, namely airway hyperresponsiveness, airway obstruc-
tion, airway remodeling, as well as mucus hypersecretion
(Santana et  al. 2016; Gulati et  al. 2016). For example,
increased recruitment of polymorphonuclear leucocytes neu-
trophils has been associated with oxidative tissue damage
due to the release of their granule-associated proteins such
as myeloperoxidase that stimulate alveolar macrophages,
leading to increased inflammatory and cytotoxic state that
amplifies the lung inflammatory response (Grattendick et  al.
2002). Besides, eosinophil peroxidase is another example of
granule protein released by activated eosinophils that serves
as a source for protein carbamylation to trigger various
inflammatory cascades and to facilitate the catalysis of cyto-
toxic oxidants associated with the pathogenesis of inflam-
matory respiratory diseases (Ye et  al. 2019; Z. Wang et  al.
2016). Thus, pharmacotherapy is essential to counteract lung
inflammation by targeting multiple cytokines and inflam-
matory markers, which can help to prevent loss of lung
function in patients suffering from respiratory diseases
(Shastri et  al. 2021). Some of this pharmacotherapy such as
mitochondrial targeted antioxidants can specifically target
specific organelle such as mitochondrial dysfunction to com-
bat chronic respiratory disease (Chellappan et  al. 2021).
Furthermore, inflammasomes are potent inducers of inflam-
mation as they can modulate the maturation and release of
pro-inflammatory cytokines. As such, excessive activation
of inflammasomes represents an exacerbating factor to the
complex inflammatory processes underlying various inflam-
matory respiratory diseases, including asthma, COPD, acute
respiratory distress syndrome (ARDS), and cystic fibrosis.
Therefore, therapies that target inflammasomes are also
essential for the management of these diseases and to pre-
vent their progression into more severe disease (Kim
et  al. 2015).
Although advancements in medical research have led to
the discovery and development of various biomolecules and
chemical compounds, efforts to effectively manage inflam-
matory lung diseases are to no avail as most of the con-
ventional therapeutics are unable to fully cure these diseases
and restore patients’ lung function (Santana et  al. 2016;
F. Lssiu et  al. 2016; Lin et  al. 2015). For instance, controlling
symptoms is currently the mainstay of asthma therapy,
whereby in cases where patients are not well-controlled, a
higher dose or intervention using more than one type
of therapeutic agent may be required, which exposes
these patients to a higher risk of experiencing adverse reac-
tions. Besides, the prolonged use of corticosteroid,
which is the primary anti-inflammatory agent used in
asthma and COPD, is also associated with suppression of
hypothalamic-pituitary-adrenal axis, osteoporosis, as well as
reduction in growth velocity that can contribute to reduced
final adult height in treated children due to the interference
of corticosteroids with various mediators involved in growth
including the secretion and activity of growth hormone and
synthesis of collagen, thereby affecting the quality of life
of these patients (Durham et  al. 2016; Heffler et  al. 2018;
Clarke, Lundy, and McGarvey 2015). Hence, there is an
unmet medical need for the use of complementary thera-
peutic approaches to address the shortcomings of conven-
tional treatments in inflammatory respiratory diseases.
Nutraceuticals are the hybrid products of nutrients and
pharmaceuticals. Apart from being a medicine, they also
possess nutritional values that act as food supplements for
the maintenance of body health whilst providing necessary
nutrition that are needed various metabolic processes in
regulating normal body functions, which ultimately protects
the body from chronic diseases (Gulati et  al. 2016; Chanda
et  al. 2019). Recently, nutraceuticals are of great interest to

medical researchers as these naturally occurring products
can potentially reduce the high production costs of modern
pharmaceuticals. Namely, the costs of setting up a produc-
tion system for growing plants with the ability of mass
production, as well as those associated with the maintenance
of infrastructure related to collection of natural products
and curation of raw material extracts are significantly lower.
Therefore, they are highly suitable for deployment in devel-
oping countries where high infrastructure costs constitute
a hurdle for the research and development of novel thera-
peutics (Sack et  al. 2015; Cragg and Newman 2013). The
lowered production costs can also contribute to therapeutics
at a more affordable price, which could address the issue
of lack of access to medicines for patients residing in rural
areas or low-income countries (Sofowora, Ogunbodede, and
Onayade 2013; Ma et  al. 2005). At the same time, the
medicinal and nutritional properties of nutraceuticals can
provide a viable therapeutic option as studies have also
shown reduced adverse effects as compared with chemically
synthesized compounds, thereby improving safety and over-
all therapeutic outcomes in patients (Gulati et  al. 2016; B.
Chauhan et  al. 2013; Varzakas et  al. 2018). In this article,
we provide a brief overview to the pathophysiology of sev-
eral inflammatory respiratory diseases, highlighting their
primary inflammatory mechanisms and the limitations of
current therapies. We then summarized recent advances in
mechanistic studies of nutraceuticals on airways inflamma-
tion, as well as their potential to be translated into clinical
application for the effective management of inflammatory
respiratory diseases.
Overview of inflammatory respiratory diseases
Asthma
Asthma is a disorder of the airways characterized by chronic
inflammation and airway hyperresponsiveness, which is an
exaggerated airway-narrowing response due to sensitization
of the airways resulting in recurrent episodes of wheezing,
chest tightness, breathlessness, and coughing that may vary
in intensity over the course of disease (Mims 2015).
Generally, asthma is a complex disease that can manifest as
episodic where symptoms can be resolved upon therapy, or
persistent where characteristic asthmatic clinical symptoms
are present. Based on its triggers, asthma can be categorized
as either allergic or non-allergic. Allergic asthma can be
caused by allergens such as animal dander, dust mites,
molds, pollens, chemical fumes, as well as air pollutants
from bushfire, biomass smoke, and motor vehicles. On the
other hand, non-allergic asthma is commonly associated
with triggering factors such as emotions and stress, physical
activities, diet, infections, and tobacco smoke (Gautier and
Charpin 2017; Chan et  al. 2021e). Nevertheless, asthma
triggers may differ between individuals and can be more
pronounced under several conditions, such as cold environ-
ment, use of certain medications including aspirin, beta
blockers, and non-steroidal anti-inflammatory drugs, phys-
ical exercise, consumption of alcohol, as well as medical
Critical Reviews in Food Science and Nutrition 3
history (Oland, Booster, and Bender 2017; Dharmage, Perret,
and Custovic 2019).
Although asthma is one of the most common chronic
respiratory disease worldwide, its pathophysiology remained
poorly understood. A precise and in-depth understanding
of asthma pathophysiology is crucial for the development
of therapeutic agents that can effectively target the under-
lying pathophysiological mechanisms of the disease. Typically,
majority of asthma cases are attributed to the sensitization
of airways by allergens, followed by a cascade of biological
events that ultimately results in chronic airway inflammation
(Chan et  al. 2021e). The traditional dogma is that the ini-
tiation of asthma is modulated via T-helper (Th) cell type-2
(Th2) immune responses, in which the recruitment of Th2
lymphocytes into the airways upregulates the expressions of
pro-inflammatory cytokines, such as interleukins (IL)-4, −5,
−9, and −13 (Quirt et  al. 2018; Kuruvilla, Lee, and Lee
2019). Among these, IL-5 is regarded as an important bio-
logical factor that is responsible for the recruitment, differ-
entiation, growth, activation, and survival of eosinophils,
thereby exerting its key role in eosinophilic inflammation
and the development of asthma (Kuruvilla, Lee, and Lee
2019; Pelaia et  al. 2019). Eosinophils have been implicated
in the development of airway remodeling in asthma via the
production of transforming growth factor (TGF)-β, leading
to airway fibrosis. Besides, eosinophils are also the source
of IL-13 and cysteinyl leukotrienes, which promote airway
hyperresponsiveness and mucus hypersecretion through the
enhancement of goblet cells differentiation (McBrien and
Menzies-Gow 2017; Nakagome and Nagata 2018). The dam-
age induced by the accumulation of eosinophils at the bron-
chial level is mainly attributed to their degranulation and
subsequent release of toxic proteins, including eosinophil
cationic protein, eosinophil-derived neurotoxin, eosinophil
peroxidase, as well as major basic protein. Collectively, these
result in bronchoconstriction and activation of mast cells
and basophils, which also secrete prostaglandins, histamine,
and more leukotrienes to complement the ongoing inflam-
matory processes (Bakakos, Loukides, and Bakakos 2019;
Matucci et  al. 2018). Additionally, the stimulation of mast
cells along with IL-4 contributes to the induction of immu-
noglobulin E (IgE) responses, leading to the production of
histamine, tryptase, leukotrienes, adenosine, as well as other
inflammatory mediators that work synergistically to trigger
smooth muscle contraction and vascular leakage, resulting
in mucus hypersecretion, bronchospasm, infiltration of
immune cells, as well as subsequent airway narrowing and
airway hyperresponsiveness that are commonly observed in
asthmatic patients (Kuruvilla, Lee, and Lee 2019; Holgate
2013; Pembrey et  al. 2018). It has been established that the
airway epithelium can modulate Th2 responses through the
production of several master regulators including IL-25,
IL-33, and thymic stromal lymphopoietin. Nevertheless, these
mediators and other pro-inflammatory cytokines that are
produced during the early phase of an immune response
could further propagate, resulting in frequent exacerbations
in severe asthmatic patients which are characterized by bron-
chus hypersensitivity and progressive airway inflammation
4 Y. CHAN ET AL.
that can greatly damage lung functions due to severe airway
obstruction (Shukla et  al. 2020; Chan et  al. 2021e; Holgate
2013). While these accurately conveys the primary inflam-
matory mechanisms of asthma, the model of asthma as a
single entity is now obsolete and “asthma” is a term now
used as an umbrella diagnosis to describe multiple disease
phenotypes and endotypes (Kuruvilla, Lee, and Lee 2019;
Pavord et  al. 2018). Phenotypes refer to the observable traits
of the disease such as its clinical presentation, symptoms,
triggers, and allergic features (e.g.: atopic, non-atopic, late
onset), whereas endotypes are the subtypes of the disease
defined by a distinct biological mechanism which links the
observed clinical characteristics with a specific molecular
pathway (e.g.: Th2-high and non-Th2) (Fitzpatrick and
Bacharier 2019). As such, asthmatic patients may have vary-
ing response to the same therapeutic interventions despite
exhibiting similar clinical symptoms of wheezing, chest tight-
ness, and shortness of breath with variable airflow obstruc-
tion, due to the diverseness and underlying heterogeneity
of the disease (Kuruvilla, Lee, and Lee 2019; Pavord et  al.
2018). Thus, categorization of patients is crucial in the man-
agement of asthma as specific traits can be targeted for
achieving an effective therapy of the disease.
Pharmacotherapy of asthma primarily aims to achieve
good control of asthmatic symptoms as well as to reduce
asthma exacerbations, prevent loss of lung function, and to
minimize risk of adverse drug reactions (Clarke, Lundy, and
McGarvey 2015). Inhaled corticosteroids (ICS) and
long-acting β2-adrenoceptor agonists are currently the main-
stay of asthma therapy; however, these agents are unable to
prevent severe exacerbations and diminish the progression
of the disease. Namely, the therapeutic efficacy of these
agents is highly dependent on the individual characteristics
of the patients, such as adherence and/or the technique of
using medications (Zoratti and O’Connor 2020; Agbetile
and Green 2011). Furthermore, these agents are also fre-
quently associated with undesirable adverse effects. For
instance, prolonged use of corticosteroids may lead to the
development of osteoporosis, adrenal suppression, candidi-
asis, dysphonia, myopathies, as well as metabolic disturbs
that could compromise patients’ quality of life and further
affects treatment compliance (Lin et al. 2015; Amaral-Machado
et  al. 2020). Additionally, increasing chronicity and severity
of the disease may result in permanent narrowing of the
airways, which significantly reduces the effectiveness of
bronchodilators for relieving asthmatic exacerbations (Chan
et  al. 2021e; Chan et  al. 2021d). Another major drawback
of conventional asthma therapeutics is their associated cost.
It is estimated that there will be a 4% annual increment in
the costs of asthma therapeutics due to increasing cost of
medicines. Therefore, the amount of money that is required
for treating asthma represents a remarkable expenditure in
public health, which may impose financial strains even in
developed countries (Amaral-Machado et  al. 2020). Hence,
given the prominent rise in global prevalence of asthma
and upon consideration of the currently available therapies,
their adverse effects, as well as their high cost, the devel-
opment of alternative therapeutics and/or complementary
therapies to current asthma therapies is becoming increas-
ingly relevant and an essential strategy in the management
of asthma.
Chronic Obstructive pulmonary disease
COPD is another common type of inflammatory respiratory
disease and a coherent term used to describe a group of
progressive, irreversible obstructive pulmonary conditions
such as emphysema, small airway deterioration, chronic
bronchitis, as well as chronic asthma. Chronic lung inflam-
mation upon exposure to inhaled gases and particles is
thought to be at the root of COPD pathophysiology, which
subsequently contributes to the recruitment and activation
a myriad of inflammatory cells in the lungs (Shukla et  al.
2020; O’Reilly 2017). The key clinical features of COPD are
chronic bronchitis and emphysema, whereby in chronic
bronchitis, bronchial tubes are narrow and inflamed with
an absence of cilia, thereby leading to mucus hypersecretion
in the lungs; whereas in emphysema, the size of small sacs
within the alveoli wall becomes larger, which then reduces
oxygen absorption capacity leading to alveoli damage (H.-X.
Zhou et  al. 2015). As such, these clinical features ultimately
deem COPD an incurable progressive disease. The earliest
symptoms presented by COPD patients are usually exertional
dyspnea, with the three essential features of COPD being
intermittent worsening episodes of dyspnea, chronic cough,
and increased sputum production (P. T. King 2015). As the
leading causative factor of COPD, cigarette smoke typically
contains more than 4,500 different substances such as toxins,
heavy metals, mutagens, and carcinogens that will be depos-
ited along the respiratory tract from the upper airways to
the smaller alveoli when inhaled (Lugg et  al. 2021). This
then leads to an imbalance between oxidants and antioxi-
dants within the respiratory system, which subsequently
results in the upregulation of the genetic expressions of
various inflammatory molecules, increased mucus secretion,
as well as deactivation of anti-proteases. These ultimately
contributed to bronchial cell apoptosis and the destruction
of local respiratory tissues (Lugg et  al. 2021; Hikichi
et  al. 2019).
An elevated number of neutrophils, macrophages, and
CD8+ lymphocytes in the alveolar and peripheral spaces
are one of the primary features of chronic inflammation in
COPD. Generally, the pathogenesis of COPD involves both
arms of the immune response linked via dendritic cell acti-
vation (Suissa, Dell’Aniello, and Ernst 2012). Starting from
innate immunity, cigarette smoke and/or other noxious gases
can directly activate pattern recognition receptors and puri-
nergic receptors to commence the inflammatory response,
which is also contributed by the necrotic apoptotic cells
releasing damage-associated molecular patterns (Aghasafari,
George, and Pidaparti 2019; Barnes 2016). Besides, these
gases can also damage epithelial cells by inhibiting vascular
endothelial growth factor (VEGF) and hepatocyte growth
factor, thereby resulting in apoptosis of alveolar cells and
the development of emphysema COPD phenotype. Damaged
alveolar epithelial cells then release TGF-β which leads to

local fibrosis via the release of connective tissue growth
factor (CTGF), resulting in collagen deposition and airway
remodeling (Hikichi et  al. 2019; Barnes 2016). Furthermore,
irritants within cigarette smoke can activate alveolar surface
macrophages and airway epithelial cells to release chemo-
tactic factors such as chemokine ligand 2 (CCL2) that
attracts monocytes, C-X-C motif ligand (CXCL)-1 and −8
that attracts neutrophils, as well as CXCL-9, −10, and −11
that attracts Th1 and cytotoxic T cells (Aghasafari, George,
and Pidaparti 2019). Alveolar macrophages can also be fur-
ther recruited as a response to chemokines CCL2 and
CXCL-1, leading to the generation of reactive oxygen species
(ROS), matrix metalloproteinase (MMP)-9, as well as cathep-
sins K, L and S, which collectively damages the alveolar
tissue. Granulocyte production is mediated by
granulocyte-macrophage colony-stimulating factor secreted
by lung macrophages, resulting in increased numbers of
granulocytes and hence, neutrophils in circulation (Barnes
2 0 1 6 ) . B e s i d e s , t h e a c c u mu l at i on of R O S
induced-phosphatidylinositol 3,4,5-triphosphate (PIP3) and
various neutrophil chemotactic factors, for instance, leukot-
riene B4, CXCL-1, CXCL-5, and CXCL-8 can also facilitate
the migration of neutrophils toward the affected area, which
contributes directly to the destruction of alveoli and pro-
motes the secretion of mucus via activation of airway goblet
cells (Hikichi et  al. 2019; Barnes 2016). Persistent inflam-
mation that is observed in COPD might also be a result of
self-sustaining mechanisms, however this is yet to be clar-
ified, and other mechanisms such as memory T cells, bac-
terial colonization or autoimmunity may contribute to the
perpetual cycle of inflammation as well, eventually leading
to increased airway remodeling and destruction of lung
parenchyma in COPD (P. T. King 2015; Barnes 2016).
Along with smoking cessation, current COPD therapies
are mainly focused on the improvement of symptoms and
the prevention of chronic exacerbations. Despite its signif-
icant effects on the quality of life of patients suffering from
COPD, disease-modifying therapeutics are yet to be devel-
oped, in which complete recovery is only possible with lung
transplantation. Existing drugs such as corticosteroids, phos-
phodiesterase (PDE) inhibitors, long acting β2 agonists, and
anticholinergics are linked with adverse reactions and
increased susceptibility to other diseases (Santana et  al. 2016;
Ram et  al. 2011). Specifically, corticosteroids resistance is
frequently observed in many COPD patients, in which the
mechanisms in suppressing the production of CXCL-8,
TNF-α, and MMP-9 from alveolar macrophages are impaired
as compared to healthy subjects, attributed to the suppres-
sion of histone deacetylase activity in macrophages. This
abnormal macrophage activity also impairs phagocytosis of
bacterial and apoptotic cells, thereby resulting in chronic
bacterial colonization of lower airways and an increased risk
of pneumonia in COPD patients (Barnes 2016). Other
adverse effects of COPD pharmacotherapy include supra-
ventricular tachycardias and acute glaucoma from anticho-
linergics, myocardial ischemia, and electrolyte disturbance
from long acting β2 agonists, as well as arrhythmias and
myocardial infarction from PDE inhibitors (Ram et  al. 2011).
Critical Reviews in Food Science and Nutrition 5
Hence, there is a compelling need for the development of
novel, potent, and safer alternatives, such as the use of
alternative and/or complementary therapies, to address the
increasing morbidity and mortality associated with this
chronic disease.
Interstitial Lung disease
Interstitial lung disease (ILD) is an umbrella term used to
describe a large group of diseases that cause fibrosis of the
lungs. There are many causes of ILD which are usually a
result of various environmental, occupational, avocational,
or medication-related exposures, or may be a result of sys-
temic autoimmune and connective tissue diseases (Chan
et  al. 2021d; Kalchiem-Dekel et  al. 2018). ILD is generally
characterized by a combination of chronic lung inflamma-
tion with elevated levels of chronic inflammatory cells
including macrophages and lymphocytes, as well as
pro-inflammatory cytokines, and varying degrees of lung
fibrosis (Kalchiem-Dekel et  al. 2018; Meyer 2014). Therefore,
any forms of ILD can manifest as an inflammatory lung
disease that has minimal fibrosis and responds favorably to
anti-inflammatory or immunosuppressive therapies; or as a
fibrotic pulmonary disease that present poor patient prog-
nosis and responds poorly to therapies; or may present with
both inflammation and fibrosis of different extent
(Kalchiem-Dekel et  al. 2018).
Among the various forms of ILD, idiopathic pulmonary
fibrosis (IPF) has gained the most attention due to its
uniquely poor prognosis and high morbidity, in which exten-
sive deposition of collagen is present within the lungs paren-
chyma and therapies are often ineffective and at times
harmful. Despite numerous studies and trials being con-
ducted over the years, identification of an effective phar-
macologic therapy for IPF remains elusive (Kalchiem-Dekel
et  al. 2018; Meyer 2014; Sgalla et  al. 2018). In normal phys-
iological conditions, fibrogenesis is usually initiated in
response to tissue injury and it is a part of the wound
healing process that leads to the restoration of homeostasis.
The process of wound healing is initiated by epithelial injury,
followed by the secretion of inflammatory mediators such
as IL-25, IL-33, and thymic stromal lymphopoietin which
facilitate the development of profibrotic Th2 responses.
Platelet activation is also induced, leading to an enhanced
vessel permeability for leucocytes recruitment. These inflam-
matory cells then release IL-4 and IL-13 that promotes the
development of a profibrotic macrophage subpopulation for
the secretion of TGF-β1, thereby mediating the recruitment
and activation of fibroblasts and their subsequent differen-
tiation into myofibroblasts. The resulting myofibroblasts then
release extracellular matrix (ECM) components for the pro-
motion of wound healing (Hadjicharalambous and Lindsay
2020; Wynn 2011). Ideally, these processes can result in the
restoration of normal tissue structure and its structural
integrity. However, during fibrosis associated with IPF, any
stage within the wound healing processes can be dysregu-
lated, which leads to an irreversible deposition of scar tissue.
These fibrotic areas are often characterized by an excessive
6 Y. CHAN ET AL.
secretion of ECM components that remarkably remodels the
architecture of the lungs and produces excessive scarring,
resulting in symptoms such as shortness of breath, persistent
cough, and chest tightness (Hadjicharalambous and Lindsay
2020; Barratt et  al. 2018).
Currently, apart from lung transplantation, there is no
effective pharmacotherapies for the management of IPF.
Although there is various evidence that chronic inflamma-
tion plays a role in the pathogenesis of IPF, therapeutics
agents that modulate or suppress immune responses have
also been unsuccessful. As such, IPF is regarded as a dif-
ficult lung disease, in which its survival outcome is com-
parable to that of malignant tumors, posing a huge challenge
to the health and quality of life of patients (Heukels et  al.
2019; Guo et  al. 2019). Recently, several anti-fibrotic agents
have been introduced and approved for use as potential
disease modifying agents for IPF, namely pirfenidone and
nintedanib. Nonetheless, these also brought new challenges
with respect to the adverse effects associated with their
chronic use. For example, pirfenidone is linked with gas-
trointestinal, dermatological, and neurological side effects,
whereas nintedanib is linked with acute nausea, diarrhea,
and modified liver enzyme activity, which may result in
poor patient compliance or discontinuation of their use in
IPF patients (Mojiri-Forushani et  al. 2017; Shaw et  al. 2017).
Hence, these deleterious and unwanted adverse effects of
conventional and chemical drugs prompted the need for
alternative and complementary therapies that are derived
from natural sources, as they may present significantly lower
occurrence of adverse effects and other benefits including
stable curative effects, long duration, as well as absence of
obvious drug dependence (Guo et  al. 2019; Mojiri-Forushani
et  al. 2017).
Acute respiratory distress syndrome
ARDS is first described as the syndrome of acute respi-
ratory failure with manifestations of arterial hypoxemia,
dyspnea, and a marked increase in the work of breathing.
ARDS frequently develops in the setting of viral and bac-
terial pneumonia, non-pulmonary sepsis, aspiration of oral
and/or gastric and esophageal contents, as well as major
trauma (Matthay et  al. 2019). Based on the Berlin defi-
nition, four criteria must be present for the diagnosis of
ARDS, namely, (i) respiratory symptoms must have begun
within a week from a known clinical insult, or there must
be presence of new or worsening symptoms within the
past week; (ii) chest radiograph or computed tomographic
scan must reveal bilateral opacities that are consistent with
pulmonary edema, which cannot be completely explained
by pleural effusions, lung collapse, lobar collapse, or pul-
monary nodules; (iii) respiratory failure shall not be com-
pletely explained by cardiac failure or fluid overload; and
lastly, (iv) there must be a presence of moderate to severe
impairment of oxygenation, as defined by the arterial
partial pressure of oxygen (PaO2) to fraction of inspired
oxygen (FiO2) ratio (Huppert, Matthay, and Ware 2019;
Rawal, Yadav, and Kumar 2018). Increased severity of
ARDS is often linked with poor patient prognosis and
high mortality.
The primary feature of ARDS is an elevated pulmonary
capillary permeability. It is a result of uncontrolled acute
inflammation and dysfunction of lung epithelial and endo-
thelial barriers, as well as augmented transepithelial migra-
tion of leucocytes, which collectively leads to loss of integrity
of the alveolar-capillary membrane and hyperproduction of
pro-inflammatory cytokines (Patel et  al. 2018). As such, the
innate immune response has a crucial role in ARDS patho-
physiology, in which multiple immunologic processes that
involve macrophages, neutrophils, and dendritic cells partake
in the mediation of tissue injury. Bronchial epithelium, alve-
olar macrophages and vascular endothelium can be affected
by inflammatory insults either systematically from extrapul-
monary sites or locally within the lungs, thereby leading to
an accumulation of protein-rich edema fluid into the alveoli,
which ultimately causes hypoxemia due to impaired gaseous
exchange (Han and Mallampalli 2015). Such accumulation
of protein-rich fluid within the alveoli signifies damage to
the alveolar epithelium and capillary endothelium, which
can further amplify the release of cytokines to produce
diffuse alveolar damage. As the lungs are generally composed
by two different types of alveolar epithelial cells, type I cells
damage can promote fluid entry into the alveoli and decrease
fluid clearance, whereas type II cells damage can suppress
production of surfactant which leads to compliance reduc-
tion and alveolar collapse (Umbrello et  al. 2017). In ARDS,
alveolar macrophages have a major role in orchestrating
inflammation and the resolution of the disease. Generally,
stimulated alveolar macrophages recruit circulating macro-
phages and neutrophils to the site of injury within the lungs
and partake in the induction of a wide range of bioactive
mediators, which include ROS, proteases, phospholipids,
eicosanoids, and cytokines that further perpetuate inflam-
matory responses. During the initial inflammatory phase
and/or the recovery phase of ARDS, alveolar macrophages
also interact with mesenchymal stem cells, lymphocytes, and
epithelial cells in a paracrine manner, which can result in
either attenuation of tissue injury or augmentation of the
inflammatory response (Han and Mallampalli 2015; Matthay
and Zemans 2011).
The primary goal of ARDS treatment is to ensure ade-
quate gaseous exchange whilst minimizing the risk of ven-
tilator induced lung injury. Supportive care remains as the
hallmark of ARDS therapy as specific therapies have yet to
be developed, although there is an increased understanding
of its underlying molecular mechanisms over the years (Patel
et  al. 2018; Umbrello et  al. 2017). Due to the significant
roles of inflammation in driving the progression of ARDS,
there have been multiple studies that evaluated
anti-inflammatory agents as potential therapeutics for the
disease. Despite that, clinically used anti-inflammatory drugs
have brought upon several drawbacks, including high cost
of treatment and occurrence of adverse effects (Huppert,
Matthay, and Ware 2019). Given the significant morbidity
and mortality of the disease, ARDS represents an unmet
medical need and the development of novel therapies for

an effective management of this disease is urgently required.
For this instance, certain natural remedies have demon-
strated inhibitory effects on multiple key inflammatory path-
ways associated with the pathogenesis of ARDS at the
molecular level, which therefore may be useful and effective
as novel ARDS therapies. Besides, the application of spe-
cialized nutrients, such as eicosapentaenoic acid and natural
antioxidants have also shown to be beneficial in patients
with ARDS (Patel et  al. 2018; Hamilton and Trobaugh 2011).
Hence, these alternative therapies can potentially be devel-
oped as next generation therapeutics to combat the injury
and inflammation associated with ARDS, thereby facilitating
an effective treatment of this devastating disease.
Nutraceuticals in the management of inflammatory
respiratory diseases
As discussed earlier, in view of the rapidly rising prevalence
of various inflammatory respiratory diseases that have
affected more than millions of people globally, medical prac-
titioners are struggling to address the growing threat of
these diseases to public health through the utilization of
various pharmacotherapeutic drugs that have been developed
thus far. Despite demonstrating a certain extent of efficacy
against these inflammatory respiratory diseases, the thera-
peutic outcomes of most conventional therapeutic agents
remain unsatisfactory, as studies and clinical practice have
reported that these agents are associated with several neg-
ative clinical consequences, including occurrence of adverse
reactions, limited therapeutic efficacy, as well as high costs
of treatment (Shukla et  al. 2020; Lin et  al. 2015; Chan et  al.
2021e; Barnes et  al. 2015; Sadikot 2018). Thus, scientists
and medical researchers are urged to expedite the identifi-
cation and development of potential alternative strategies to
address the increasing ineffectiveness and safety concerns
of conventional drug therapies for inflammatory respiratory
diseases.
The relation of food and its role in the management of
various health conditions has been conceptualized almost
25 centuries ago, signified by the popular quote from the
father of modern medicine, Hippocrates, “Let food be thy
medicine and medicine be thy food” (Chanda et  al. 2019;
Helal et  al. 2019). There is a vast cornucopia of foods, herbs,
and plants which have been an integral part of culture and
history, serving as the backbone of traditional healing sys-
tems in multiple countries since the ancient times. Though
multiple plants and food sources were documented in the
early years having notable medicinal and healing properties
in various pathological conditions, these are overshadowed
by modern therapeutics as the means for treating human
diseases (Chanda et  al. 2019; Chan et  al. 2021e; Veeresham
2012). Nutraceutical is a term that is derived from “nutri-
tion” and “pharmaceutical” in which it is referred to as
products that possess medicinal values in the prevention
and treatment of disease, as well as nutritional values that
can promote physical health, support proper functioning of
the human body, and improve longevity (Nasri et  al. 2014).
Over the last decade, the role of nutrition to the
Critical Reviews in Food Science and Nutrition 7
maintenance of body health as well as the importance of
nutritional supplements and natural substances in preventive
healthcare are being increasingly recognized and promoted
globally as an alternative strategy to confer protection
against chronic diseases, therefore, they have received con-
siderable research interest in the field of modern medicine
(Santana et  al. 2016; Chanda et  al. 2019; Alamgeer et  al.
2018). In addition, as nutraceuticals are typically derived
from natural sources, they can greatly reduce the high treat-
ment costs of chronic diseases and most importantly, they
do not suffer from the drawbacks of poor tolerability and
toxicities, as well as compromised safety issues that are
commonly linked with conventional therapeutics. As such,
nutraceuticals such as dietary fiber, probiotics, polyunsatu-
rated fatty acids, and medicinal plants have been widely
regarded as the potential alternatives for the management
of a wide range of human diseases (Gulati et  al. 2016; Moss,
Williams, and Ramji 2018). Nonetheless, it is important to
note that a potential nutraceutical can only be established
upon elucidation of sufficient clinical data on its health and
medical benefits, as well as its safety profile (Das et  al. 2012).
In terms of inflammatory respiratory diseases, nutraceu-
ticals hold exciting opportunities to revolutionize therapeutic
approaches, as there have been multiple studies which doc-
umented their ability to modulate inflammation and other
cellular mechanisms associated with the pathogenesis of
these diseases (Figure 1) (Clarke, Lundy, and McGarvey
2015; Berthon and Wood 2015). For instance, green tea,
curcumin, caffeine, and gallic acid are nutraceuticals with
remarkable antioxidative properties, which can be utilized
to counter against ROS overproduction as observed in
COPD and ARDS, whereas grape seed oil, resveratrol, lipoic
acid, and coenzyme Q10 possess anti-inflammatory activities
which can potentially be exploited to target the underlying
inflammatory pathways of inflammatory respiratory diseases
(Helal et  al. 2019; Fasano et  al. 2014). In the following
sections, we present the general concept and health pro-
moting effects of several nutraceuticals with respect to
inflammatory respiratory diseases, justified by several studies
conducted in this field of research.
(MMP: matrix metalloproteinase; TLR: Toll-like receptor;
STAT3: signal transducer and activator of transcription 3;
IFN: interferon; NF-κB: nuclear factor kappa-light-
chain-enhancer of activated B cells; MAPK: mitogen-activated
protein kinase; TGF-β: transforming growth factor beta; IL:
interleukin; BALF: bronchoalveolar lavage fluid; NO: nitric
oxide; EPO: eosinophil peroxidase; Smad: small mothers
against decapentaplegic; PGE2: prostaglandin E2; TNF-α:
Tumor necrosis factor-α; Nrf2: nuclear factor-erythroid fac-
tor 2-related factor 2; COPD: chronic obstructive pulmonary
disease).
Foods and nutrients
Probiotics, prebiotics, and synbiotics
Probiotics are defined by the Food and Agriculture
Organization of the United Nations (FAO) and WHO as
“live strains of strictly selected microorganisms which, when
8 Y. CHAN ET AL.

Figure 1. Targeting inflammatory respiratory diseases with nutraceuticals. Nutraceuticals such as vitamins, food and nutrient, trace elements, polyunsaturated
fatty acid and phytochemicals are promising source for the management of chronic respiratory disease such as asthma, COPD, pulmonary fibrosis. These nutra-
ceuticals target various cytokines such as IL-4, IL-5, IL-13, IL-2, IgE, IFN-γ, NO, TNF-α, and PGE2, enzyme such as MMP, and EPO, receptor such as TLR, and
cellular signaling pathway such as STAT, Smad, NF-κB, MAPK, TGF-β, Nrf2 to control the airway inflammation. Furthermore, nutraceuticals also decrease airway
neutrophilia, eosinophilia, airway hyperresponsiveness, collagen production, oxidative stress, goblet cell hyperplasia in various in-vitro and in-vivo models of
inflammatory respiratory diseases.

administered in adequate amounts, confer a health benefit
on the host” (Aponte, Murru, and Shoukat 2020; L. Shi
et  al. 2016). The symbiotic relationship between human host
and its bacteria residents that are present within the gas-
trointestinal system along with their collective genomes,
known as the gut microbiome, has gained increasing research
attention in the recent years, as there are growing evidence
that indicates that the gut microbiome plays a central role
in maintaining human host homeostasis, promoting health
and well-being, as well as preventing disease (Day et  al.
2019). Recently, it has also been established that lung micro-
biomes can induce innate immune response leading to the
progression of chronic respiratory diseases (Paudel et  al.
2020b). A shift in gut bacterial composition and the inter-
action of metabolites that are produced from bacterial
metabolism of dietary components are frequently associated
with various health conditions. Therefore, probiotic supple-
ments have been regarded as potential promoters of good
health whilst acting as therapeutic modulators of disease
initiation and progression (Day et  al. 2019; Mortaz et  al.
2013). As such, probiotics have been employed as therapeu-
tic and/or preventive approach for a wide range of human
diseases by modulating the gut microbiome in a beneficial
manner, such as inflammator y bowel disease,
antibiotic-associated diarrhea, and Helicobacter pylori infec-
tion (L. Shi et  al. 2016; Day et  al. 2019; Mortaz et  al. 2013).
Numerous bacteria species are the natural and predom-
inant constituents of the gut microbiome, among which,
those anticipated to exhibit modulatory effects on the gut
microbiome are usually selected as probiotics (Aponte,
Murru, and Shoukat 2020; L. Shi et  al. 2016). However,
according to the recommendations of the European Food
Safety Authority, FAO, and WHO, several safety, function-
ality, and technological criteria must be strictly fulfilled
during the selection of a probiotic strain before it can be
safely authorized for human use (Table 1) (Markowiak and
Śliżewska 2017; Syngai et  al. 2016). In general, the safety
of a probiotic strain refers to its origin, non-association
with pathogenic cultures, and antimicrobial resistance pro-
file; functionality refers to its ability to survive in the gut
and their immunomodulatory capabilities; whereas techno-
logical feasibility refers to its ability to survive and maintain
its properties throughout the processes of storage and dis-
tribution (Markowiak and Śliżewska 2017). These
 Critical Reviews in Food Science and Nutrition 9

Table 1.  Criteria for the use of probiotic strains in humans (Markowiak and Śliżewska 2017; Syngai et  al. 2016)
Criterion Properties
Safety • Human or animal origin and are isolated from the gastrointestinal tract of healthy subjects.
• Precisely identified at the genus, species, and strain level.
• Do not possess the ability to conjugate bile acids.
• Susceptible to antibiotics and lack of genes that are responsible for antibiotic resistance.
• Nonpathogenic.
• Do not degrade the intestinal mucosa.
Functionality • Ability to adhere to mucosal surfaces and colonize particular sites within the host organism.
• Competitiveness against the gut microbiota.
• Ability to survive, grow, and maintain metabolic activities.
• Tolerance to low pH and bile salts.
• Antagonistic activity against pathogens and able to produce antimicrobial substances.
• Resistance to acids and bacteriocins produced by the endogenic intestinal microbiota.
Technological feasibility • Genetic stability during processing, storage, and distribution.
• Simple production of high biomass amount.
• High productivity of cultures.
• Resistance to bacteriophages.

characteristics of probiotics are not linked with the genus
or species of a microorganism, instead, they are associated
with few and specially selected strains of a specific species.
Primarily, probiotics belongs to the Gram-positive family of
bacteria due to the presence of their natural habitat in the
human’s gut. Lactobacillus spp., Enterococcus spp., and
Bifidobacterium spp. are among the most utilized probiotic
microorganisms in humans and have been regarded as safe
from the basis of long-term application, in which their appli-
cations as probiotics are extensive in both fermented and
non-fermented food products, as well as functional dietary
supplements (Markowiak and Śliżewska 2017; Syngai et  al.
2016). Nevertheless, it should not be assumed that all mem-
bers from the same genus can be safely employed as pro-
biotics. For instance, certain strains within the Bacillus genus
are found to be associated with diseases, such as Bacillus
cereus, which can result in food-borne illnesses (L. Shi
et  al. 2016).
Probiotics are commonly utilized as dietary supple-
ments to bring upon health benefits in the gastrointestinal
system, which include inflammatory bowel disease, infec-
tions, and colon cancer. In this respect, probiotics most
likely exert immunomodulatory effects and as activators
of host defence pathways, which suggest that probiotics
can influence incidence and severity of disease at sites
distal to the gut (Mortaz et  al. 2013). Though the exact
mechanisms by which probiotics exert their effects are
not completely understood, the immune response to pro-
biotics is thought to be strain dependent, in which the
differences are proposed to be a result of the vast protein
and carbohydrate/glycan profiles within their cell walls,
varying content of 5′-C-phosphate-G-3′ (CpG) of their
deoxyribonucleic acid (DNA), as well as the metabolites
and other molecules that they excrete. Therefore, the pro-
biotic effects are not universal to all bacterial species
(Mortaz et  al. 2013; Stavropoulou and Bezirtzoglou 2020).
One of the greatest effects of probiotics is their ability to
modulate both innate and adaptive immune system
through the crosstalk between bacterial, epithelial, and
immune cells (Figure 2). Typically, probiotics can act as
the ligands for receptors of the innate immune system,
such as Toll-like receptors (TLR), that are expressed on
the intestinal epithelial cells and mucosal immune cells
for the modulation of multiple crucial signaling pathways,
including mitogen-activated protein kinases (MAPK),
nuclear factor kappa B (NF-κB), phosphoinositide-3-kinase
(PI3K), as well as peroxisome proliferator activated recep-
tor gamma (PPAR-γ) pathways, to induce the production
of various cytokines and chemokines (Chan et  al. 2021b;
Y. Liu, Tran, and Rhoads 2018; Maldonado Galdeano et  al.
2019; Chan et  al. 2021c). The interaction of probiotics
with the intestinal epithelial cells also helps in the pro-
duction of macrophage chemoattractant protein 1 (MCP-1),
which propagate signals to other immune cells to activate
the mucosal immune system. Furthermore, probiotics can
be taken up by immune cells such as dendritic cells,
thereby facilitating the maturation of dendritic cells and
stimulation of regulatory T cells (Treg) that are crucial
in establishing immune homeostasis and maintaining gut
immune tolerance. Ultimately, tolerogenic T cells responses
can be generated against food antigens and the commensal
microbiota which avoid undesirable hypersensitivity and
inflammation (Y. Liu, Tran, and Rhoads 2018; Maldonado
Galdeano et  al. 2019).
In terms of inflammatory respiratory diseases, there have
been increasing evidence that orally administered probiotics
can regulate immune responses of the respiratory system.
For instance, in COPD, it has been established that the
extent of inflammation in the airways is strongly correlated
with the severity of disease in patients. Therefore, any pro-
biotic strain that can exert or promote an anti-inflammatory
effect can potentially be utilized as nutraceuticals in the
management of COPD (Mortaz et  al. 2013). A study by
Carvalho et  al. has investigated the effect of probiotic
Lactobacillus rhamnosus on a cigarette smoke-induced
COPD mice model. It was reported that oral feeding of the
probiotic strain suppressed inflammatory cells infiltration
in the lung and attenuated lung tissue remodeling, including
excess collagen deposition, alveolar enlargement, and mucus
hypersecretion. The researchers reported that Lactobacillus
rhamnosus reduced the expression of TLR2, TLR4, and
TLR9, which are the key players in the initial immune
response in COPD, as well as pro-inflammatory transcrip-
tion factors, such as signal transducer and activator of
10 Y. CHAN ET AL.

Figure 2. A general overview of probiotic-mediated immunomodulatory pathways. Dendritic cells can endocytose bacterial products either by extending into
the enteric lumen through the epithelial tight junctions, bacterial transit through M cells, or by pinocytosis of probiotic bacteria by intestinal epithelial cells.
Probiotics bacteria can also influence their interaction with immune cells through membrane receptors, particularly TLRs, that are expressed on dendritic cells
and intestinal epithelial cells. Innate immunity by natural killer cells can be stimulated by IL-12 produced by the macrophages, whereas mast cells can be
induced by IgE which is produced via B cells that is activated by dendritic cells and macrophages. The intracellular signaling pathways of immune cells can
also be altered by probiotics, which eventually modulates the expression of transcription factors including NF-κB, MAPK and STATs, thereby influencing the
production of various cytokines. On the other hand, adaptive immune responses can be triggered by dendritic cells, macrophages, and intestinal epithelial
cells which process and present probiotics that skew T cells toward the regulatory T cells (Treg) subpopulation, which suppresses the responses of effector
T-helper (Th)-1, Th2, and Th17 cells (Dargahi et  al. 2019; Cristofori et  al. 2021; Harzallah and Belhadj 2013).

transcription (STAT)-3 and NF-κB, to the levels comparable
to those of the controls. In parallel to that, there was a
remarkable increase in the levels of proteins that facilitate
an anti-inflammatory milieu in the lungs when compared
with the controls, namely IL-10, TGF-β, and suppressor of
cytokine signaling 3 (SOCS3), thereby mitigating cytokine
storm linked to the pathogenesis of COPD. Tissue inhibitor
of matrix metalloproteinase (TIMP) 1/2 were also upregu-
lated by Lactobacillus rhamnosus, leading to lowered metal-
loproteases and reduced remodeling in the lung tissues. In
short, these findings suggest that probiotics can restore the
equilibrium between pro- and anti-inflammatory cytokines
and chemokines, thus, daily supplementation with probiotics
may offer a protective effect on the lung milieu whilst
attenuating inflammation and exacerbation of immune
response associated with COPD (Carvalho et  al. 2020). In
another similar study by Mortaz et  al., the anti-inflammatory
effects of Lactobacillus rhamnosus and Bifidobacterium breve
probiotic strains on a human macrophage cell line exposed
to cigarette smoke as a model of COPD were studied. It
was demonstrated that both the probiotic strains were effi-
ciently phagocytosed by human macrophages, and they
remarkably inhibited the expressions of IL-10, IL-6, IL-1β,
IL-23, TNF-α, CXCL-8, and high mobility group box protein
1 (HMGB1), which would normally be induced by exposure
to cigarette smoke. Notably, a remarkable inhibition of
NF-κB activity was reported, which positively correlated
with the suppressed release of pro-inflammatory mediators
(Mortaz et  al. 2015). Hence, these findings indicate that
probiotics may be a useful nutraceutical to promote lung
protective effects in inflammatory respiratory diseases such
as COPD.
Apart from that, the anti-allergic effects of probiotics
have also been documented in multiple studies. Over the
past decades, a reduced exposure to microbes early in life
has been proposed as one of the major mechanisms leading
to a greater risk for allergic diseases, which is commonly
referred to as the “hygiene hypothesis” by Strachan in 1989

(Toh et  al. 2012). As such, the rationale for probiotic inter-
vention is to provide a safe, sufficient, and timely microbial
contact to avoid dysbiosis in the gut microbiota and to
prevent immune responsiveness, which ultimately decreases
the risk of developing immunoinflammatory diseases.
Namely, a balanced gut microbiota can also avoid the retar-
dation of gut barrier function maturation and perturbation
upon extrinsic and intrinsic triggers (Toh et  al. 2012;
Isolauri, Rautava, and Salminen 2012). Furthermore, probi-
otics are useful in modulating allergic diseases as they can
regulate Th1/Th2 balance, whilst stimulating the levels of
mucosal IgA as well as B and T cells of the immune system.
As asthma is an allergic disease, such anti-allergy properties
of probiotics can potentially be extrapolated to their appli-
cation in the management of asthma (Mortaz et  al. 2013;
Toh et  al. 2012; Lopez-Santamarina et  al. 2021). One study
by Wang et  al. has investigated the effects of probiotics
application in treating allergic asthma in a mice model. The
study reported that oral administration of Bifidobacterium
infantis alleviated infiltration of inflammatory cells and air-
way hyperreactivity, as well as the numbers of inflammatory
cells in the bronchoalveolar lavage fluid (BALF) of the
ovalbumin-induced mice model. Namely, a decrease in IgE
upon probiotics treatment was observed. As IgE typically
mediates mast cell activation and the subsequent aggregation
of eosinophils and Th2 lymphocytes, downregulation of IgE
can alleviate contraction of airway smooth muscle and type
I allergic reactions in asthma. Besides, Bifidobacterium infan-
tis remarkably suppressed the protein expression of mucin
5AC (MUC5AC) in the airway epithelium, thereby attenu-
ating mucus hypersecretion and airway obstruction. The
expressions of IL-4, IL-5, and IL-13, which are the primary
contributors to asthma initiation produced by Th2 cells,
were also found to be downregulated, whereas the expres-
sions of IL-2 and IFN-γ, which are the key cytokines pro-
duced by Th1 cells, were upregulated. These findings
suggested that Bifidobacterium infantis can regulate the bal-
ance of Th1/Th2 immune responses to exert therapeutic
effects on allergic asthma (W. Wang et  al. 2020). The ben-
eficial effects of probiotics in treating asthma were also
demonstrated in a non-randomized clinical study by Moura
et  al. which evaluated the application of probiotics as a
supplementary therapy in the management of childhood and
adolescent asthma. All thirty patients from six to seventeen
years old were given beclomethasone, a corticosteroid, while
fourteen patients also received an additional probiotic con-
taining Lactobacillus reuteri. After 60 days, all patients were
assessed with an Asthma Control Test (ACT) which evalu-
ated the frequency of shortness of breath and general asth-
matic symptoms, effect of asthma on daily functioning, use
of rescue medications, as well as an overall self-assessment
of asthma control over the past four weeks, in which higher
ACT scores signify better asthma control. It was found that
patients who received Lactobacillus reuteri supplement had
increased ACT scores and decreased asthmatic symptoms,
particularly the occurrence of wheezing. An increase in the
peak expiratory flow was also observed in patients who
received probiotics. In short, this study supported the
hypothesis that supplementary probiotics facilitate the
Critical Reviews in Food Science and Nutrition 11
improvement of clinical condition of patients suffering from
asthma (Moura et  al. 2019).
On the other hand, prebiotics are metabolic substrates
that are referred to as “food supplements that are
non-digestible by humans but can exert advantageous health
effects on the host by inducing the growth and/or the activ-
ity of one or a limited number of microorganisms in the
gastrointestinal tract”. In order to classify a compound as a
prebiotic, several criteria must be met, namely, (i) it must
possess resistance toward the acidic pH conditions of the
stomach, not susceptible to hydrolysis by mammalian
enzymes, as well as not absorbed in the gastrointestinal
tract; (ii) able to be fermented by the gut microbiota; and
lastly, (iii) able to selectively stimulate the growth and/or
the activity of gastrointestinal bacteria to improve health of
the host (Davani-Davari et  al. 2019). Prebiotics are often
used as substrates for probiotics, with fructo-oligosaccharides,
galacto-oligosaccharides, and trans-galacto-oligosaccharides
being the most used prebiotics at present. Other examples
of prebiotics are resistant starch, as well as soluble and
insoluble fibers. Prebiotics can also be naturally obtained
from various fruits, vegetables, and edible plants, such as
tomatoes, bananas, berries, garlic, asparagus, onions, oats,
and wheat (Markowiak and Śliżewska 2017; Davani-Davari
et  al. 2019). Generally, fermentation of prebiotics by the gut
microbiota yields short-chain fatty acids, which include lactic
acid, propionic acid, and butyric acid, where these products
can exert multiple effects on the body. For instance, propi-
onate regulates dendritic cells in the bone marrows as well
as Th2 cells in the airways and macrophages. Peptidoglycan
is another product of prebiotics fermentation which facili-
tates in the stimulation of innate immune responses against
pathogenic microorganisms (Y. Liu, Tran, and Rhoads 2018;
Davani-Davari et  al. 2019). The term “synbiotics” is used
when mixtures of probiotics and prebiotics are used to syn-
ergistically impact the gut microbiota, where the prebiotic
compound(s) selectively favour(s) the probiotic organism(s).
The rationale of the development and application of synbi-
otics is based on findings that prebiotics improve the sur-
vival of probiotics during their passage through the
gastrointestinal system (Y. Liu, Tran, and Rhoads 2018;
Davani-Davari et  al. 2019; Pandey, Naik, and Vakil 2015).
To sum up, due to the immunomodulatory properties of
probiotics, prebiotics, and synbiotics, they may be beneficial
agents to treat, manage, and prevent inflammatory respira-
tory diseases (Table 2). Nevertheless, the understanding of
the exact mechanism underling the beneficial effects of pro-
biotics, prebiotics, and synbiotics remains superficial, and
the outcome of various research regarding their roles in the
management of inflammatory respiratory diseases varies
considerably (Gulati et  al. 2016; Pandey, Naik, and Vakil
2015). Hence, further studies are warranted to clearly elu-
cidate the mechanisms involved in the gut-lung axis cross-
talk between the gastrointestinal and respiratory systems.
Vitamins
Diets high in fruits and vegetables have historically held a
place in most dietary guidelines due to their abundance of

Table 2. Summary of key findings from several studies that presented the beneficial effects of probiotics, prebiotics, and synbiotics in the management of inflammatory respiratory diseases. This list is non-exhaustive
Probiotic / Prebiotic / Synbiotic
Bifidobacterium breve and
Lactobacillus rhamnosus
Bifidobacterium breve, 90%
short-chain
galacto-oligosaccharides, and
10% long-chain
fructo-oligosaccharides
Bifidobacterium infantis
Inulin, or inulin with Lactobacillus
acidophilus, Lactobacillus
rhamnosus, and Bifidobacterium
animalis
Lactobacillus paracasei
Lactobacillus reuteri
Lactobacillus rhamnosus
Lactobacillus rhamnosus and
Bifidobacterium breve
Lactobacillus rhamnosus and/or
turmeric powder
12
Disease Study model Findings Reference
COPD C57BL/6 mice • In BALF, both probiotic strains reduced the levels of pro-inflammatory cytokines such as TNF-α, IL-1β, and (Fialho et  al. 2019)
IL-6, whereas the level of the anti-inflammatory cytokine IL-10 was increased.
• Downregulated the transcriptional expressions of MMP-9 and MMP-12, TLR2, TLR4, and TLR9, STAT3, as well
as NF-κB in the lungs.
• Ameliorated airway remodeling in terms of inflammatory infiltrate, alveolar enlargement, collagen
Y. CHAN ET AL.
deposition, and elastic fibers.
Asthma Randomized clinical • Significantly increased peak expiratory flow volume. (van de Pol et  al.
study • Remarkably inhibited the increase in serum IL-5 upon challenge by allergens. 2011)
• Reduced the production of Th2 cytokines such as IL-4, IL-5, and IL-13 by peripheral blood mononuclear
cells.
• However, no significant effect on bronchial inflammation.
Asthma BALB/c mice • Alleviated inflammatory cells infiltration in BALF and airway hyperreactivity. (W. Wang et  al.
• Downregulated IgE and alleviated contraction of airway smooth muscle and type I allergic reactions. 2020)
• Remarkably suppressed the protein expression of MUC5AC in the airway epithelium, which attenuated
mucus hypersecretion and airway obstruction.
• Downregulated the expressions of IL-4, IL-5, and IL-13 that are produced by Th2 cells.
• Upregulated the expressions of IL-2 and IFN-γ that are produced by Th1 cells.
• Restored homeostasis between Th1/Th2 immune responses.
Asthma Randomized clinical • Soluble fiber prebiotic led to significant improvement in asthma control and airway inflammation. (McLoughlin et  al.
study • Prebiotic produced changes in forced expiratory volume that was positively correlated with change in total 2019)
fecal propionate, butyrate, and short-chain fatty acids.
• Prebiotic significantly decreased sputum eosinophils.
• However, no significant difference in clinical outcomes were observed between prebiotics and synbiotics.
Asthma BALB/c mice • Ameliorated airway hyperresponsiveness and prevented excess infiltration of eosinophils and neutrophils in (X. Wang et  al.
BALF. 2017)
• Decreased serum total IgE and ovalbumin-specific IgG1.
• Remarkably decreased Th2-related cytokines such as IL-4, IL-5, and IL-13, but increased Th1-related IFN-γ in
BALF.
• Reduced the level of IL-17A while TGF-β was increased.
• Exerted anti-allergic properties via restoration of Th1/Th2 homeostasis.
Asthma Non-randomized • Improved asthma control with reduced asthmatic symptoms, particularly the occurrence of wheezing. (Moura et  al. 2019)
clinical study • Increased peak expiratory flow volume.
• Improved the overall clinical condition of asthmatic patients.
COPD C57BL/6 mice • Suppressed inflammatory cells lung infiltration. (Carvalho et  al.
• Attenuated lung tissue remodeling, collagen deposition, alveolar enlargement, and mucus hypersecretion. 2020)
• Downregulated the expressions of TLR2, TLR4, and TLR9, as well as pro-inflammatory transcription factors
such as STAT3 and NF-κB.
• Upregulated IL-10, TGF-β, and SOCS3, and mitigated cytokine storm in the lungs.
• Upregulated TIMP1/2 which lowered metalloproteases and reduced remodeling in the lung tissues.
COPD Human • Both the probiotic strains were efficiently phagocytosed by human macrophages. (Mortaz et  al. 2015)
macrophage cell • Remarkably inhibited the expressions of IL-10, IL-6, IL-1β, IL-23, TNF-α, CXCL-8, and HMGB1.
line THP-1 • Suppressed TLR4- and TLR9-induced expression of CXCL-8.
• Inhibited the release of pro-inflammatory mediators by downregulation of NF-κB signaling.
Asthma BALB/c mice • Significantly suppressed the development of airway hyperresponsiveness. (Ghiamati Yazdi
• Downregulated eosinophilia, IL-5, IL-13, and CCL17. et  al. 2020)
• Reduced the levels of CD4+ Th2 cells and CD4+ Th17 populations in the splenocytes.
• Synbiotic formulation produced higher elevation of CD25 + Foxp3 + Treg as compared to the probiotic or
prebiotic alone.
• Suppressed allergic responses with reduced number of inflammatory cells in BALF.

vitamins. Throughout these years, multivitamin supplements
have been used by most people over the world for the
treatment and/or prevention of chronic diseases. Despite
the unclear effectiveness of multivitamins, the prevalence
for the use of multivitamin supplements is rapidly rising,
in which it was reported that one third of adults and half
of the population aging more than 55 years consume at
least one multivitamin supplement per day (Slavin and
Lloyd 2012; Hamishehkar et  al. 2016). Among the vitamins,
vitamins C and E are antioxidants that exert their protective
action via their free radical scavenging mechanisms. Free
radicals can result in the development of multiple human
diseases, including inflammatory respiratory diseases where
oxidative imbalance in the lungs have been associated with
increased disease severity, reduced lung function, as well
as epigenetic changes that can induce resistance toward
corticosteroids (Victoni et  al. 2021).
Vitamin C, or ascorbic acid, is a water-soluble vitamin
commonly found in raw leafy vegetables, tomatoes, berries,
broccoli, melons, and citrus fruits (Chambial et  al. 2013).
Although most plant and animal species possess the ability
to synthesize vitamin C from galactose and glucose via the
uronic acid pathway, humans lack the ability to do so due
to a defect in L-gulono-1,4-lactone oxidase, which is an
enzyme essential for the biosynthesis of vitamin C. Therefore,
humans must depend on dietary intake to prevent its defi-
ciency, as it is an essential nutrient required for the regu-
lation of multiple physiological processes and have been
proposed to exert a beneficial and/or therapeutic role in
immune responses and other disorders, including common
cold, cardiovascular diseases, diabetes, atherosclerosis, stroke,
and cancer (Chambial et al. 2013; Farbstein, Kozak-Blickstein,
and Levy 2010). The health-promoting effects of vitamin C
is attributed to its unique structure that consists of two
adjacent hydroxyl groups and a carbonyl group, thereby
deeming it an excellent electron donor for participating as
a co-factor in various enzymatic reactions, such as hydrox-
ylases involved in the synthesis of collagen, whilst acting as
a plasma localized antioxidant (Farbstein, Kozak-Blickstein,
and Levy 2010; Traber and Stevens 2011). In terms of
inflammatory respiratory diseases, supplementation or treat-
ment with vitamin C have been demonstrated to produce
symptom-relieving effects and improve lung functions. One
study by Koike et  al. evaluated the effects of vitamin C
treatment on cigarette smoke-induced pulmonary emphy-
sema in senescence marker protein-30 knockout mice, which
lack the ability to synthesize vitamin C. As the emphysema
closely resembled the physiological properties of human
COPD, the findings from this study can be a valuable exper-
imental model in COPD research. It was found that oxida-
tive stress and apoptosis of alveolar septal cells were subsided
upon vitamin C treatment, which then restored the concen-
tration of VEGF in the BALF and in the lungs, indicating
that vitamin C revitalized the lung structure maintenance
program. Besides, the synthesis of collagen I and IV was
promoted, supporting the hypothesis that vitamin C facili-
tates rapid alveolar repair mechanisms as collagen I is nec-
essary for the maintenance of lung structure whereas
Critical Reviews in Food Science and Nutrition 13
collagen IV is required for angiogenesis. In short, these
findings suggest that vitamin C prevents emphysema and
restores emphysematous lungs, which therefore may offer a
novel therapeutic strategy in treating COPD (Koike et  al.
2014). The advantages of vitamin C were also evaluated by
da Silva et  al. on a mice model of paraquat-induced pul-
monary fibrosis. It was observed that vitamin C treatment
increased the levels of superoxide dismutase and catalase,
which reduced total ROS in the lungs and improved the
antioxidant defence mechanisms that ultimately suppressed
fibroproliferation and the expression of pro-fibrotic factors.
Lowered levels of TGF-β and IL-17 were also reported,
indicating that vitamin C ameliorated the pro-inflammatory
effects displayed by IL-17, and diminished excessive pro-
duction of collagen as TGF-β is a pro-fibrotic cytokine that
mediates the production of collagen and its subsequent
deposition within the inflamed lung tissues. Moreover, vita-
min C halted the recruitment of leucocytes and reduced the
influx of pro-inflammatory cytokines, thereby resulting in
reduced number of apoptotic cells in the lungs as well as
abrogation of lung fibrosis development and progression.
Collectively, these results hypothesize that vitamin C may
be able to treat IPF or other forms of ILD linked to oxi-
dative stress (da Silva et  al. 2018).
Vitamin E represents a group of eight hydrophobic mol-
ecules consisting of four tocopherols and four tocotrienols,
all of which possess antioxidant properties. They are com-
monly found in green vegetables and various vegetable oils,
nuts, grains, as well as eggs and milk (Farbstein,
Kozak-Blickstein, and Levy 2010). α-tocopherol is the most
abundant form of vitamin E in humans, and it is a potent
peroxyl radical scavenger that halts the propagation of free
radicals within membranes and plasma lipoproteins. When
peroxyl radicals are generated, the hydroxyl group of
α-tocopherol reacts with them to produce the corresponding
lipid hydroperoxide and tocopheryl radical, which then
reacts with other hydrogen donors such as vitamin C to
oxidize the latter, thereby returning vitamin E to its native
unoxidized state (Traber and Stevens 2011; Rizvi et  al. 2014).
Vitamin E is also involved in the regulation of inflammatory
processes, namely, by suppressing the production of
pro-inflammatory cytokines such as IL-1β and TNF-α, as
well as by downregulating the expressions of other inflam-
matory mediators such as inducible nitric oxide synthase
(iNOS), NF-κB, and prostaglandin E2 (PGE2) (Gulati et  al.
2016; Farbstein, Kozak-Blickstein, and Levy 2010). Therefore,
as oxidative stress and inflammation have been linked to
the pathogenesis of various inflammatory respiratory dis-
eases, vitamin E may help treat, prevent, or delay the devel-
opment of progression of these chronic diseases. A work
by Quoc et  al. had studied the effects of vitamin E admin-
istration in an ovalbumin-induced mouse model of asthma.
The researchers reported that vitamin E downregulated the
NF-κB signaling pathway and the expression of eosinophil
peroxidase, thereby suppressing the production of ROS and
activation of eosinophils. Vitamin E administration also
restored homeostasis of the nuclear factor-erythroid factor
2-related factor 2 (Nrf2), heme oxygenase 1 (HO1) and
14 Y. CHAN ET AL.
Kelch-like ECH-associated protein 1 (Keap1) pathway
(Nrf2-HO1-Keap1), whereby vitamin E decreased the levels
of Keap1 to induce the release of active Nrf2 that was earlier
attenuated in alveolar macrophages by free radicals during
the late phase of IgE-mediated inflammation. As a result,
vitamin E treatment led to the suppression of ROS levels
in the lung tissues and ultimately, the attenuation of airway
hyperresponsiveness and airway inflammation in asthma.
Such effects were more pronounced in the older asthmatic
mice as compared to the younger mice, indicating that vita-
min E may possess antioxidant and anti-inflammatory poten-
tial via the regulation of Nrf2 and NF-κB transcriptional
activities, especially in elderly asthma (Quoc et  al. 2021).
The effects of γ-tocopherol, a specific isoform of vitamin
E, were also explored in a work by Wu et  al. on an
ovalbumin-induced mouse asthmatic model. A decrease in
eotaxin, which is a factor that regulates eosinophil func-
tioning and its trafficking into the airways, was observed
in both blood serum and BALF, where such effects were
comparable to those of dexamethasone. Besides, γ-tocopherol
attenuated the increase in the levels of the pleiotropic cyto-
kine IL-4, along with significant inhibition on the exudation
of inflammatory cells and goblet cells hyperplasia. These
indicated that γ-tocopherol could restore the unbalanced
condition of the immune response and help in the preven-
tion and/or treatment of asthma (Y.-M. Wu et  al. 2016).
Tocotrienols isoform of vitamin E have also been shown to
elicit anti-inflammatory and antioxidative actions for the
management of inflammatory respiratory diseases. For
instance, a study by Peh et  al. has demonstrated remarkable
amelioration of oxidative damage and airway inflammation
in a house dust mite-induced asthmatic mice model treated
with γ-tocotrienol. In the study, γ-tocotrienol had decreased
free radical levels and markers of oxidative damage in BALF
whilst inhibiting gene expressions of iNOS and NADPH
oxidase, which were transcriptionally regulated by the NF-κB
pathway. Such inhibition on NF-κB by γ-tocotrienol further
suppressed pro-inflammatory genes encoding for IL-17,
MUC5AC, TNF-α, and E-selectin. Apart from being a free
radical scavenger, γ-tocotrienol also upregulated Nrf2 in
lung tissues, leading to decreased airway hyperresponsive-
ness, eosinophil infiltration, as well as mucus hypersecretion
with effects comparable to those of prednisolone. Notably,
there was a profound protection against elevation in serum
IgE, neutrophil lung infiltration, and oxidative stress as com-
pared to prednisolone, suggesting that γ-tocotrienol can
prevent airway damage and neutrophil-induced chronic per-
sistent asthma (Peh et  al. 2015).
Vitamin D is another example of lipophilic nutrient,
which is traditionally known for its role as the modulator
of calcium and phosphate absorption, as well as bone health.
Two forms of vitamin D are present, namely, vitamin D2
or ergocalciferol, and vitamin D3 or cholecalciferol. Both
forms of vitamin D occur in limited amounts in diet, with
vitamin D3 that can be produced via sunlight exposure
being the most abundant in humans (Goldsmith 2015). In
the recent years, the scientific community has come to
appreciate the role of vitamin D in the modulation of
immune responses, in which the vitamin D receptor has
been identified in all primary T cell lineages, as well as
macrophages and monocytes. Besides, vitamin D has also
been shown to inhibit the maturation of dendritic cells,
stimulatory function of T cells, as well as the differentiation
and proliferation of B cells (Goldsmith 2015; Sassi, Tamone,
and D’Amelio 2018). Research over the years has identified
that vitamin D deficiency (VDD) is associated with various
pathogenic mechanisms in COPD, as it has been shown
that the prevalence of VDD is greater in COPD patients
and increases with the severity of the disease (Janssens et  al.
2011). For instance, a double-blind, randomized controlled
trial by Foumani et  al. found that supplementation of vita-
min D3 in daily diet can increase the quality of life of
COPD patients, as pulmonary functions began to recover
without any worsening of exacerbations after six months
upon initiation of supplement intervention (Foumani et  al.
2019). Likewise, Heulens et  al. demonstrated that VDD
aggravated the development of COPD characteristic features
in a mice model of cigarette smoke-induced COPD. It is
worth noting that vitamin D decreased the expression of
pro-inflammatory cytokines in BALF and lung tissue, includ-
ing MCP-1, IL-12, and TNF-α in macrophages, neutrophils,
and airway epithelial cells via modulation of the NF-κB and
p38 MAPK signaling pathways. Early signs of emphysema
were only reported in VDD mice, along with upregulated
levels of MMP-12 in the lungs. Neutrophilic infiltration in
the airways and lung parenchyma was also more pronounced
in VDD mice, which was suppressed upon supplementation
with vitamin D (Heulens et  al. 2015).
To sum up, vitamins are nutraceuticals that may exert
protective effects on the respiratory system for the treatment
of various inflammatory respiratory diseases (Table 3).
Nevertheless, there is no clear evidence regarding their exact
health benefits as the results from various studies are still
inconsistent (Janssens et  al. 2011; Tsiligianni and van der
Molen 2010). Hence, further studies must be performed to
explore the detailed effectiveness of vitamin supplements on
health outcomes and patients’ quality of life.
Polyunsaturated fatty acids
Polyunsaturated fatty acids (PUFA) are essential fatty acids
that possess beneficial roles to human health. They are the
foundational building materials for the synthesis of specific
biologically active substances, as well as for the structural
components of various cells, tissues, and organs. Like vita-
mins, PUFAs cannot be synthesized by the body, and they
need to be obtained through dietar y means
(Sokoła-Wysoczańska et  al. 2018). The structure of each
PUFA is characterized by an acyl chain with the presence
of one methyl end and one acid end. As such, PUFAs can
be further classified depending on the location of the first
double bond from the methyl end of the chain, in which
the difference between them is referred to as the number
of omega (Figure 3). The two main compound groups of
PUFAs are the omega-3 fatty acids, where the first double
bond is found at the third carbon from the methyl end of
the chain, and omega-6 fatty acids, where the first double
Table 3. Summary of key findings from several studies that presented the beneficial effects of different vitamins in the management of inflammatory respiratory diseases
Vitamin / Compound Disease Study model Findings Reference
Vitamin C Asthma BALB/c mice • Significantly decreased the levels of neutrophils, IL-4, TNF-α, and IFN-γ in the BALF. (Swierczynska-Machura et  al.
• Decreased the level of thiobarbituric acid reactive substance in the serum of vitamin 2015)
supplemented mice.
• Lowered the total number of cells in the BALF.
• Reduced inflammation and oxidative stress in the lungs.
Vitamin C COPD Senescence marker • Subsided oxidative stress and apoptosis of alveolar septal cells, which restored the (Koike et  al. 2014)
protein-30 knockout mice concentration of VEGF in the BALF and in the lungs.
• Promoted the synthesis of collagen I and IV which facilitated rapid alveolar repair
mechanisms.
• Prevented emphysema and restored emphysematous lungs.
Vitamin C Pulmonary fibrosis C57BL/6 mice • Increased the levels of superoxide dismutase and catalase, which reduced total ROS in the (da Silva et  al. 2018)
lungs and improved antioxidant defence mechanisms.
• Suppressed fibroproliferation and the expression of pro-fibrotic factors.
• Ameliorated the pro-inflammatory effects of IL-17 and diminished excessive production of
collagen by TGF-β.
• Halted the recruitment of leucocytes and reduced the influx of pro-inflammatory cytokines.
• Reduced the number of apoptotic cells in the lungs and abrogated lung fibrosis
development and progression.
Vitamin D Asthma Case-control study • Severe asthmatic patients with vitamin D deficiency had lower forced expiratory volume in (Lan et  al. 2014)
one second as compared to patients with vitamin D sufficiency.
• Vitamin D deficiency exaggerated ROS release and DNA damage and increased the levels
of TNF-α and NF-κB, which were inhibited by supplemental vitamin D3.
• Vitamin D deficiency aggravated oxidative stress and reduced nuclear translocation of
glucocorticoid receptors in airway epithelial cells, which led to corticosteroid resistance.
Vitamin D COPD C57BL/6J mice • Decreased the expression of pro-inflammatory cytokines in BALF and lung tissue, including (Heulens et  al. 2015)
MCP-1, IL-12, and TNF-α in macrophages, neutrophils, and airway epithelial cells.
• Inhibited the pro-inflammatory NF-κB and p38 MAPK p39 signaling pathways.
• Early signs of emphysema were only reported in VDD mice, along with upregulated levels
of MMP-12 in the lungs.
• Suppressed neutrophilic infiltration in the airways and lung parenchyma and aggravated
the development of COPD characteristic features.
Vitamin D Pulmonary fibrosis C57BL/6J mice • Chronic vitamin D deficiency impaired lung development, destructed lung structures, and (Y. Shi et  al. 2017)
induced ECM deposition.
• Increased component of the renin-angiotensin system that worsened with prolonged
vitamin D deficiency.
• Deficiency of vitamin D activated TGF-β1 that preserved ECM and induced fibroblast
proliferation, which led to thickened alveolar walls.
• Vitamin D deficiency stimulated the expression of pro-fibrotic factors to activate the
fibrotic cascade.
Vitamin D3 COPD Randomized clinical study • Recovered pulmonary functions without any worsening of exacerbations after six months (Foumani et  al. 2019)
upon initiation of supplement intervention.
• Improved the quality of life of COPD patients.
Vitamin E Asthma BALB/c mice • Downregulated NF-κB and the expression of eosinophil peroxidase, which suppressed the (Quoc et  al. 2021)
production of ROS and activation of eosinophils.
• Restored homeostasis of the Nrf2-HO1-Keap1 signaling pathway.
• Decreased the levels of Keap1 to induce the release of active Nrf2, which led to the
suppression of ROS levels in the lung tissues.
• Attenuated airway hyperresponsiveness and airway inflammation, with more pronounced
effects in the older asthmatic mice as compared to the younger mice.
(Continued)
Critical Reviews in Food Science and Nutrition
15
 16
Y. CHAN ET AL.

Table 3. (Continued)
Vitamin / Compound Disease Study model Findings Reference
α-tocopherol Allergic rhinitis BALB/c mice • Significantly reduced the appearance of inflammatory cells in the nasal membranes. (G. Wu et  al. 2020)
• Reduced the level of eosinophils in the nasal mucosa.
• Lowered the levels of total IgE, ovalbumin-specific IgG1, and ovalbumin-specific IgG2.
• Reduced subepithelial distribution of tryptase positive mast cells.
• Suppressed the PI3K-PKB signaling pathway in mast cells.
γ-tocopherol Asthma BALB/C6 mice • Decreased the level of eotaxin in both serum and BALF, and prevented eosinophil (Y.-M. Wu et  al. 2016)
trafficking into the airways, where such effects were comparable to those of
dexamethasone.
• Attenuated the increase in the levels of the pleiotropic cytokine IL-4 and inhibited the
exudation of inflammatory cells and goblet cells hyperplasia.
• Regulation of eotaxin and IL-4 levels prevented airway inflammation with a significant
reduction in eosinophilic granulocyte.
γ-tocotrienol Asthma BALB/c mice • Remarkably ameliorated oxidative damage and airway inflammation. (Peh et  al. 2015)
• Decreased free radical levels and markers of oxidative damage in BALF, and inhibited gene
expressions of iNOS and NADPH oxidase.
• Inhibited NF-κB and suppressed pro-inflammatory genes encoding for IL-17, MUC5AC,
TNF-α, and E-selectin.
• Upregulated Nrf2 in lung tissues and decreased airway hyperresponsiveness, eosinophil
infiltration, as well as mucus hypersecretion with effects comparable to those of
prednisolone.
• Suppressed the elevation in serum IgE, neutrophil lung infiltration, and oxidative stress
with greater effects as compared to prednisolone.
γ-tocotrienol COPD C57BL/6N mice • Decreased collagen deposition and mucus accumulation in the bronchioles. (Meister et  al. 2020)
• Reduced the expression of IL-4, TIM1, and CX3CL1, which alleviated accumulation of
inflammatory cells and emphysema.
• Preserved lung functions after 8 weeks of e-cigarette exposure.
• Decreased the presence of macrophages in BALF.

Figure 3. The structures of polyunsaturated fatty acids. Generally, the name of the polyunsaturated fatty acid is derived from the location of the first double
bond from the methyl (-CH3) of the chain. Therefore, the structure which double bond is present at the site of third carbon from the methyl end of the chain
is known as omega-3 fatty acids (n-3 PUFAs), whereas the structure which double bond is present at the sixth carbon from the methyl end of the chain is
known as omega-6 fatty acids (n-6 PUFAs).
bond is found at the sixth carbon from the methyl end of
the chain (Sokoła-Wysoczańska et  al. 2018; Bentsen 2017).
Prominent representatives of omega-3 fatty acids are
α-linolenic acid (ALA), docosahexaenoic acid (DHA), and
eicosapentaenoic acid (EPA), where ALA acts as the pre-
cursor of the omega-3 family of fatty acids. Therefore, ALA
is the only omega-3 that must be obtained from diet as it
is not synthesized by the body, in which it can be commonly
found in vegetable oils including canola, flaxseed, soybeans,
and hemp oil, nuts, as well as in seeds. Although EPA and
DHA can also be delivered into the body by food from
various marine sources such as salmon, tuna, sardines, and
algae, ALA can be naturally converted into EPA and DHA
in the body, thereby conferring ALA with the ability to
modulate their physiological activity (Sokoła-Wysoczańska
et  al. 2018; Gammone et  al. 2018). On the other hand,
linoleic acid (LA) is the parent compound of omega-6 fatty
acids. As the human body is too unable to produce LA, it
constitutes another essential fatty acid that must be obtained
from diet, apart from omega-3 ALA. Upon ingestion of LA,
it is then converted into arachidonic acid (AA). LA occurs
primarily in vegetable oils of sunflower, soybean, and corn,
as well as nuts. Certain animal origin products are also
regarded as great sources of omega-6 fatty acids, which may
include meat, poultry, and eggs (Sokoła-Wysoczańska et  al.
2018; Patterson et  al. 2012).
Throughout these years, increasing research interest has
been shown regarding the preventative and/or therapeutic
roles of dietary PUFAs on chronic inflammatory diseases,
Critical Reviews in Food Science and Nutrition 17
in which its rising prevalence has been hypothesized to be
due to the disruption in the balance of omega-3 fatty acids
to omega-6 fatty acids ratio (Patterson et  al. 2012). This is
typically associated with the Western dietary pattern which
has seen an increasing trend for the consumption of
omega-6 fatty acids as they are primarily found in vegetable
oils, in contrast to omega-3 fatty acids that are mainly
found in marine oils. As mentioned earlier, LA, which is
the most abundant omega-6 fatty acid in Western diet, will
be converted into AA upon ingestion leading to an increased
bioavailability of AA within the human body. Being the
precursor of inflammatory eicosanoids such as the well
described prostaglandins and leukotrienes, increased levels
of AA can induce their production from inflammatory cells
to exert potent bronchoconstriction and pro-inflammatory
properties, thereby contributing to the pathogenesis of
inflammatory respiratory diseases, such as asthma and
COPD (Adams et  al. 2018; Pizzini et  al. 2018; Duvall and
Levy 2016). In the contrary, an increased intake of dietary
omega-3 fatty acids as seen in the Mediterranean dietary
pattern can alter the omega-3 to omega-6 balance that
results in fewer substrates for the synthesis of AA-derived
eicosanoids. As such, supplementation of omega-3 fatty
acids to the human diet has been associated with reduced
production of omega-6-derived eicosanoid inflammatory
mediators, including PGE2, leukotriene B4, leukotriene E4,
and thromboxane A2 (Patterson et  al. 2012; Adams et  al.
2018; Pizzini et  al. 2018). Besides, omega-3 fatty acids also
act as the precursor of several pro-resolving and
18 Y. CHAN ET AL.
anti-inflammatory eicosanoids. For instance, resolvins,
which are derived from DHA, facilitate the clearance of
allergens and apoptotic cells whilst limiting transmigration
of neutrophils (Pizzini et  al. 2018; Barnig, Frossard, and
Levy 2018). Protectins are another example of pro-resolving
eicosanoids that are responsible in the inhibition of T cell
migration and apoptosis, suppression of the production of
TNF-α and IFN-γ, as well as downregulation of neutrophil
activity and induction of macrophage activation. Besides,
maresins predominantly exert their effects on pulmonary
tissue through the reduction of overall neutrophils within
the lungs as well as the suppression of tissue hypoxia,
edema, and pro-inflammatory cytokines (Pizzini et  al. 2018;
Duvall and Levy 2016). Thus, maintaining a delicate balance
between omega-3 and omega-6 fatty acids through dietary
supplementation to achieve a homeostasis between pro- and
anti-inflammatory molecules could effectively prevent the
exacerbation of inflammation as observed in multiple
inflammatory respiratory diseases.
The beneficial effects of PUFAs in the management of
inflammatory respiratory disease have been reported by
various researchers. In one study, Bargut et  al. evaluated
the influence of fish oil, which is rich in omega-3 fatty
acids, on ovalbumin-induced airway hyperresponsiveness
and lung inflammation in mice. The researchers showed
that treatment with fish oil containing EPA and DHA mod-
ified the cell membrane lipid profile, leading to decreased
production of essential eicosanoid pro-inflammatory medi-
ators such as 2-series prostaglandins and 4-series leukot-
rienes, thus attenuating classic asthmatic features including
eosinophil infiltration, mucus deposition, peribronchiolar
fibrosis, as well as airway hyperresponsiveness. The increase
in inflammatory cytokines production from ovalbumin chal-
lenge was also reversed by fish oil. Besides, fish oil down-
regulated the expression of GATA-binding protein (GATA)-3,
a transcription factor involved in the development and dif-
ferentiation of CD4+ lymphocytes. The phosphorylation of
IκB was also reduced, thereby inhibiting the activation of
the NF-κB signaling cascade and the subsequent production
of inflammatory proteins. At the same time, fish oil upreg-
ulated the activity of PPAR-γ which further suppressed the
nuclear translocation of NF-κB and its pro-inflammatory
properties. Taken together, these findings indicated that the
intake of fish oil attenuated inflammatory response and
prevented systemic sensitization, therefore, it can be con-
sidered as a prophylactic adjuvant in the management and
prevention of asthma (Bargut et al. 2013). Likewise, Nordgren
et  al. have demonstrated that dietary supplementation with
DHA can attenuate airway inflammation resulting from
allergen exposures. It was reported that DHA treatment
dose-dependently suppressed the organic dust-induced
release of IL-6 and IL-8 and downregulated the expression
of bronchial epithelial cell intercellular adhesion molecule
(ICAM)-1 in-vitro. Notably, the inhibition on
pro-inflammatory cytokines and chemokines was not limited
only to bronchial epithelial cells, but such effect was
extended to fibroblasts, mononuclear phagocytes, as well as
the whole lung tissues. In-vivo, mice that was given DHA
supplementation presented significant reduction in airway
infiltration of total inflammatory cells, which correlated with
the suppression of neutrophil chemoattractants CXCL1 and
CXCL2 in the BALF, as well as reduced pro-inflammatory
cytokines TNF-α and IL-6. Collectively, these data suggested
that the application of DHA dietary supplements may exert
therapeutic potential for mitigating airway inflammation in
diseases such as asthma and COPD (Nordgren et  al. 2014).
In another work, Lawrenz et  al. studied the effects of flax-
seed oil that is rich in the omega-3 fatty acid ALA on
protecting against pulmonary fibrosis. The study found that
flaxseed oil was effective in shielding lung tissue from
bleomycin-induced pulmonary toxicity in-vivo, demonstrated
by reduced pulmonary septal thickness, increased lumen
patency, reduced inflammatory cells infiltrate, retarded
edema formation, as well as decreased vasculitis and
peribronchial fibrosis. Such findings can be attributed to
the production of lung eicosanoids by EPA and DHA that
minimized the synthesis of active pro-inflammatory products
through the competitive inhibition of AA transformation to
leukotrienes. In short, dietary flaxseed oil can decrease lung
inflammation and exert protective effects against pulmonary
fibrosis and the deleterious effects of antineoplastic drugs
on the lungs (Lawrenz et  al. 2012).
Other than laboratory studies, studies performed on
humans using PUFA supplementation have also recorded
positive effects in managing inflammatory respiratory dis-
eases. Brigham et  al. in their study attempted to identify
the relationship between dietary intake of omega-3 and
omega-6 fatty acids on disease outcomes in 149 asthmatic
children. In contrast to higher levels of omega-3 fatty acids,
it was reported that higher intake of omega-6 fatty acids
was associated with more severe asthma and lower forced
expiratory volume in one second to forced vital capacity
ratio (FEV1/FVC), signifying reduced lung function.
Namely, a diminished strength of effects by exposure to
indoor particulate matter (PM) was noted at higher levels
of omega-3, whereas amplification of PM effects on asth-
matic symptoms and circulating neutrophil percentage was
observed at higher levels of omega-6. These suggest that
omega-3 and omega-6 intake is closely linked to pediatric
asthma morbidity, in which dysregulation in omega-3 to
omega-6 fatty acids ratio may modify asthmatic response
to PM and other allergens (Brigham et  al. 2019). Similarly,
Stoodley et  al. in their study evaluated the relationship
between omega-3 fatty acids and clinical outcomes of asth-
matic adults. It was examined using the omega-3 index
(O3I), which is the sum of erythrocyte EPA and DHA
expressed as percentage of total erythrocyte membrane fatty
acids, as it has been established as a reliable parameter of
dietary omega-3 fatty acid intake and reflects its status in
the long-term. The researchers demonstrated that adults
with higher O3I was linked to better asthmatic control and
remarkably reduced range of maintenance inhaled cortico-
steroids dosage. In contrast, subjects with uncontrolled
asthma had lower O3I with increased systemic inflamma-
tory markers. Thus, this study reaffirmed the beneficial
roles of omega-3 fatty acids in asthma management, where
the researchers have recommended that an O3I of more
than 8%, or equivalent to the dietary consumption of more

than 800 mg EPA and DHA per day, could be advantageous
for asthmatic patients to reduce their maintenance dosage
(Stoodley et  al. 2020).
In summary, although PUFAs have been recognized for
their ability to improve morbidity and mortality of patients
suffering from a wide range of diseases, an unbalanced
dietary consumption of PUFAs may be detrimental to
human health. Specifically, a decrease in the ratio of omega-3
to omega-6 PUFAs could potentiate inflammatory responses
and predispose an individual to various chronic diseases,
including inflammatory respiratory diseases. Nonetheless,
there is also evidence that a diet high in omega-6 fatty acids
m ay ov e r p ow e r t h e a nt i - i n f l a m m at or y a n d
inflammation-resolving properties of omega-3 fatty acids
(Pizzini et  al. 2018; Innes and Calder 2018). Hence, the
complex interactions between omega-3 and omega-6 fatty
acids, as well as their lipid mediators in terms of inflam-
mation remain unclear. Further studies should be focused
on identifying these interactions, where successful trials may
help in the introduction of effective, standardized supple-
mentation of PUFAs in patients with inflammation respira-
tory diseases.
Trace elements
“Trace elements” is a term used to describe elements that
exist in natural and perturbed environment in minute quan-
tity while an excess bioavailability can produce a toxic effect
on the living microorganism. As there are two faces regard-
ing trace elements, the dietary requirement for an essential
trace element refers to an intake level that fulfills a specified
criterion for its adequacy and minimizes the risk of nutri-
tional deficiency or excess (Bhattacharya, Misra, and Hussain
2016; Mehri 2020). Trace elements are micronutrients that
play a vital role in maintaining the integrity of multiple
metabolic and physiological processes within the human
body. They are specifically involved in both humoral and
cellular immune responses, act as cofactors for essential
enzymes, and as antioxidant molecules. Therefore, instead
of a specific presentation, deficiency of any of these micro-
nutrients can result in a wide range of clinical manifestations
as each trace element is generally associated with the func-
tioning of many enzyme systems (Bhattacharya, Misra, and
Hussain 2016; Cannas et  al. 2020).
Iron is an essential trace element for almost every living
organism due to their role in a wide range of metabolic
processes, including the transport of oxygen and electron,
as well as synthesis of DNA. In the human body, iron pri-
marily exists in the forms of complex that is bound to
protein as heme compounds such as hemoglobin and myo-
globin, heme enzymes, or non-heme compounds such as
ferritin, transferrin, and flavin-iron enzymes (Abbaspour,
Hurrell, and Kelishadi 2014). Despite the abundance of iron
on earth, iron deficiency is predicted to be the most prev-
alent micronutrient deficiency globally, especially in
low-income countries where poor dietary intake and high
incidences of infection chronically limits iron uptake (Beck
et  al. 2014; Prentice et  al. 2017). Several strategies are cur-
rently employed to augment the level of dietary iron in the
Critical Reviews in Food Science and Nutrition 19
human body. Namely, direct iron supplementation, point-of-
use fortification that utilizes micronutrient powder that can
be added to prepared food, and food fortification that adds
micronutrients at the point of manufacture (Prentice et  al.
2017). Alterations in iron levels and dysregulated homeo-
stasis have been implicated in the development of inflam-
matory respiratory diseases. Sato et  al. in a study reported
that iron deficiency augmented pulmonary inflammation
and may accelerate the development of COPD. The research-
ers showed that mice exposed to cigarette smoke in an
iron-deficient condition strongly induced inflammatory
responses, signified by increased macrophages migration
into the alveolar space and production of TNF-α, IL-6, and
MCP-1 by airway epithelial cells, which led to early devel-
opment of pulmonary emphysema and increased physiolog-
ical air trapping within the lungs. These were found to be
attributed to enhanced phosphorylation of Ser536 on p65
which further activated the NF-κB signaling cascade. The
effect of iron deficiency on enhancing inflammatory
responses also correlated to the findings that iron pretreat-
ment diminished the activation of NF-κB, Nrf2, and MAPK
transcription factors. In short, the study suggested that iron
deficiency may be an aggravating factor for lung inflamma-
tion and a risk factor for smoking susceptibility in the onset
and development of COPD (Sato et  al. 2020). Maazi et  al.
also reported that iron supplementation in a mouse model
of ovalbumin-induced allergic asthma led to a remarkable
decline in airway eosinophilia, whereas systemic iron injec-
tions resulted in notable inhibition of allergen-induced air-
way hyperresponsiveness that was attributed to reduced
levels of Th2 cytokines within lung tissue (Maazi et  al.
2011). On the other hand, Ali et  al. reported that excess
iron accumulation played a key role in the pathogenesis of
pulmonary fibrosis and subsequent decline in lung function.
Administration of exogenous iron was found to induce cel-
lular proliferation and pro-inflammatory cytokines, as well
as ECM gene expression in lung fibroblasts. Besides, elevated
iron levels promoted the activity of prolyl hydroxylase, which
is a major enzyme involved in the synthesis of collagen,
thereby increasing ECM deposition and the promotion of
IPF. Notably, treatment with deferoxamine, an iron chelator,
completely suppressed the decline in lung function and
reversed the increase in Tfr1+ macrophages associated with
pulmonary fibrosis. Hence, targeting excess iron accumula-
tion may be an effective strategy for the management of
fibrotic lung diseases, such as IPF (Ali et  al. 2020).
Zinc is another example of a nutritionally essential trace
element, and it is the second most abundant trace element
that is present in the human body after iron. Unlike iron,
there is an absence of specialized zinc storage system in the
human body, therefore, a sufficient daily intake of zinc is
important for the maintenance of its steady state (Gammoh
and Rink 2017). Despite oral zinc supplements being readily
available in the market, not all offer the same bioavailability.
Namely, zinc that is bound to amino acids displayed highest
concentration, followed by chloride, sulfate, and acetate,
while zinc oxide has the lowest absorption. Apart from that,
zinc is also present in a vast range of food groups and
20 Y. CHAN ET AL.
among which, foods with the largest concentration of zinc
include red meat, shellfish, whole grains, fortified cereals,
and legumes. However, the bioavailability of zinc is generally
greater in animal sources as compared to plant sources,
therefore, individuals who are vegetarians, vegans, or abstain
from consuming red meats may have inadequate zinc intake
and present with a higher risk of developing zinc deficiency
(Gammoh and Rink 2017; J. C. King et  al. 2015; Prasad
2014). In terms of inflammatory respiratory diseases, the
hypothesis that zinc deficiency can impact airway inflam-
matory response to allergens has been validated in a study
by Knoell et  al. In the study, it was observed that exposure
to hog confinement facility dust extract (HDE) induced
influx of total inflammatory cells and BALF neutrophils,
increased pro-inflammatory mediators including TNF-α,
IL-6, and CXCL1, and enhanced tissue pathology in-vivo,
which were more pronounced in zinc deficient mice in
contrast to the normal diet group. Besides, the researchers
also reported that zinc deficiency induced the production
of IL-8 and IL-23 in macrophages, which are potent che-
moattractants that enhanced inflammatory response against
HDE exposure. It is worth noting that such increase in
IL-23 production was reversed following zinc supplementa-
tion, thereby affirming the zinc-specific immunomodulatory
effect. There was also a significant increase in NF-κB/p65
activity in zinc deficient macrophages in contrast to zinc
sufficient macrophages, which produced an amplified inflam-
matory response that can lead to more collateral tissue
damage. Collectively, these findings supported that dietary
zinc intake may play an essential role in regulating lung
inflammatory responses to allergens, thus exerting protective
effects against inflammatory respiratory diseases (Knoell
et  al. 2019). Similar findings were also reported in a work
by Boudreault et  al., where dietary zinc deficiency in
mechanically ventilated mice produced greater inflammation
with increased BALF protein and inflammatory cells infil-
tration. Besides, circulating plasma zinc levels were also
found to be reduced in critically ill patients who further
developed ARDS, thereby supporting the role of zinc in
priming the injury response of the lung. In short, these
findings suggest that zinc supplementation may be a strategy
for lung-protective interventions in patients who require
mechanical ventilation, as mounting evidence showed that
increase in intracellular zinc levels can reflect a homeostatic
program that limits stretch-induced injury (Boudreault et  al.
2017). Also, in an asthmatic model of mice, Morgan et  al.
presented that zinc supplementation remarkably decreased
neutrophil infiltration and release of TNF-α into the airways,
which correlated with inhibited NF-κB signaling in the lung.
Airway hyperresponsiveness and serum IgE levels were also
lowered, thereby proving the feasibility of zinc supplemen-
tation in treating asthma (Morgan et  al. 2011).
Selenium is also an essential trace element that is respon-
sible for the proper functioning of all living organisms.
Traditionally, selenium was considered as a toxic element
as the poisoning of this element has resulted in severe
anemia, hair loss, bone stiffness, and blindness. However,
it is important to note that either excess selenium or its
deficiency are both harmful to human health (Kieliszek
2019). Therefore, one should strive to adhere to the rec-
ommended supply dosage of selenium and its upper toler-
able intake limit. The suggested maximum daily intake of
selenium shall not exceed 70 µg per day according to the
WHO, whereas doses higher than 400 to 700 µg per day
may exert toxic effects (Kieliszek 2019; Kieliszek and
Błażejak 2016). The content of selenium in food sources
varies greatly depending on its concentration in the soil of
a given geographical area. Generally, selenium in food prod-
ucts occurs in combination with proteins, therefore, prod-
ucts containing high protein such as fish, meat, offal, and
cereals are usually characterized by a greater content of
selenium. Other plant sources of selenium include mush-
rooms, nuts, onions, and garlic (Kieliszek and Błażejak
2016). Both inorganic and organic forms of selenium are
absorbed by the small intestine and are subsequently dis-
tributed to multiple body tissues to exert their biological
functions. The regulation of selenoprotein synthesis is one
of the primary activities of selenium, where the major role
of selenoproteins such as iodothyronine deiodinase, gluta-
thione peroxidase, and glutathione peroxidase is to act as
potent intracellular antioxidants to prevent oxidative injury.
As such, selenium supplementation has seen its importance
in boosting the body’s antioxidative defence and cellular
homeostasis for remitting various pathological conditions,
including inflammatory respiratory diseases (N. Wang et  al.
2017). In a work, Ghorbel et  al. investigated the ability of
selenium supplementation in alleviating aluminum
chloride-induced oxidative stress in lung tissue in-vivo.
Addition of dietary selenium had reduced the pulmonary
histology changes such as alveolar edema and emphysema,
indicating the protective potential of selenium and its ability
to modulate the proliferation and differentiation, as well
as secretion of prostaglandins and cytokines from macro-
phages and lymphocytes during an inflammatory response.
Besides, selenium also presented free radical scavenging
activity as an inhibition of lipid, hydrogen peroxide, and
protein oxidation levels were observed upon its supplemen-
tation. These data suggested that selenium may be effective
in preventing lung damage by mitigating oxidative damage
via the induction of selenoproteins, which ultimately
improved the redox state and lung histological damage
(Ghorbel et  al. 2017). Similar findings were also noted in
a study by Tabatabaei et  al. It was observed that the enzy-
matic activity of glutathione peroxidase and selenium levels
were significantly suppressed in asthmatic patients. Such a
decrease in enzymatic activity may contribute to the patho-
genesis and severity of asthma, as it has led to elevated
concentrations of protein carbonyls, serum nitrates, lipid
peroxidation products, as well as superoxide in the leuco-
cytes of asthmatic patients. These further resulted in acti-
vation of NF-κB, MAPK, and other pro-inflammatory
transcription factors by ROS and the subsequent induction
of lung inflammation. Thus, dietary micronutrient supple-
mentation with selenium may be beneficial to reduce lung
inflammation and remodeling in asthma via anti-oxidative
stress (Tabatabaei et  al. 2020).

In a nutshell, deficient intake of essential trace elements
can suppress crucial biological functions and any impairment
in the functions of body tissues can be restored and/or
prevented by restoration of that element to the physiological
levels. Hence, dietary supplementation of essential trace
elements at an optimal concentration can be advantageous
in the modulation of inflammatory respiratory diseases and
maintenance of the overall health status of the body.
Medicinal Plants and phytochemicals
Medicinal plants and their derived components have been
the backbone of traditional healing systems since the incep-
tion of human beings. In contrast to traditional application
of plant-based therapies which utilized unmodified whole
plant for preserving the integrity and the original compo-
sition of the source plant, the focus of modern therapeutics
has been placed on the identification of biologically active
compounds from plant extracts and their extraction for
specific therapeutic application (Falzon and Balabanova
2017; Wright 2019). As reported by the WHO,
phyto-therapeutic agents are actively utilized by approxi-
mately 80% of the world population for their primary
health-related needs, whereas there are about 11% of mar-
keted therapeutics that are formulated from natural
plant-based chemical moieties (Chan et  al. 2021e). Over the
years, there have been numerous studies that proved the
efficacies of plant-based chemical moieties in combating
chronic human diseases. In terms of inflammatory respira-
tory diseases, a vast range of herbal and plant products has
attracted considerable attention due to the structural diver-
sity of compounds that are present in these plants, as well
as their great capability in modulating the complex biological
pathways underlying the pathogenesis of these diseases. The
potent pharmacological activities of these plants can be
attributed to the presence of active constituents from various
classes, namely, iridoids, triterpenoids, and flavonoids
(Atanasov et  al. 2015; Nderitu et  al. 2017). Furthermore,
these phytochemicals also exhibited lower systemic toxicities
in contrast to chemically synthesized compounds with a
lower cost of production as they are naturally occurring
and can be easily obtained. As a result, there has been
paradigm shift from the application of chemically synthe-
sized drugs toward the utilization of phytochemicals for the
development of novel therapeutics in the management of
inflammatory respiratory diseases (Atanasov et  al. 2015;
Karunamoorthi et  al. 2012).
As discussed earlier, the imbalance in Th1/Th2 is widely
known to induce the development of allergic asthma.
GATA-3 and T-box protein expressed in T cells (T-bet) are
the transcription factors involved in the regulation of Th1/
Th2 homeostasis, therefore, phytochemicals that can mod-
ulate their expression may be beneficial in treating asthma
(van Rijt, von Richthofen, and van Ree 2016). A study by
Jin et  al. evaluated the effects of Psoraleae fructus, which is
the seeds of Psoralea corylifolia, on Th2 responses in an
ovalbumin-induced rat model of asthma, as well as the
effects of psoralen, a major constituent of Psoraleae fructus,
Critical Reviews in Food Science and Nutrition 21
on Th2 responses in-vitro. It was found that psoralen effec-
tively inhibited the production of Th2 cytokines, including
Il-4, IL-5, and IL-13, with remarkable suppression on
GATA-3 protein expression in-vitro. Oral administration of
Psoraleae fructus at a dose of 10.0 g/kg also remarkably
decreased airway hyperresponsiveness, airway inflammation,
and mucus hypersecretion, and reduced the levels of IL-4
and IL-13 in the BALF of the asthmatic rats. Taken together,
these suggest that Psoraleae fructus can exert therapeutic
effects in asthma by suppressing Th2 response, which may
be attributed to the immunomodulatory properties of pso-
ralen as the critical component of the plant (Jin et  al. 2014).
In another work, Ryu et  al. investigated the therapeutic
value of wogonin, a plant flavone obtained from the root
of Scutellaria baicalensis, in an ovalbumin-induced mouse
model of asthma. Oral administration of wogonin greatly
reduced the activation of STAT6 in the lung, as well as the
expression of eotaxin in the BALF. These correlated to the
findings that wogonin suppressed total IgE and
ovalbumin-specfic IgE, thereby inhibiting allergen-induced
eosinophilic inflammation. In human bronchial epithelial
cells (BEAS-2B), wogonin at concentration of 50 µM also
potently downregulated both IL-4-induced eotaxin-3 mRNA
expression and the level of eotaxin-3 protein in a
dose-dependent manner. These findings implicate the poten-
tial benefits of wogonin in treating asthma via the inhibition
of IL-4/STAT6 signaling pathway, thereby suppressing Th2
cytokine-mediated inflammation (Ryu et  al. 2015). Another
strategy that can be exploited for treating asthma is the
targeting of Tregs and Th17 cells. In asthma, Tregs, driven
by the forkhead box P3 (FOXP3) transcription factor are
responsible for regulating pulmonary immunity homeostasis
by suppressing excessive immune responses that are delete-
rious to the body, whereas RAR-related orphan receptor
gamma T (RORγT) is the transcription factor that regulates
Th17 cells, which are responsible for inducing airway hyper-
responsiveness in response to allergens (Chung 2015;
Ohkura, Kitagawa, and Sakaguchi 2013). Ligustrazine, an
alkaloid isolated from Ligusticum striatum, has been shown
in a mouse model of ovalbumin-induced asthma to regulate
Tregs and Th17 by facilitating the homeostasis between
FOXP3 and RORγT transcription factors. The downregula-
tion in RORγT and induction of FOXP3 subsequently
resulted in the attenuation of airway inflammation and
improvement in airway function, signified by balanced Th1/
Th2 cytokine profiles as well as reduced influx of neutro-
phils and eosinophils in the lung of asthmatic mice (Ji et  al.
2014). Additionally, inhibition of mast cell degranulation
can also prevent the release of mediators that induce migra-
tion of leucocytes to inflammatory sites, thereby suppressing
inflammatory response (Krystel-Whittemore, Dileepan, and
Wood 2015). Apart from that, petatewalide B isolated from
Petasites japonicus has been shown to inhibit antigen-induced
degranulation of β-hexosaminidase in mast cells. This has
contributed to a strong suppression against the accumulation
of lymphocytes, macrophages, and eosinophils in the BALF
of a mouse model of ovalbumin-induced asthma. In short,
such findings have reaffirmed the anti-allergic and
22 Y. CHAN ET AL.
anti-inflammatory potential of petatewalide B for its utili-
zation against inflammatory respiratory diseases (Choi
et  al. 2016).
Certain phytochemicals have also been found to modulate
the pro-inflammatory NF-κB and MAPK signaling pathways
for the treatment of inflammatory respiratory diseases. This
was seen in a study by Chauhan et  al. which documented
the anti-inflammatory and antioxidant properties of cur-
cumin, a bioactive constituent found in Curcuma longa. In
an ovalbumin-induced mice model of chronic asthma, cur-
cumin significantly reduced the level of TNF-α in BALF,
which subsequently inhibited the production of nitric oxide
in the airways and downregulated the levels of IL-4, IL-5,
and IgE, as well as the recruitment of eosinophils. The
generation of ROS in BALF was also attenuated with similar
effects as compared to those of dexamethasone. It was
revealed that the protective effects of curcumin were
attributed to decreased phosphorylation of c-Jun N-terminal
kinase, extracellular signal-regulated kinase (Erk) 1/2, and
p38 which ultimately suppressed the NF-κB/MAPK pathway,
as well as inhibition of COX-2 protein in the lung tissues
that inhibited the production of prostaglandins (P. S.
Chauhan et  al. 2018). Likewise, Lee et  al. reported down-
regulation of NF-κB and MAPK by the root extract of
Pistacia weinmannifolia. Treatment with the plant extract
on ovalbumin-induced mice decreased the levels of Th2
cytokines, including IL-4, IL-5, and IL-13, as well as the
number of eosinophils in the BALF. This eventually led to
the suppression of airway inflammatory cells influx and
mucus hypersecretion, indicating that Pistacia weinmanni-
folia could be an effective adjuvant for the therapeutic of
asthma (Lee et  al. 2019). Moreover, casticin, a compound
isolated from Vitex rotundifolia, also presented inhibitory
activity on NF-κB and MAPK. As such, casticin reduced
the levels of TNF-α, IL-6 and IL-6, and suppressed the
expression of COX-2 and PGE2 production. It also decreased
MUC5AC, downregulated ICAM-1, and inhibited the phos-
phorylation of protein kinase B (Akt) and PI3K, which
provided evidence that casticin possess anti-inflammatory
effects for the treating inflammatory lung diseases (Liou
et  al. 2017). Similarly, oral administration of Eriobotrya
japonica leaves extract (50 mg/kg, 100 mg/kg, 200 mg/kg) in
ovalbumin induced BALB/c mice model of allergic asthma
revealed that the extract showed protection against airway
inflammation as revealed by dose dependent decrease in
inflammatory cell infiltration (from H/E staining of lung
section), inhibition of goblet cell hyperplasia (from PAS
staining of lung section), decrease level of serum IgE
(ELISA) and BALF’s IL-13 and IL-4 (ELISA). Similarly, there
was concentration dependent inhibition of nitric oxide pro-
duction and eosinophil peroxidase in BALF while decrease
protein expression of ERK1/2 MAPK and NFκB nuclear
translocation in TNF-α induced human tracheal smooth
muscle cells and decrease protein expression of iNOS and
COX-2 in lipopolysaccharide (LPS) stimulated mice macro-
phage cell line (Muk Kim, Paudel, and Kim 2020).
Apart from that, the TGF-β1/small mothers against
decapentaplegic (Smad) signaling pathway is responsible for
the induction of platelet-derived growth factor and TGF-β
that are involved in airway remodeling associated with
inflammatory respiratory diseases. Jang et  al. demonstrated
that skullcapflavone II, a flavonoid isolated from Scutellaria
baicalensis, reduced several major asthmatic pathophysio-
logical features such as airway eosinophilia, airway hyper-
responsiveness, Th2 cytokine production, as well as elevated
TGF-β1 levels in the BALF and lungs in a mouse model of
ovalbumin-induced allergic asthma. The administration of
skullcapflavone II also remarkably inhibited subepithelial
deposition of collagen and goblet cell hyperplasia accompa-
nied with upregulated Smad7 expression and downregulated
Smad2/2 expressions. The anti-asthmatic effects of skullcap-
flavone II in alleviating airway inflammation and early-stage
airway remodeling were comparable to those of dexameth-
asone and montelukast, suggesting that this phytochemical
may possess therapeutic benefit for the management of
asthma by regulating the TGF-β1/Smad signaling pathway
(Jang et  al. 2012). Xu et  al. in a study have also demon-
strated that Astragali radix, the dried roots of Astragalus
membranaceus, displayed TGF-β1-suppressing property that
alleviated airway remodeling in a mouse model of
ovalbumin-induced chronic asthma. Besides, treatment with
Astragali radix greatly reduced airway hyperresponsiveness,
eosinophilic airway inflammation, as well as deposition of
collagen in the airways, which were contributed by down-
regulation of IL-13, a Th2 cytokine that mediates the mucus
obstruction phenotype of asthma (Xu et  al. 2013). TGF-β
is also one of the most potent inducers of ECM production
that leads to the deposition of excessive collagen and other
matrix proteins as seen in pulmonary fibrosis. Yao et  al.
have demonstrated that Nervilia fordii extract remarkably
decreased lung index and attenuated bleomycin-induced
pulmonary fibrosis in rats. Lung inflammation and collagen
deposition were alleviated in the lung tissues, which can be
associated with the inhibitory effects of Nervilia fordii on
the migration of LPS- and TGF-β1-induced fibroblasts.
These suggest that the plant extract exerted therapeutic
effects on pulmonary fibrosis via the alleviation of inflam-
mation, oxidative stress, and pro-fibrotic activities through
the TGF-β/Smad signaling cascade, as evidenced by the
downregulation of TGF-β1, Smad3/4, and CTGF (Yao
et  al. 2021).
The modulation of oxidative stress by enhancing the
endogenous levels of antioxidants represents a promising
strategy in treating inflammatory respiratory diseases. As
such, the Nrf2 transcription factor and its associated sig-
naling pathways can be targeted to mitigate inflammation
and yield antioxidant defence due to their roles in regulating
oxidative stress (P. B. Gonçalves and Romeiro 2019). Namely,
the sesquiterpenoid 3S-(+)-9-oxonerolidol (NLD) and the
biphenyl 3,3′,4,4′-tetrahydroxydiphenyl (THD) isolated from
Cinnamomum chartophyllum was found to induce Nrf2 and
its downstream genes, which improved the nuclear translo-
cation and stabilization of Nrf2 in lung epithelial cells. As
a result, treatment with NLD and THD enhanced the levels
of the endogenous antioxidant glutathione and reduced the
levels of ROS, thus, Cinnamomum chartophyllum can prevent

Figure 4. Nutraceuticals inhibits different inflammatory pathways involved in the pathogenesis of various respiratory diseases.
oxidative insults in the lungs and may be beneficial in the
treatment of COPD (M. X. Zhou et  al. 2018). Forsythiaside,
a phytoconstituent extracted from Forsythia suspensa, also
demonstrated Nrf2 inducing activity in a mouse model of
cigarette smoke-induced lung inflammation. It was showed
that forsythiaside alleviated infiltration of inflammatory cells,
nitric oxide, and pro-inflammatory cytokines including
TNF-α, IL-1β, and IL-6 in the BALF and lung tissues, which
was attributed to the downregulation of NF-κB signaling
pathway. The induction of Nrf2 also led to an increase in
the levels of reduced glutathione to orchestrate cellular anti-
oxidant defenses against cigarette smoke-induced lung
inflammation (Cheng et  al. 2015). Likewise, quercetin, a
flavonoid that is ubiquitously found in vegetables, fruit, tea,
and wine, has presented anti-fibrogenic and anti-inflammatory
effects via the induction of Nrf2. Boots et  al. reported that
bleomycin-challenged mice that were fed with quercetin had
lowered expression of collagen and fibronectin, as well as
Critical Reviews in Food Science and Nutrition 23
a reduced tendency of developing inflammatory lesions that
were accompanied by downregulated gene expression of
TNF-α and keratinocyte chemoattractant. Redox balance was
modulated via enhanced Nrf2 and the activity of protein
kinases including PI3K and Akt. Thus, quercetin can poten-
tially be utilized as an anti-fibrotic agent in pulmonary
fibrotic diseases, such as IPF (Boots et  al. 2020).
In conclusion, all the above findings have proven the
capabilities of plant-derived phytochemicals in targeting the
major cellular signaling pathways and the pathological mech-
anisms underlying the development of inflammatory respi-
ratory diseases (Figure 4). Therefore, these phytochemicals
may potentially represent as novel nutraceuticals and alter-
natives to conventional therapeutics for the effective pre-
vention, treatment, and management of inflammatory
respiratory diseases. Nonetheless, it is important to note
that the list of phytochemicals that were highlighted here
are not exhaustive as there are numerous plants that have
24 Y. CHAN ET AL.
been studied for their therapeutic effects but are not covered
in this review. On top of that, there are also a diversity of
plant species from different families that remain undiscov-
ered across the world. Therefore, research must be continued
to explore further opportunities and to establish sufficient
evidence where plant-based products can be safely utilized
as effective nutraceuticals in inflammatory respiratory
diseases.
Nanotechnological approach for the delivery of
nutraceuticals
Despite the multitude of advantages of nutraceuticals in
the management of inflammatory respiratory diseases,
there are several challenges associated with their incor-
poration into foods, which may include low aqueous sol-
ubility, poor chemical stability, as well as vulnerability
toward changes in the gastrointestinal tract and external
environment. As the effectiveness of nutraceuticals in
exerting physiologic or therapeutic benefits relies greatly
on preserving their bioavailability, the development of
nanoscale carriers for the delivery of these nutraceuticals
may be an effective way to overcome their drawbacks (R.
F. S. Gonçalves et  al. 2018; Chen and Hu 2019).
Nanotechnology refers to the field of scientific research
that involves the know-how of the manufacturing as well
as the understanding of the structure, property, and behav-
ior of materials in the nanoscale range, or nanomaterials.
Over the years, nanomaterials have been widely applied
in the biomedical field for drug and gene delivery, bio-
imaging and biosensing, as well as tissue engineering
(Mehta et  al. 2021c; Mehta et  al. 2021b; Chan et  al. 2021f).
The popularity of nanomaterials as delivery carriers can
be attributed to their unique physical, biological, and
chemical properties that allow their interaction with the
biological system, cell surface biologic substances, as well
as the intracellular microenvironment to achieve efficient
targeting to sites of disease pathology (Bahadori and
Mohammadi 2012). These fundamental concepts in the
development of various delivery systems can also be
applied in the delivery of nutraceuticals for improving
their bioavailability and the subsequent enhancement of
their efficacy in the management of inflammatory respi-
ratory diseases.
Examples of nanotechnology-based delivery systems
include nanoliposomes, nanoemulsions, solid lipid nanopar-
ticles, nanostructured lipid carriers, chitosan nanoparticles,
polysaccharides as well as polymeric nanoparticles. These
must be fabricated entirely using food-grade ingredients
from economical manufacturing processes (Chen and Hu
2019; McClements 2012; Solanki et  al. 2020; Prasher et  al.
2021). Typically, the utilization of these delivery systems
can potentially increase the functionality of nutraceuticals
by shielding them from premature degradation from harsh
conditions during their manufacture, storage, and transport,
or by digestive enzymes within the gastrointestinal tract,
enhancement of stability, masking unpleasant taste and/or
unwanted odors, achieving a controlled and sustained release
profile, and most importantly, enhancing the solubility and
bioavailability of nutraceuticals within the body (R. F. S.
Gonçalves et  al. 2018; Chen and Hu 2019; Yhee, Im, and
Nho 2016). Besides, scientific advancements have allowed
for customization of these delivery vehicles to enable the
delivery of nutraceuticals to their targeted sites within the
gastrointestinal tract for their absorption with specificity
(McClements 2012).
Considerable scientific study supports that the efficacy
or biological activity of a nutraceutical’s compounds with
poor solubility, cellular uptakes, and bioavailability can be
improved by modifying/designing the formulation using
nanotechnology approach. Phytochemicals derived nano for-
mulations are promising approach to manage chronic lung
disease by targeting various cellular signaling pathway, gene
expression and enzyme expression (Mehta et  al. 2020; Mehta
et  al. 2021a). For example, liquid crystalline nanoparticles
(LCNs) offer great versatility in improving the physiochem-
ical parameter of poor solubility drug and enhance its activ-
ity against inflammatory respiratory disease (Chan et  al.
2021a). In this context, a recent study by Paudel et  al.
revealed that rutin loaded LCNs showed better anticancer
activity than rutin powder with significant inhibition of
proliferation and migration in lung cancer cell line (A549)
(Paudel et  al. 2021). Likewise, rutin LCNs also showed pro-
tective effect against LPS-induced oxidative stress in human
bronchoepithelial cell line (BEAS-2B) inhibiting the oxidative
stress gene Nox4, Nox2B and upregulating antioxidant gene
Gclc, Nqo1 (Paudel et  al. 2021; Paudel et  al. 2020a). Similarly,
the anti-inflammatory activity of naringenin loaded LCNs
was better than powder naringenin in LPS induced in-vitro
model of airway inflammation where treatment of LPS
increased the inflammatory gene expression of IL-6, IL-8,
IL-1β and TNF-α in human bronchial epithelial cell line
(BCiNS1.1), and treatment of naringenin-LCNs remarkably
decreased those gene expression. This suggest that remark-
able therapeutic benefits naringenin can be enhanced if the
problem of low solubility and bioavailability is rectified by
advance nanotechnology approach (Chin et  al. 2020). A
well-known polyphenol curcumin can be encapsulated into
vesicular drug delivery systems to downregulate MMP-2,
MMP-9, VEGF, and STAT-3 pathways in lung cancer
(Hardwick et  al. 2021).
In short, a successful nutraceutical delivery system should
be designed to address specific drawbacks affecting the func-
tionality of the loaded nutraceutical, without adversely
impacting the desirable quality attributes of the food that
they are incorporated into. Future research on
nanotechnology-based delivery of nutraceuticals should
explore the potential of nanoscale delivery systems in the
promotion of personalized nutrition. In addition, the prac-
ticability issues of these delivery systems must be carefully
addressed through a series of laboratory and clinical trials,
in order to confirm the efficacy and safety of
nano-nutraceuticals for human consumption. It is also the
responsibility of developers and regulators to cooperate in
assuring the feasibility of these novel products and technol-
ogies before they are introduced into the market.

Conclusion and future perspectives
The rapidly rising prevalence of inflammatory lung diseases
is a worrying phenomenon, as they have contributed to
significant morbidity and mortality, as well as heavy burden
on socioeconomic growth and public health systems through-
out the world. Despite the development of various thera-
peutic agents for the treatment of inflammatory respiratory
diseases, most of these agents are associated with various
drawbacks that limited their effective clinical application,
resulting in poor therapeutic outcomes. As a result, the
discovery and development of alternative strategies for the
effective management of these diseases is urgently required
with regards to the present scenario. Nutraceuticals such as
probiotics, vitamins, polyunsaturated fatty acids, trace ele-
ments, and phytochemicals are compounds that play an
essential role in the prevention and treatment of various
human diseases. They have gained attention as the potential
alternatives to conventional therapeutics as they possess
nutritional properties that are helpful in maintaining
well-being, modulating immunity, and minimizing the risks
of developing human disorders, including inflammatory
respiratory diseases. Apart from that, nutraceutical com-
pounds have also been found to regulate multiple cellular
pathways and pathological mechanisms underlying these
diseases, and their scientific validation in multiple studies
have proven the efficacies of nutraceuticals in managing
these diseases. Nanotechnological approaches have also been
proposed as a strategy to further enhance the health benefits
of nutraceuticals, as encapsulation of nutraceuticals within
delivery systems can improve their pharmacokinetic prop-
erties to offer the greatest functionality in terms of their
bioavailability, bioaccessibility, and intake by the gastroin-
testinal tract. Nonetheless, further studies are still required
to clearly establish the beneficial effects of nutraceuticals in
managing inflammatory respiratory diseases, especially on
the parameters for safety, toxicity, and quality in human
subjects. It is believed that food-derived nutrients and plant
products will continue to serve as reliable alternatives to
conventional therapeutics, where modern scientific research
can facilitate in expanding the horizons in this field of
research.
Disclosure statement
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
Funding
The author(s) reported there is no funding associated with the work
featured in this article.
ORCID
Sachin K. Singh http://orcid.org/0000-0003-3823-6572
Piyush Kumar Gupta http://orcid.org/0000-0002-3346-910X
Critical Reviews in Food Science and Nutrition 25
Niraj Kumar Jha http://orcid.org/0000-0001-9486-4069
Hari Prasad Devkota http://orcid.org/0000-0002-0509-1621
Philip M Hansbro http://orcid.org/0000-0002-4741-3035
Dinesh Kumar Chellappanl http://orcid.org/0000-0001-5567-6663
Kamal Dua http://orcid.org/0000-0002-7507-1159
References
Abbaspour, N., R. Hurrell, and R. Kelishadi. 2014. Review on iron
and its importance for human health. Journal of Research in Medical
Sciences : The Official Journal of Isfahan University of Medical
Sciences 19:164.
Adams, S., A. L. Lopata, C. M. Smuts, R. Baatjies, and M. F. Jeebhay.
2018. Relationship between serum omega-3 fatty acid and asthma
endpoints. International Journal of Environmental Research and Public
Health 16 (1):43. doi: 10.3390/ijerph16010043.
Agbetile, J., and R. Green. 2011. New therapies and management
strategies in the treatment of asthma: Patient-focused developments.
Journal of Asthma and Allergy 4:1–12. doi: 10.2147/JAA.S8671.
Aghasafari, P., U. George, and R. Pidaparti. 2019. A review of inflam-
matory mechanism in airway diseases, Inflammation Research .
Inflammation Research 68:59–74. doi: 10.1007/S00011-018-1191-2.
Alamgeer, W., Younis, H. Asif, A. Sharif, H. Riaz, I. A. Bukhari, and
A. M. Assiri. 2018. Traditional medicinal plants used for respirato-
ry disorders in Pakistan: A review of the ethno-medicinal and
pharmacological evidence. Chinese Medicine 13:1–29. doi: 10.1186/
S13020-018-0204-Y.
Ali, M. K., R. Y. Kim, A. C. Brown, C. Donovan, K. S. Vanka, J. R.
Mayall, G. Liu, A. L. Pillar, B. Jones-Freeman, D. Xenaki, et  al.
2020. Critical role for iron accumulation in the pathogenesis of
fibrotic lung disease. The Journal of Pathology 251 (1):49–62. doi:
10.1002/path.5401.
Amaral-Machado, L., W. N. Oliveira, S. S. Moreira-Oliveira, D. T.
Pereira, É. N. Alencar, N. Tsapis, and E. S. T. Egito. 2020. Use of
natural products in asthma treatment. Evidence-Based Complementary
and Alternative Medicine 2020:1021258. doi: 10.1155/2020/1021258.
Aponte, M., N. Murru, and M. Shoukat. 2020. Therapeutic, prophy-
lactic, and functional use of probiotics: A current perspective.
Frontiers in Microbiology 11. doi: 10.3389/fmicb.2020.562048.
Atanasov, A. G., B. Waltenberger, E. M. Pferschy-Wenzig, T. Linder,
C. Wawrosch, P. Uhrin, V. Temml, L. Wang, S. Schwaiger, E. H.
Heiss, et  al. 2015. Discovery and resupply of pharmacologically
active plant-derived natural products: A review. Biotechnology
Advances 33 (8):1582–1614. doi: 10.1016/j.biotechadv.2015.08.001.
Bahadori, M., and F. Mohammadi. 2012. Nanomedicine for respirato-
ry diseases. Tanaffos 11 (4):18–22.
Bakakos, A., S. Loukides, and P. Bakakos. 2019. Severe eosinophilic
asthma. Journal of Clinical Medicine 8:1375. doi: 10.3390/jcm8091375.
Bargut, T. C. L., T. P. T. Ferreira, J. B. Daleprane, M. A. Martins, P.
M. R. Silva, and M. B. Aguila. 2013. Fish oil has beneficial effects
on allergen-induced airway inflammation and hyperreactivity in
mice. PLoS One 8 (9):e75059. doi: 10.1371/journal.pone.0075059.
Barnes, P. J. 2016. Inflammatory mechanisms in patients with chron-
ic obstructive pulmonary disease. The Journal of Allergy and Clinical
Immunology 138:16–27. doi: 10.1016/J.JACI.2016.05.011.
Barnes, P. J., S. Bonini, W. Seeger, M. G. Belvisi, B. Ward, and A.
Holmes. 2015. Barriers to new drug development in respiratory
disease. The European Respiratory Journal 45:1197–207. doi:
10.1183/09031936.00007915.
Barnig, C., N. Frossard, and B. D. Levy. 2018. Towards targeting
resolution pathways of airway inflammation in asthma.
Pharmacology & Therapeutics 186:98–113. doi: 10.1016/j.
pharmthera.2018.01.004.
Barratt, S. L., A. Creamer, C. Hayton, and N. Chaudhuri. 2018.
Idiopathic pulmonary fibrosis (IPF): An overview. Journal of Clinical
Medicine 7 (8):201. doi: 10.3390/jcm7080201.
Beck, K. L., C. A. Conlon, R. Kruger, and J. Coad. 2014. Dietary
determinants of and possible solutions to iron deficiency for young
26 Y. CHAN ET AL.
women living in industrialized countries: A review. Nutrients 6
(9):3747–3776. doi: 10.3390/nu6093747.
Bentsen, H. 2017. Dietary polyunsaturated fatty acids, brain function
and mental health. Microbial Ecology in Health and Disease 28
(sup1):1281916. doi: 10.1080/16512235.2017.1281916.
Berthon, B. S., and L. G. Wood. 2015. Nutrition and respiratory
health-feature review. Nutrients 7 (3):1618–43. doi: 10.3390/
nu7031618.
Bhattacharya, P. T., S. R. Misra, and M. Hussain. 2016. Nutritional
aspects of essential trace elements in oral health and disease: An
extensive review. Scientifica 2016:1–12. doi: 10.1155/2016/5464373.
Boots, A. W., C. Veith, C. Albrecht, R. Bartholome, M.-J. Drittij, S.
M. H. Claessen, A. Bast, M. Rosenbruch, L. Jonkers, F.-J. van
Schooten, et  al. 2020. The dietary antioxidant quercetin reduces
hallmarks of bleomycin-induced lung fibrogenesis in mice. BMC
Pulmonary Medicine 20 (1):1–16. doi: 10.1186/s12890-020-1142-x.
Boudreault, F., M. Pinilla-Vera, J. A. Englert, A. T. Kho, C. Isabelle,
A. J. Arciniegas, D. Barragan-Bradford, C. Quintana, D.
Amador-Munoz, J. Guan, et  al. 2017. Zinc deficiency primes the
lung for ventilator-induced injury. JCI Insight 2 (11):e86507. doi:
10.1172/jci.insight.86507.
Brigham, E. P., H. Woo, M. McCormack, J. Rice, K. Koehler, T. Vulcain,
T. Wu, A. Koch, S. Sharma, F. Kolahdooz, et  al. 2019. Omega-3
and Omega-6 intake modifies asthma severity and response to in-
door air pollution in children. American Journal of Respiratory and
Critical Care Medicine 199 (12):1478–1486. doi: 10.1164/rc-
cm.201808-1474OC.
Burney, P. 2017. Chronic respiratory disease – The acceptable epidem-
ic?, Clinical Medicine 17 (1):29–32. doi: 10.7861/clinmedicine.17-1-29.
Cannas, D., E. Loi, M. Serra, D. Firinu, P. Valera, and P. Zavattari.
2020. Relevance of essential trace elements in nutrition and drink-
ing water for human health and autoimmune disease risk. Nutrients
12 (7):2074. doi: 10.3390/nu12072074.
Carvalho, J. L., M. Miranda, A. K. Fialho, H. Castro-Faria-Neto, E.
Anatriello, A. C. Keller, and F. Aimbire. 2020. Oral feeding with
probiotic Lactobacillus rhamnosus attenuates cigarette smoke-induced
COPD in C57Bl/6 mice: Relevance to inflammatory markers in
human bronchial epithelial cells. PLoS One 15 (4):e0225560. doi:
10.1371/journal.pone.0225560.
Chambial, S., S. Dwivedi, K. K. Shukla, P. J. John, and P. Sharma.
2013. Vitamin C in disease prevention and cure: An overview. Indian
Journal of Clinical Biochemistry 28 (4):314–28. doi: 10.1007/
s12291-013-0375-3.
Chan, Y., M. Mehta, K. R. Paudel, T. Madheswaran, J. Panneerselvam,
G. Gupta, Q. P. Su, P. M. Hansbro, R. MacLoughlin, K. Dua, et  al.
2021a. Versatility of liquid crystalline nanoparticles in inflammato-
ry lung diseases. Nanomedicine (London, England) 16 (18):1545–
1548. doi: 10.2217/nnm-2021-0114.
Chan, Y., P. Prasher, R. Löbenberg, G. Gupta, S. K. Singh, B. G. Oliver,
D. K. Chellappan, and K. Dua. 2021b. Applications and practice of
advanced drug delivery systems for targeting Toll-like receptors in
pulmonary diseases. Nanomedicine (London, England) 16 (10):783–
6. doi: 10.2217/nnm-2021-0056.
Chan, Y., R. MacLoughlin, F. C. Zacconi, M. M. Tambuwala, R. M.
Pabari, S. K. Singh, T. de, J. A. Pinto, G. Gupta, D. K. Chellappan,
et  al. 2021c. Advances in nanotechnology-based drug delivery in
targeting PI3K signaling in respiratory diseases. Nanomedicine
(London, England) 16 (16):1351–5. doi: 10.2217/nnm-2021-0087.
Chan, Y., S. W. Ng, H. S. Liew, L. J. W. Pua, L. Soon, J. S. Lim, K.
Dua, and D. K. Chellappan. 2021d. Introduction to chronic respi-
ratory diseases: A pressing need for novel therapeutic approaches.
In Medicinal plants for lung diseases, K. Dua, S. Nammi, D. Chang,
D. K. Chellappan, G. Gupta, and T. Collet, 47–84. Singapore:
Springer. doi: 10.1007/978-981-33-6850-7_2.
Chan, Y., S. W. Ng, K. Dua, and D. K. Chellappan. 2021e. Plant-based
chemical moieties for targeting chronic respiratory diseases. In
Targeting cellular signalling pathways in lung diseases, ed. K. Dua,
R. Löbenberg, Â. C. M. Luzo, S. Shukla, S. Satija, 741–81. Singapore:
Springer. doi: 10.1007/978-981-33-6827-9_34.
Chan, Y., X. H. Wu, B. W. Chieng, N. A. Ibrahim, and Y. Y. Then.
2021f. Superhydrophobic nanocoatings as intervention against
biofilm-associated bacterial infections. Nanomaterials 11 (4):1046.
doi: 10.3390/nano11041046.
Chanda, S., R. K. Tiwari, A. Kumar, and K. Singh. 2019. Nutraceuticals
inspiring the current therapy for lifestyle diseases. Advances in
Pharmacological Sciences 2019:6908716. doi: 10.1155/2019/6908716.
Chauhan, B., G. Kumar, N. Kalam, and S. H. Ansari. 2013. Current
concepts and prospects of herbal nutraceutical: A review. Journal
of Advanced Pharmaceutical Technology & Research 4 (1):4–8. doi:
10.4103/2231-4040.107494.
Chauhan, P. S., D. K. Singh, D. Dash, and R. Singh. 2018. Intranasal
curcumin regulates chronic asthma in mice by modulating NF-ĸB
activation and MAPK signaling. Phytomedicine 51:29–38. doi:
10.1016/j.phymed.2018.06.022.
Chellappan, D. K., V. Dharwal, K. R. Paudel, N. K. Jha, R. MacLoughlin,
B. G. Oliver, P. M. Hansbro, and K. Dua. 2021. Mitochondrial
dysfunctions associated with chronic respiratory diseases and their
targeted therapies: An update. Future Medicinal Chemistry 13
(15):1249–51. doi: 10.4155/fmc-2021-0097.
Chen, J., and L. Hu. 2019. Nanoscale delivery system for nutraceuticals:
Preparation. Application, Characterization, Safety, and Future Trends,
Food Engineering Reviews 12:14–31. doi: 10.1007/S12393-019-09208-W.
Cheng, L., F. Li, R. Ma, and X. Hu. 2015. Forsythiaside inhibits cig-
arette smoke-induced lung inflammation by activation of Nrf2 and
inhibition of NF-κB. International Immunopharmacology 28 (1):494–
499. doi: 10.1016/j.intimp.2015.07.011.
Chin, L. H., C. M. Hon, D. K. Chellappan, J. Chellian, T. Madheswaran,
F. Zeeshan, R. Awasthi, A. A. Aljabali, M. M. Tambuwala, H. Dureja,
et  al. 2020. Molecular mechanisms of action of naringenin in chron-
ic airway diseases. European Journal of Pharmacology 879:173139.
doi: 10.1016/j.ejphar.2020.173139.
Choi, Y. W., K. P. Lee, J. M. Kim, S. Kang, S. J. Park, J. M. Lee, H.
R. Moon, J. H. Jung, Y. G. Lee, and D. S. Im. 2016. Petatewalide
B, a novel compound from Petasites japonicus with anti-allergic
activity. Journal of Ethnopharmacology 178:17–24. doi: 10.1016/j.
jep.2015.12.010.
Chronic respiratory diseases, World Health Organization. (n.d.).
Accessed June 25, 2021. https://www.who.int/health-topics/
chronic-respiratory-diseases
Chung, K. F. 2015. Targeting the interleukin pathway in the treatment
of asthma. The Lancet 386 (9998):1086–1096. doi: 10.1016/
S0140-6736(15)00157-9.
Clarke, R., F. T. Lundy, and L. McGarvey. 2015. Herbal treatment in
asthma and COPD – current evidence. Clinical Phytoscience 1
(1):1–7. doi: 10.1186/s40816-015-0005-0.
Cragg, G. M., and D. J. Newman. 2013. Natural products: A continu-
ing source of novel drug leads. Biochimica et Biophysica Acta 1830
(6):3670–95. doi: 10.1016/j.bbagen.2013.02.008.
Cristofori, F., V. N. Dargenio, C. Dargenio, V. L. Miniello, M. Barone,
and R. Francavilla. 2021. Anti-inflammatory and immunomodula-
tory effects of probiotics in gut inflammation: A door to the body.
Frontiers in Immunology 12:578386. doi: 10.3389/FIMMU.2021.578386.
da Silva, M. R., A. Schapochnik, M. P. Leal, J. Esteves, C. B. Hebeda,
S. Sandri, C. Pavani, A. C. R. T. Horliana, S. H. P. Farsky, and A.
Lino-dos-Santos-Franco. 2018. Beneficial effects of ascorbic acid to
treat lung fibrosis induced by paraquat. PLoS One 13 (11):e0205535.
doi: 10.1371/journal.pone.0205535.
Dargahi, N., J. Johnson, O. Donkor, T. Vasiljevic, and V. Apostolopoulos.
2019. Immunomodulatory effects of probiotics: Can they be used
to treat allergies and autoimmune diseases? Maturitas 119:25–38.
doi: 10.1016/j.maturitas.2018.11.002.
Das, L., E. Bhaumik, U. Raychaudhuri, and R. Chakraborty. 2012. Role
of nutraceuticals in human health. Journal of Food Science and
Technology 49 (2):173–83. doi: 10.1007/s13197-011-0269-4.
Davani-Davari, D., M. Negahdaripour, I. Karimzadeh, M. Seifan, M.
Mohkam, S. J. Masoumi, A. Berenjian, and Y. Ghasemi. 2019.
Prebiotics: Definition, types, sources, mechanisms, and clinical ap-
plications. Foods 8 (3):92. doi: 10.3390/foods8030092.

Day, R. L. J., A. J. Harper, R. M. Woods, O. G. Davies, and L. M.
Heaney. 2019. Probiotics: Current landscape and future horizons.
Future Science OA 5 (4):FSO391. doi: 10.4155/fsoa-2019-0004.
Dharmage, S. C., J. L. Perret, and A. Custovic. 2019. Epidemiology of
Asthma in Children and Adults. Frontiers in Pediatrics 7:246. doi:
10.3389/fped.2019.00246.
Duncan, D. 2016. Chronic obstructive pulmonary disease: An overview.
British Journal of Nursing 25 (7):360–6. doi: 10.12968/bjon.2016.25.7.360.
Durham, A. L., G. Caramori, K. F. Chung, and I. M. Adcock. 2016.
Targeted anti-inflammatory therapeutics in asthma and chronic
obstructive lung disease. Translational Research 167 (1):192–203.
doi: 10.1016/j.trsl.2015.08.004.
Duvall, M. G., and B. D. Levy. 2016. DHA- and EPA-derived resolvins,
protectins, and maresins in airway inflammation. European Journal
of Pharmacology 785:144–155. doi: 10.1016/j.ejphar.2015.11.001.
Falzon, C. C., and A. Balabanova. 2017. Phytotherapy: An introduction
to herbal medicine. Primary Care 44 (2):217–227. doi: 10.1016/j.
pop.2017.02.001.
Farbstein, D., A. Kozak-Blickstein, and A. P. Levy. 2010. Antioxidant
vitamins and their use in preventing cardiovascular disease.
Molecules (Basel, Switzerland) 15 (11):8098–110. doi: 10.3390/mol-
ecules15118098.
Fasano, E., S. Serini, N. Mondella, S. Trombino, L. Celleno, P. Lanza,
A. Cittadini, and G. Calviello. 2014. Antioxidant and
anti-inflammatory effects of selected natural compounds contained
in a dietary supplement on two human immortalized keratinocyte
lines. BioMed Research International 2014:1–11. doi:
10.1155/2014/327452.
Fialho, A. K. C. D. S., M. T. F. Miranda, J. L. C. Carvalho, A. A.
Brito, R. Albertini, and F. Aimbire. 2019. Role of probiotics
Bifidobacterium breve and Lactobacillus rhamnosus on inflammation
lung in an experimental model of chronic obstructive pulmonary
disease. The FASEB Journal 33 (S1):516.4–.4. doi: 10.1096/fase-
bj.2019.33.1_supplement.516.4.
Fitzpatrick, A. M., and L. B. Bacharier. 2019. One step forward, 2 steps
back: The enigma of preschool wheeze. The Journal of Allergy and
Clinical Immunology 143 (5):1734–5. doi: 10.1016/j.jaci.2019.01.005.
Foumani, A. A., M. Mehrdad, A. Jafarinezhad, K. Nokani, and A.
Jafari. 2019. Impact of vitamin D on spirometry findings and qual-
ity of life in patients with chronic obstructive pulmonary disease:
A randomized, double-blinded, placebo-controlled clinical trial.
International Journal of Chronic Obstructive Pulmonary Disease
14:1495–501. doi: 10.2147/COPD.S207400.
Gammoh, N. Z., and L. Rink. 2017. Zinc in Infection and Inflammation.
Nutrients 9 (6):624. doi: 10.3390/nu9060624.
Gammone, M. A., G. Riccioni, G. Parrinello, and N. D’Orazio. 2018.
Omega-3 polyunsaturated fatty acids: Benefits and endpoints in
sport. Nutrients 11 (1):46. doi: 10.3390/nu11010046.
Gautier, C., and D. Charpin. 2017. Environmental triggers and avoid-
ance in the management of asthma. Journal of Asthma and Allergy
10:47–56. doi: 10.2147/JAA.S121276.
Ghiamati Yazdi, F., A. Zakeri, I. van Ark, T. Leusink-Muis, S. Braber,
S. Soleimanian-Zad, and G. Folkerts. 2020. Crude turmeric extract
improves the suppressive effects of Lactobacillus rhamnosus GG on
allergic inflammation in a murine model of house dust mite-induced
asthma. Frontiers in Immunology 11:1092. doi: 10.3389/fim-
mu.2020.01092.
Ghorbel, I., A. Elwej, M. Chaabane, K. Jamoussi, H. Mnif, T. Boudawara,
and N. Zeghal. 2017. Selenium alleviates oxidative stress and lung
damage induced by aluminum chloride in adult rats: Biochemical
and histological approach. Biological Trace Element Research 176
(1):181–191. doi: 10.1007/s12011-016-0818-9.
Goldsmith, J. R. 2015. Vitamin D as an immunomodulator: Risks with
deficiencies and benefits of supplementation. Healthcare (Basel,
Switzerland) 3 (2):219–32. doi: 10.3390/healthcare3020219.
Gonçalves, P. B., and N. C. Romeiro. 2019. Multi-target natural prod-
ucts as alternatives against oxidative stress in Chronic Obstructive
Pulmonary Disease (COPD). European Journal of Medicinal
Chemistry 163:911–931. doi: 10.1016/j.ejmech.2018.12.020.
Gonçalves, R. F. S., J. T. Martins, C. M. M. Duarte, A. A. Vicente,
and A. C. Pinheiro. 2018. Advances in nutraceutical delivery sys-
Critical Reviews in Food Science and Nutrition 27
tems: From formulation design for bioavailability enhancement to
efficacy and safety evaluation. Trends in Food Science & Technology
78:270–291. doi: 10.1016/j.tifs.2018.06.011.
Grattendick, K., R. Stuart, E. Roberts, J. Lincoln, S. S. Lefkowitz, A.
Bollen, N. Moguilevsky, H. Friedman, and D. L. Lefkowitz. 2002.
Alveolar Macrophage Activation by myeloperoxidase: A model for
exacerbation of lung inflammation. American Journal of Respiratory
Cell and Molecular Biology 26 (6):716–22. doi: 10.1165/
ajrcmb.26.6.4723.
Gulati, K., N. Rai, S. Chaudhary, and A. Ray. 2016. Nutraceuticals in
respiratory disorders. In Nutraceuticals: Efficacy, safety and toxicity,
ed. R. C. Gupta, 75–86. London: Elsevier. doi: 10.1016/
B978-0-12-802147-7.00006-1.
Guo, J., B. Li, W. Wu, Z. Wang, F. Wang, and T. Guo. 2019. Chinese
herbal medicines compared with N-acetylcysteine for the treatment
of idiopathic pulmonary fibrosis: A systematic review of randomized
controlled trials. Evidence-Based Complementary and Alternative
Medicine 2019:1–18. doi: 10.1155/2019/5170638.
Hadjicharalambous, M. R., and M. A. Lindsay. 2020. Idiopathic pul-
monary fibrosis: Pathogenesis and the emerging role of long
non-coding RNAs. International Journal of Molecular Sciences 21
(2):524. doi: 10.3390/ijms21020524.
Hamilton, L. A., and K. A. Trobaugh. 2011. Invited review: Acute
respiratory distress syndrome: Use of specialized nutrients in pedi-
atric patients and infants. Nutrition in Clinical Practice 26 (1):26–30.
doi: 10.1177/0884533610392922.
Hamishehkar, H., F. Ranjdoost, P. Asgharian, A. Mahmoodpoor, and
S. Sanaie. 2016. Vitamins, are they safe? Advanced Pharmaceutical
Bulletin 6 (4):467–77. doi: 10.15171/apb.2016.061.
Han, S., and R. K. Mallampalli. 2015. The acute respiratory distress
syndrome: From mechanism to translation. Journal of Immunology
(Baltimore, Md. : 1950) 194:855. doi: 10.4049/JIMMUNOL.1402513.
Hardwick, J., J. Taylor, M. Mehta, S. Satija, K. R. Paudel, P. M. Hansbro,
D. K. Chellappan, M. Bebawy, and K. Dua. 2021. Targeting cancer
using curcumin encapsulated vesicular drug delivery systems.
Current Pharmaceutical Design 27 (1):2–14. doi: 10.2174/13816128
26666200728151610.
Harzallah, D., and H. Belhadj. 2013. Lactic acid bacteria as probiotics:
Characteristics, selection criteria and role in immunomodulation of
human GI muccosal barrier. In Lactic Acid Bacteria - R & D for
Food, Health and Livestock Purposes, ed. J. Marcelino Kongo, 197–
216. London: InTechOpen. doi: 10.5772/50732.
Hatipoglu, U. 2018. Chronic obstructive pulmonary disease: More than
meets the eye. Annals of Thoracic Medicine 13 (1):1–6. doi: 10.4103/
atm.ATM_193_17.
Heffler, E., L. N. G. Madeira, M. Ferrando, F. Puggioni, F. Racca, L.
Malvezzi, G. Passalacqua, and G. W. Canonica. 2018. Inhaled corti-
costeroids safety and adverse effects in patients with asthma. The
Journal of Allergy and Clinical Immunology 6 (3):776–81. doi:
10.1016/j.jaip.2018.01.025.
Helal, N. A., H. A. Eassa, A. M. Amer, M. A. Eltokhy, I. Edafiogho,
and M. I. Nounou. 2019. Nutraceuticals’ novel formulations: The
good, the bad, the unknown and patents involved. Recent Patents
on Drug Delivery & Formulation 13 (2):105–56. doi: 10.2174/1872
211313666190503112040.
Heukels, P., C. C. Moor, J. H. von der Thüsen, M. S. Wijsenbeek, and
M. Kool. 2019. Inflammation and immunity in IPF pathogenesis
and treatment. Respiratory Medicine 147:79–91. doi: 10.1016/j.
rmed.2018.12.015.
Heulens, N., H. Korf, N. Cielen, E. de Smidt, K. Maes, C. Gysemans,
E. Verbeken, G. Gayan-Ramirez, C. Mathieu, and W. Janssens. 2015.
Vitamin D deficiency exacerbates COPD-like characteristics in the
lungs of cigarette smoke-exposed mice. Respiratory Research 16
(1):110. doi: 10.1186/s12931-015-0271-x.
Hikichi, M., K. Mizumura, S. Maruoka, and Y. Gon. 2019. Pathogenesis
of chronic obstructive pulmonary disease (COPD) induced by cig-
arette smoke. Journal of Thoracic Disease 11 (Suppl 17):S2129–S2140.
doi: 10.21037/jtd.2019.10.43.
Holgate, S. T. 2013. Mechanisms of asthma and implications for its
prevention and treatment: A personal journey. Allergy, Asthma &
Immunology Research 5:343–7. doi: 10.4168/AAIR.2013.5.6.343.
28 Y. CHAN ET AL.
Huppert, L. A., M. A. Matthay, and L. B. Ware. 2019. Pathogenesis of
acute respiratory distress syndrome. Seminars in Respiratory and
Critical Care Medicine 40 (1):31–9. doi: 10.1055/s-0039-1683996.
Innes, J. K., and P. C. Calder. 2018. Omega-6 fatty acids and inflam-
mation. Prostaglandins, Leukotrienes, and Essential Fatty Acids
132:41–48. doi: 10.1016/j.plefa.2018.03.004.
Isolauri, E., S. Rautava, and S. Salminen. 2012. Probiotics in the de-
velopment and treatment of allergic disease. Gastroenterology Clinics
of North America 41 (4):747–62. doi: 10.1016/j.gtc.2012.08.007.
Jang, H. Y., K. S. Ahn, M. J. Park, O. K. Kwon, H. K. Lee, and S. R.
Oh. 2012. Skullcapflavone II inhibits ovalbumin-induced airway
inflammation in a mouse model of asthma. International
Immunopharmacology 12 (4):666–674. doi: 10.1016/j.in-
timp.2012.01.010.
Janssens, W., C. Mathieu, S. Boonen, and M. Decramer. 2011. Vitamin
D deficiency and chronic obstructive pulmonary disease: A vicious
circle. Vitamins and Hormones 86:379–99. doi: 10.1016/
B978-0-12-386960-9.00017-4.
Ji, N. F., Y. C. Xie, M. S. Zhang, X. Zhao, H. Cheng, H. Wang, K. S.
Yin, and M. Huang. 2014. Ligustrazine corrects Th1/Th2 and Treg/
Th17 imbalance in a mouse asthma model. International
Immunopharmacology 21 (1):76–81. doi: 10.1016/j.intimp.2014.04.015.
Jin, H., L. Wang, C. Xu, B. Li, Q. Luo, J. Wu, Y. Lv, G. Wang, and J.
Dong. 2014. Effects of Psoraleae fructus and its major component
psoralen on Th2 response in allergic asthma. The American Journal
of Chinese Medicine 42 (3):665–678. doi: 10.1142/S0192415X14500438.
Kalchiem-Dekel, O., J. R. Galvin, A. P. Burke, S. P. Atamas, and N.
W. Todd. 2018. Interstitial lung disease and pulmonary fibrosis: A
practical approach for general medicine physicians with focus on
the medical history. Journal of Clinical Medicine 7 (12):476. doi:
10.3390/jcm7120476.
Karunamoorthi, K., K. Jegajeevanram, J. Vijayalakshmi, and E.
Mengistie. 2012. Traditional medicinal plants: A source of phyto-
therapeutic modality in resource-constrained health care settings.
Journal of Evidence-Based Integrative Medicine 18:67–74. doi:
10.1177/2156587212460241.
Kieliszek, M. 2019. Selenium – fascinating microelement, properties
and sources in food. Molecules 24 (7):1298. doi: 10.3390/mole-
cules24071298.
Kieliszek, M., and S. Błażejak. 2016. Current knowledge on the im-
portance of selenium in food for living organisms: A review.
Molecules 21 (5):609. doi: 10.3390/molecules21050609.
Kim, R. Y., J. W. Pinkerton, P. G. Gibson, M. A. Cooper, J. C. Horvat,
and P. M. Hansbro. 2015. Inflammasomes in COPD and neutro-
philic asthma. Thorax 70 (12):1199–201. doi: 10.1136/
thoraxjnl-2014-206736.
King, J. C., K. H. Brown, R. S. Gibson, N. F. Krebs, N. M. Lowe, J.
H. Siekmann, and D. J. Raiten. 2015. Biomarkers of nutrition for
development (BOND) – zinc review. The Journal of Nutrition 146
(4):858S–885S. doi: 10.3945/jn.115.220079.
King, P. T. 2015. Inflammation in chronic obstructive pulmonary dis-
ease and its role in cardiovascular disease and lung cancer. Clinical
and Translational Medicine 4 (1):68. doi: 10.1186/s40169-015-0068-z.
Knoell, D. L., D. A. Smith, M. Sapkota, A. J. Heires, C. K. Hanson,
L. M. Smith, J. A. Poole, T. A. Wyatt, and D. J. Romberger. 2019.
Insufficient zinc intake enhances lung inflammation in response to
agricultural organic dust exposure. Journal of Nutritional Biochemistry
70:56–64. doi: 10.1016/j.jnutbio.2019.04.007.
Koike, K., A. Ishigami, Y. Sato, T. Hirai, Y. Yuan, E. Kobayashi, K.
Tobino, T. Sato, M. Sekiya, K. Takahashi, et  al. 2014. Vitamin C
prevents cigarette smoke-induced pulmonary emphysema in mice
and provides pulmonary restoration. American Journal of Respiratory
Cell and Molecular Biology 50 (2):347–57. doi: 10.1165/
rcmb.2013-0121OC.
Krystel-Whittemore, M., K. N. Dileepan, and J. G. Wood. 2015. Mast
cell: A multi-functional master cell. Frontiers in Immunology 6:620.
doi: 10.3389/fimmu.2015.00620.
Kuruvilla, M. E., F. E.-H. Lee, and G. B. Lee. 2019. Understanding
asthma phenotypes, endotypes, and mechanisms of disease. Clinical
Reviews in Allergy & Immunology 56 (2):219–33. doi: 10.1007/
s12016-018-8712-1.
Lan, N., G. Luo, X. Yang, Y. Cheng, Y. Zhang, X. Wang, X. Wang, T.
Xie, G. Li, Z. Liu, et  al. 2014. 25-hydroxyvitamin D3-deficiency
enhances oxidative stress and corticosteroid resistance in severe
asthma exacerbation. PLoS One 9 (11):e111599. doi: 10.1371/journal.
pone.0111599.
Lawrenz, J., B. Herndon, A. Kamal, A. Mehrer, D. C. Dim, C.
Baidoo, D. Gasper, J. Nitz, A. Molteni, and R. C. Baybutt. 2012.
Dietary flaxseed oil protects against bleomycin-induced pulmo-
nary fibrosis in rats. Pulmonary Medicine 2012:1–11. doi:
10.1155/2012/457031.
Lee, J., J. Min, M. Kim, S. Kim, O. Kwon, T. K. Oh, J. K. Lee, T. Y.
Kim, S. W. Lee, S. Choi, et  al. 2019. Pistacia weinmannifolia root
exerts a protective role in ovalbumin-induced lung inflammation
in a mouse allergic asthma model. International Journal of Molecular
Medicine 44:2171–2180. doi: 10.3892/IJMM.2019.4367.
Lin, B. F., B. L. Chiang, Y. Ma, J. Y. Lin, and M. L. Chen. 2015. Traditional
herbal medicine and allergic asthma. Evidence-Based Complementary
and Alternative Medicine 2015:510989. doi: 10.1155/2015/510989.
Liou, C.-J., W.-C. Huang, C.-J. Liou, and W.-C. Huang. 2017. Casticin
inhibits interleukin-1β-induced ICAM-1 and MUC5AC expression
by blocking NF-κB, PI3K-Akt, and MAPK signaling in human lung
epithelial cells. Oncotarget 8 (60):101175–101188. doi: 10.18632/
oncotarget.20933.
Liu, F., N. X. Xuan, S. M. Ying, W. Li, Z. H. Chen, and H. H. Shen.
2016. Herbal medicines for asthmatic inflammation: From basic
researches to clinical applications. Mediators of Inflammation
2016:6943135. doi: 10.1155/2016/6943135.
Liu, Y., D. Q. Tran, and J. M. Rhoads. 2018. Probiotics in disease
prevention and treatment. The Journal of Clinical Pharmacology
58:S164–S179. doi: 10.1002/jcph.1121.
Lopez-Santamarina, A., E. G. Gonzalez, A. Lamas, A. d C. Mondragon,
P. Regal, and J. M. Miranda. 2021. Probiotics as a possible strategy
for the prevention and treatment of allergies. A narrative review.
Foods 10 (4):701. doi: 10.3390/foods10040701.
Lugg, S. T., A. Scott, D. Parekh, B. Naidu, and D. R. Thickett. 2021.
Cigarette smoke exposure and alveolar macrophages: Mechanisms
for lung disease. Thorax. doi: 10.1136/thoraxjnl-2020-216296. online
ahead of print.
Ma, J. K.-C., R. Chikwamba, P. Sparrow, R. Fischer, R. Mahoney, and
R. M. Twyman. 2005. Plant-derived pharmaceuticals-the road for-
ward. Trends in Plant Science 10 (12):580–5. doi: 10.1016/j.
tplants.2005.10.009.
Maazi, H., S. Shirinbak, N. Bloksma, M. C. Nawijn, and A. J. M. van
Oosterhout. 2011. Iron administration reduces airway hyperreactiv-
ity and eosinophilia in a mouse model of allergic asthma. Clinical
& E x p e r ime ntal Immunol o g y 1 6 6 ( 1 ) : 8 0 – 8 6 . d oi :
10.1111/j.1365-2249.2011.04448.x.
Maldonado Galdeano, C., S. I. Cazorla, J. M. Lemme Dumit, E. Vélez,
and G. Perdigón. 2019. Beneficial effects of probiotic consumption
on the immune system. Annals of Nutrition & Metabolism 74
(2):115–24. doi: 10.1159/000496426.
Markowiak, P., and K. Śliżewska. 2017. Effects of probiotics. Prebiotics,
and Synbiotics on Human Health, Nutrients 9:1021. doi: 10.3390/
NU9091021.
Matthay, M. A., and R. L. Zemans. 2011. The acute respiratory distress
syndrome: Pathogenesis and treatment. Annual Review of Pathology
6:147–63. doi: 10.1146/annurev-pathol-011110-130158.
Matthay, M. A., R. L. Zemans, G. A. Zimmerman, Y. M. Arabi, J. R.
Beitler, A. Mercat, M. Herridge, A. G. Randolph, and C. S. Calfee.
2019. Acute respiratory distress syndrome. Nature Reviews Disease
Primers 5:18. doi: 10.1038/S41572-019-0069-0.
Matucci, A., A. Vultaggio, E. Maggi, and I. Kasujee. 2018. Is IgE or
eosinophils the key player in allergic asthma pathogenesis? Are we
asking the right question? Respiratory Research 19 (1):1–10. doi:
10.1186/s12931-018-0813-0.
McBrien, C. N., and A. Menzies-Gow. 2017. The biology of eosinophils
and their role in asthma. Frontiers in Medicine 4:93. doi: 10.3389/
fmed.2017.00093.
McClements, D. J. 2012. Edible delivery systems for nutraceuticals:
Designing functional foods for improved health. Therapeutic Delivery
3 (7):801–803. doi: 10.4155/tde.12.56.

McLoughlin, R., B. S. Berthon, G. B. Rogers, K. J. Baines, L. E. X.
Leong, P. G. Gibson, E. J. Williams, and L. G. Wood. 2019. Soluble
fibre supplementation with and without a probiotic in adults with
asthma: A 7-day randomised, double blind, three way cross-over
trial. EBioMedicine 46:473–85. doi: 10.1016/j.ebiom.2019.07.048.
Mehri, A. 2020. Trace elements in human nutrition (II) – An update.
International Journal of Preventive Medicine 11:2. doi: 10.4103/ijpvm.
IJPVM_48_19.
Mehta, M., D. S. Dhanjal, K. R. Paudel, B. Singh, G. Gupta, S.
Rajeshkumar, L. Thangavelu, M. M. Tambuwala, H. A. Bakshi, D.
K. Chellappan, et  al. 2020. Cellular signalling pathways mediating
the pathogenesis of chronic inflammatory respiratory diseases: An
update. Inflammopharmacology 28:795–817. doi: 10.1007/
S10787-020-00698-3.
Mehta, M., K. R. Paudel, N. Panth, D. Xenaki, R. Macloughlin, B. G.
Oliver, R. Lobenberg, P. M. Hansbro, D. K. Chellappan, and K.
Dua. 2021a. Drug delivery advances in mitigating inflammation via
matrix metalloproteinases in respiratory diseases. Nanomedicine
(London, England) 16:437–439. doi: 10.2217/NNM-2021-0016.
Mehta, M., K. R. Paudel, S. D. Shukla, V. S. R. R. Allam, V. K.
Kannaujiya, N. Panth, A. Das, V. K. Parihar, A. Chakraborty, M.
K. Ali, et  al. 2021b. Recent trends of NFκB decoy
oligodeoxynucleotide-based nanotherapeutics in lung diseases.
Journal of Controlled Release: Official Journal of the Controlled
Release Society 337:629–644. doi: 10.1016/j.jconrel.2021.08.010.
Mehta, M., S. Satija, K. R. Paudel, V. Malyla, V. K. Kannaujiya, D. K.
Chellappan, M. Bebawy, P. M. Hansbro, P. R. Wich, and K. Dua.
2021c. Targeting respiratory diseases using miRNA inhibitor based
nanotherapeutics: Current status and future perspectives.
Nanomedicine: Nanotechnology, Biology and Medicine 31:102303. doi:
10.1016/j.nano.2020.102303.
Meister, M., W. Conrad, A. Adhya, S. Zhang, C. I. Vong, and X. Ji.
2020. Ability of γ-tocotrienol to mitigate inflammation and preserve
lung function in a model of E-cigarette induced chronic obstructive
pulmonary disease. Current Developments in Nutrition 4
(Supplement_2):437. doi: 10.1093/cdn/nzaa045_070.
Meyer, K. C. 2014. Diagnosis and management of interstitial lung
disease. Translational Respirator y Medicine 2:4. doi:
10.1186/2213-0802-2-4.
Mims, J. W. 2015. Asthma: Definitions and pathophysiology.
International Forum of Allergy & Rhinology 5 (S1):S2–S6. doi:
10.1002/alr.21609.
Mojiri-Forushani, H., A. A. Hemmati, M. A. Dehghani, A. R. Malayeri,
and H. H. Pour. 2017. Effects of herbal extracts and compounds
and pharmacological agents on pulmonary fibrosis in animal mod-
els: A review. Journal of Integrative Medicine 15 (6):433–41. doi:
10.1016/S2095-4964(17)60363-7.
Morgan, C. I., J. R. Ledford, P. Zhou, and K. Page. 2011. Zinc sup-
plementation alters airway inflammation and airway hyperrespon-
siveness to a common allergen. Journal of Inflammation 8 (1):1–10.
doi: 10.1186/1476-9255-8-36.
Mortaz, E., I. M. Adcock, F. L. M. Ricciardolo, M. Varahram, H.
Jamaati, A. A. Velayati, G. Folkerts, and J. Garssen. 2015.
Anti-inflammatory effects of lactobacillus rahmnosus and bifidobac-
terium breve on cigarette smoke activated human macrophages.
PLoS One 10 (8):e0136455. doi: 10.1371/journal.pone.0136455.
Mortaz, E., I. M. Adcock, G. Folkerts, P. J. Barnes, A. P. Vos, and J.
Garssen. 2013. Probiotics in the management of lung diseases.
Mediators of Inflammation 2013:1–10. doi: 10.1155/2013/751068.
Moss, J. W. E., J. O. Williams, and D. P. Ramji. 2018. Nutraceuticals
as therapeutic agents for atherosclerosis. Biochimica et Biophysica
Acta (BBA) - Molecular Basis of Disease 1864 (5 Pt A):1562–72. doi:
10.1016/j.bbadis.2018.02.006.
Moura, J. C. V., I. C. G. Moura, G. R. Gaspar, G. M. S. Mendes, B.
A. V. Faria, N. S. Jentzsch, M. do, C. F. Passos, A. Kurdi, B. Godman,
et  al. 2019. The use of probiotics as a supplementary therapy in the
treatment of patients with asthma: A pilot study and implications.
Clinics (Sao Paulo, Brazil) 74:e950. doi: 10.6061/clinics/2019/e950.
Muk Kim, T., K. R. Paudel, and D. W. Kim. 2020. Eriobotrya japon-
ica leaf extract attenuates airway inflammation in ovalbumin-induced
Critical Reviews in Food Science and Nutrition 29
mice model of asthma. Journal of Ethnopharmacology 253:112082.
doi: 10.1016/J.JEP.2019.112082.
Nakagome, K., and M. Nagata. 2018. Involvement and possible role
of eosinophils in asthma exacerbation. Frontiers in Immunology
9:2220. doi: 10.3389/fimmu.2018.02220.
Nasri, H., A. Baradaran, H. Shirzad, and M. Rafieian-Kopaei. 2014.
New concepts in nutraceuticals as alternative for pharmaceuticals.
International Journal of Preventive Medicine 5 (12):1487–99.
Nderitu, K. W., N. S. Mwenda, N. J. Macharia, S. S. Barasa, and M.
P. Ngugi. 2017. Antiobesity Activities of Methanolic Extracts of
Amaranthus dubius, Cucurbita pepo, and Vigna unguiculata in
Progesterone-Induced Obese Mice. Evidence-Based Complementary
and Alternative Medicine 2017:4317321. doi: 10.1155/2017/4317321.
Nordgren, T. M., T. D. Friemel, A. J. Heires, J. A. Poole, T. A. Wyatt,
and D. J. Romberger. 2014. The omega-3 fatty acid docosahexae-
noic acid attenuates organic dust-induced airway inflammation.
Nutrients 6 (12):5434–5452. doi: 10.3390/nu6125434.
O’Reilly, S. 2017. Chronic obstructive pulmonary disease. American
Journal of Lifestyle Medicine 11 (4):296–302. doi:
10.1177/1559827616656593.
Ohkura, N., Y. Kitagawa, and S. Sakaguchi. 2013. Development and
maintenance of regulatory T cells. Immunity 38 (3):414–423. doi:
10.1016/j.immuni.2013.03.002.
Oland, A. A., G. D. Booster, and B. G. Bender. 2017. Psychological
and lifestyle risk factors for asthma exacerbations and morbidity in
children. The World Allergy Organization Journal 10 (1):35. doi:
10.1186/s40413-017-0169-9.
Pandey, K. R., S. R. Naik, and B. v Vakil. 2015. Probiotics, prebiotics
and synbiotics – A review. Journal of Food Science and Technology
52 (12):7577–87. doi: 10.1007/s13197-015-1921-1.
Patel, V. J., S. B. Roy, H. J. Mehta, M. Joo, and R. T. Sadikot. 2018.
Alternative and natural therapies for acute lung injury and acute
respiratory distress syndrome. BioMed Research International 2018:1–
9. doi: 10.1155/2018/2476824.
Patterson, E., R. Wall, G. F. Fitzgerald, R. P. Ross, and C. Stanton.
2012. Health implications of high dietary omega-6 polyunsaturated
fatty acids. Journal of Nutrition and Metabolism 2012:539426. doi:
10.1155/2012/539426.
Paudel, K. R., R. Wadhwa, M. Mehta, D. K. Chellappan, P. M. Hansbro,
and K. Dua. 2020a. Rutin loaded liquid crystalline nanoparticles
inhibit lipopolysaccharide induced oxidative stress and apoptosis in
bronchial epithelial cells in vitro. Toxicology in Vitro 68:104961. doi:
10.1016/j.tiv.2020.104961.
Paudel, K. R., R. Wadhwa, X. N. Tew, N. J. X. Lau, T. Madheswaran,
J. Panneerselvam, F. Zeeshan, P. Kumar, G. Gupta, K. Anand, et  al.
2021. Rutin loaded liquid crystalline nanoparticles inhibit non-small
cell lung cancer proliferation and migration in vitro. Life Sciences
276:119436. doi: 10.1016/j.lfs.2021.119436.
Paudel, K. R., V. Dharwal, V. K. Patel, I. Galvao, R. Wadhwa, V. Malyla,
S. S. Shen, K. F. Budden, N. G. Hansbro, A. Vaughan, et  al. 2020b.
Role of lung microbiome in innate immune response associated
with chronic lung diseases. Frontiers in Medicine 7:554. doi: 10.3389/
fmed.2020.00554.
Pavord, I. D., R. Beasley, A, Agusti, G. P. Anderson, E. Bel, G.
Brusselle, P. Cullinan, A. Custovic, F. M. Ducharme, J. V. Fahy,
et  al. 2018. After asthma: Redefining airways diseases. Lancet
(London, England) 391:350–400. doi: 10.1016/
S0140-6736(17)30879-6.
Peh, H. Y., W. E. Ho, C. Cheng, T. K. Chan, A. C. G. Seow, A. Y. H.
Lim, C. W. Fong, K. Y. Seng, C. N. Ong, and W. S. F. Wong. 2015.
Vitamin E isoform γ-tocotrienol downregulates house dust
mite-induced asthma. Journal of Immunology (Baltimore, Md. : 1950)
195 (2):437–44. doi: 10.4049/jimmunol.1500362.
Pelaia, C., G. Paoletti, F. Puggioni, F. Racca, G. Pelaia, G. W. Canonica,
and E. Heffler. 2019. Interleukin-5 in the pathophysiology of severe
asthma. Frontiers in Physiology 10:1514. doi: 10.3389/
fphys.2019.01514.
Pembrey, L., M. L. Barreto, J. Douwes, P. Cooper, J. Henderson, H.
Mpairwe, C. Ardura-Garcia, M. Chico, C. Brooks, A. A. Cruz, et  al.
2018. Understanding asthma phenotypes: The World Asthma
30 Y. CHAN ET AL.
Phenotypes (WASP) international collaboration. ERJ Open Research
4 (3):00013-2018. doi: 10.1183/23120541.00013-2018.
Pizzini, A., L. Lunger, T. Sonnweber, G. Weiss, and I. Tancevski. 2018.
The role of omega-3 fatty acids in the setting of coronary artery
disease and COPD: A review. Nutrients 10 (12):1864. doi: 10.3390/
nu10121864.
Prasad, A. S. 2014. Zinc is an antioxidant and anti-inflammatory agent:
Its role in human health. Frontiers in Nutrition 1:14. doi: 10.3389/
fnut.2014.00014.
Prasher, P., M. Sharma, M. Mehta, K. R. Paudel, S. Satija, D. K.
Chellappan, H. Dureja, G. Gupta, M. M. Tambuwala, P. Negi, et  al.
2020. Plants derived therapeutic strategies targeting chronic respi-
ratory diseases: Chemical and immunological perspective.
Chemico-Biological Interactions 325:109125. doi: 10.1016/j.
cbi.2020.109125.
Prasher, P., M. Sharma, M. Mehta, S. Satija, A. A. Aljabali, M. M.
Tambuwala, K. Anand, N. Sharma, H. Dureja, N. K. Jha, et  al. 2021.
Current-status and applications of polysaccharides in drug delivery
systems. Colloid and Interface Science Communications 42:100418.
doi: 10.1016/j.colcom.2021.100418.
Prentice, A. M., Y. A. Mendoza, D. Pereira, C. Cerami, R. Wegmuller,
A. Constable, and J. Spieldenner. 2017. Dietary strategies for im-
proving iron status: Balancing safety and efficacy. Nutrition Reviews
75 (1):49–60. doi: 10.1093/nutrit/nuw055.
Quirt, J., K. J. Hildebrand, J. Mazza, F. Noya, and H. Kim. 2018.
CSACI position statement: Prescribing sublingual immunotherapy
tablets for aeroallergens. Allergy, Asthma & Clinical Immunology 14
(S2):1–16. doi: 10.1186/s13223-018-0279-0.
Quoc, Q. L., T. C. T. Bich, S. Kim, H. Park, and Y. S. Shin. 2021.
Administration of vitamin E attenuates airway inflammation
through restoration of Nrf2 in a mouse model of asthma. Journal
of Cellular and Molecular Medicine 25 (14):6721–32. doi: 10.1111/
jcmm.16675.
Ram, A., S. Balachandar, P. Vijayananth, and V. P. Singh. 2011.
Medicinal plants useful for treating chronic obstructive pulmonary
disease (COPD): Current status and future perspectives. Fitoterapia
82 (2):141–51. doi: 10.1016/j.fitote.2010.09.005.
Rawal, G., S. Yadav, and R. Kumar. 2018. Acute respiratory distress
syndrome: An update and review. Journal of Translational Internal
Medicine 6 (2):74–7. doi: 10.1515/jtim-2016-0012.
Rizvi, S., S. T. Raza, F. Ahmed, A. Ahmad, S. Abbas, and F. Mahdi.
2014. The role of vitamin E in human health and some diseases.
Sultan Qaboos University Medical Journal 14 (2):e157–e165.
Ryu, E. K., T.-H. Kim, E. J. Jang, Y. S. Choi, S. T. Kim, K. B. Hahm,
and H.-J. Lee. 2015. Wogonin, a plant flavone from Scutellariae
radix, attenuated ovalbumin-induced airway inflammation in mouse
model of asthma via the suppression of IL-4/STAT6 signaling.
Journal of Clinical Biochemistry and Nutrition 57 (2):105–112. doi:
10.3164/jcbn.15-45.
Sack, M., A. Hofbauer, R. Fischer, and E. Stoger. 2015. The increasing
value of plant-made proteins. Current Opinion in Biotechnology
32:163–70. doi: 10.1016/j.copbio.2014.12.008.
Sadikot, R. T. 2018. The potential role of nanomedicine in lung dis-
eases. Medical Research Archives 6 (5). doi: 10.18103/MRA.V6I5.1723.
Santana, F. P. R., N. M. Pinheiro, M. I. B. Mernak, R. F. Righetti, M.
A. Martins, J. H. G. Lago, F. D. T. Q. D. S. Lopes, I. F. L. C. Tibério,
and C. M. Prado. 2016. Evidences of herbal medicine-derived nat-
ural products effects in inflammatory lung diseases. Mediators of
Inflammation 2016:2348968. doi: 10.1155/2016/2348968.
Sassi, F., C. Tamone, and P. D’Amelio. 2018. Vitamin D: Nutrient,
hormone, and immunomodulator. Nutrients 10 (11):1656. doi:
10.3390/nu10111656.
Sato, K., S. Inoue, A. Igarashi, Y. Tokairin, K. Yamauchi, T. Kimura,
M. Nishiwaki, T. Nemoto, H. Nakano, M. Sato, et  al. 2020. Effect
of iron deficiency on a murine model of smoke-induced emphyse-
ma. American Journal of Respiratory Cell and Molecular Biology 62
(5):588–597. doi: 10.1165/rcmb.2018-0239OC.
Sgalla, G., B. Iovene, M. Calvello, M. Ori, F. Varone, and L. Richeldi.
2018. Idiopathic pulmonary fibrosis: Pathogenesis and management.
Respiratory Research 19 (1):32. doi: 10.1186/s12931-018-0730-2.
Shastri, M. D., V. S. R. R. Allam, S. D. Shukla, N. K. Jha, K. R. Paudel,
G. M. Peterson, R. P. Patel, P. M. Hansbro, D. K. Chellappan, and
K. Dua. 2021. Interleukin-13: A pivotal target against
influenza-induced exacerbation of chronic lung diseases. Life Sciences
283:119871. doi: 10.1016/j.lfs.2021.119871.
Shaw, J., T. Marshall, H. Morris, C. Hayton, and N. Chaudhuri. 2017.
Idiopathic pulmonary fibrosis: A holistic approach to disease man-
agement in the antifibrotic age. Journal of Thoracic Disease 9
(11):4700–7. doi: 10.21037/jtd.2017.10.111.
Shi, L. H., K. Balakrishnan, K. Thiagarajah, N. I. M. Ismail, and O.
S. Yin. 2016. Beneficial properties of probiotics. Tropical Life Sciences
Research 27 (2):73–90. doi: 10.21315/tlsr2016.27.2.6.
Shi, Y., T. Liu, L. Yao, Y. Xing, X. Zhao, J. Fu, and X. Xue. 2017.
Chronic vitamin D deficiency induces lung fibrosis through activa-
tion of the renin-angiotensin system. Scientific Reports 7 (1):3312.
doi: 10.1038/s41598-017-03474-6.
Shukla, S. D., K. Swaroop Vanka, A. Chavelier, M. D. Shastri, M. M.
Tambuwala, H. A. Bakshi, K. Pabreja, M. Q. Mahmood, and R. F.
O’Toole. 2020. Chronic respiratory diseases: An introduction and
need for novel drug delivery approaches. In Targeting chronic in-
flammatory lung diseases using advanced drug delivery systems, ed.
K. Dua, P. B. Hansbro, R. Wadhwa, M. Haghi, L. G. Pont, and K.
A. Williams, 1–31. London: Elsevier. doi: 10.1016/b978-0-12-820658-
4.00001-7.
Slavin, J. L., and B. Lloyd. 2012. Health benefits of fruits and vegeta-
bles. Advances in Nutrition (Bethesda, Md.) 3 (4):506–16. doi:
10.3945/an.112.002154.
Sofowora, A., E. Ogunbodede, and A. Onayade. 2013. The role and
place of medicinal plants in the strategies for disease prevention.
African Journal of Traditional, Complementary, and Alternative
Medicines 10 (5):210–29. doi: 10.4314/ajtcam.v10i5.2.
Sokoła-Wysoczańska, E., T. Wysoczański, J. Wagner, K. Czyż, R.
Bodkowski, S. Lochyński, and B. Patkowska-Sokoła. 2018.
Polyunsaturated fatty acids and their potential therapeutic role in
cardiovascular system disorders—A review. Nutrients 10 (10):1561.
doi: 10.3390/nu10101561.
Solanki, N., M. Mehta, D. K. Chellappan, G. Gupta, N. G. Hansbro,
M. M. Tambuwala, A. Aa Aljabali, K. R. Paudel, G. Liu, S. Satija,
et  al. 2020. Antiproliferative effects of boswellic acid-loaded chitosan
nanoparticles on human lung cancer cell line A549. Future Medicinal
Chemistry 12 (22):2019–2034. doi: 10.4155/fmc-2020-0083.
Stavropoulou, E., and E. Bezirtzoglou. 2020. Probiotics in medicine:
A long debate. Frontiers in Immunology 11:2192. doi: 10.3389/fim-
mu.2020.02192.
Stoodley, I., M. Garg, H. Scott, L. Macdonald-Wicks, B. Berthon, and
L. Wood. 2020. Higher Omega-3 index is associated with better
asthma control and lower medication dose: A cross-sectional study.
Nutrients 12:74. doi: 10.3390/NU12010074.
Suissa, S., S. Dell’Aniello, and P. Ernst. 2012. Long-term natural history
of chronic obstructive pulmonary disease: Severe exacerbations and
mortality. Thorax 67 (11):957–63. doi: 10.1136/thoraxjnl-2011-201518.
Swierczynska-Machura, D., E. Nowakowska-Swirta, J. Piasecka-Zelga,
R. Swiercz, J. Gromadzinska, W. Wasowicz, J. Walusiak-Skorupa,
and C. Palczynski. 2015. Vitamin C inhibits the diisocyanate-induced
lung inflammatory response in mice. European Respiratory Journal
46:PA3898. doi: 10.1183/13993003.congress-2015.PA3898.
Syngai, G. G., R. Gopi, R. Bharali, S. Dey, G. M. A. Lakshmanan, and
G. Ahmed. 2016. Probiotics – The versatile functional food ingre-
dients. Journal of Food Science and Technology 53 (2):921–33. doi:
10.1007/s13197-015-2011-0.
Tabatabaei, A., M. Babaee, N. Moradi, M. Nabavi, S. Arshi, and S.
Fallah. 2020. Serum concentration of selenium and GPX enzyme
activity in iranian children with asthma. Modern Care Journal 17
(2):e102396. doi: 10.5812/modernc102396.
Toh, Z. Q., A. Anzela, M. L. K. Tang, and P. v Licciardi. 2012. Probiotic
therapy as a novel approach for allergic disease. Frontiers in
Pharmacology 3:171. doi: 10.3389/fphar.2012.00171.
Traber, M. G., and J. F. Stevens. 2011. Vitamins C and E: Beneficial
effects from a mechanistic perspective. Free Radical Biology &
Medicine 51 (5):1000–13. doi: 10.1016/j.freeradbiomed.2011.05.017.

Tsiligianni, I. G., and T. van der Molen. 2010. A systematic review of
the role of vitamin insufficiencies and supplementation in COPD.
Respiratory Research 11:171. doi: 10.1186/1465-9921-11-171.
Umbrello, M., P. Formenti, L. Bolgiaghi, and D. Chiumello. 2017.
Current concepts of ARDS: A narrative review. International Journal
of Molecular Sciences 18:64. doi: 10.3390/IJMS18010064.
van de Pol, M. A., R. Lutter, B. S. Smids, E. J. M. Weersink, and J.
S. van der Zee. 2011. Synbiotics reduce allergen-induced T-helper
2 response and improve peak expiratory flow in allergic asthmatics.
Allergy 66 (1):39–47. doi: 10.1111/j.1398-9995.2010.02454.x.
[InsertedFromOnline[pubmedMismatch]]
van Rijt, L., H. von Richthofen, and R. van Ree. 2016. Type 2 innate
lymphoid cells: At the cross-roads in allergic asthma. Seminars in
Immunopathology 38 (4):483–496. doi: 10.1007/s00281-016-0556-2.
Varzakas, T., P. Kandylis, D. Dimitrellou, C. Salamoura, G. Zakynthinos,
and C. Proestos. 2018. Innovative and fortified food: Probiotics,
prebiotics, GMOs, and superfood. In Preparation and processing of
religious and cultural foods, ed. E. Ali, N. Naquiah, A. Nizar, 67–129.
Cambridge, MA: Elsevier. doi: 10.1016/B978-0-08-101892-7.00006-7.
Veeresham, C. 2012. Natural products derived from plants as a source
of drugs. Journal of Advanced Pharmaceutical Technology & Research
3 (4):200–1. doi: 10.4103/2231-4040.104709.
Victoni, T., E. Barreto, V. Lagente, and V. F. Carvalho. 2021. Oxidative
imbalance as a crucial factor in inflammatory lung diseases: Could
antioxidant treatment constitute a new therapeutic strategy? Oxidative
Medicine and Cellular Longevity 2021:6646923. doi: 10.1155/2021/6646923.
Wang, N., H.-Y. Tan, S. Li, Y. Xu, W. Guo, and Y. Feng. 2017a.
Supplementation of micronutrient selenium in metabolic diseases:
Its role as an antioxidant. Oxidative Medicine and Cellular Longevity
2017:1–13. doi: 10.1155/2017/7478523.
Wang, W., X. Luo, Q. Zhang, X. He, Z. Zhang, X. Wang. 2020.
Bifidobacterium infantis relieves allergic asthma in mice by regu-
lating Th1/Th2. Medical Science Monitor : International Medical
Journal of Experimental and Clinical Research. 26:e920583-1. doi:
10.12659/MSM.920583.
Wang, X., Y. Hui, L. Zhao, Y. Hao, H. Guo, and F. Ren. 2017b. Oral
administration of Lactobacillus paracasei L9 attenuates PM2.5-induced
enhancement of airway hyperresponsiveness and allergic airway
response in murine model of asthma. PLoS One 12 (2):e0171721.
doi: 10.1371/journal.pone.0171721.
Wang, Z., J. A. DiDonato, J. Buffa, S. A. Comhair, M. A. Aronica, R.
A. Dweik, N. A. Lee, J. J. Lee, M. J. Thomassen, M. Kavuru, et  al.
2016. Eosinophil peroxidase catalyzed protein carbamylation par-
ticipates in asthma*. The Journal of Biological Chemistry 291
(42):22118–35. doi: 10.1074/jbc.M116.750034.
Critical Reviews in Food Science and Nutrition 31
Wright, G. D. 2019. Unlocking the potential of natural products in
drug discovery. Microbial Biotechnology 12 (1):55–57. doi:
10.1111/1751-7915.13351.
Wu, G., H. Zhu, X. Wu, L. Liu, X. Ma, Y. Yuan, X. Fu, L. Zhang, Y.
Lv, D. Li, et  al. 2020. Anti-allergic function of α-Tocopherol is
mediated by suppression of PI3K-PKB activity in mast cells in
mouse model of allergic rhinitis. Allergologia et Immunopathologia
48 (4):395–400. doi: 10.1016/j.aller.2019.11.005.
Wu, Y.-M., Z.-W. Xue, L.-L. Zhang, N.-M. Gao, X.-M. Du, X.-Y.
Zhang, Z.-H. Zhang, and Z.-G. Zhang. 2016. Comparable function
of γ-tocopherols in asthma remission by affecting eotaxin and
IL-4. Advances in Clinical and Experimental Medicine: Official
Organ Wroclaw Medical University 25 (4):643–8. doi: 10.17219/
acem/41191.
Wynn, T. A. 2011. Integrating mechanisms of pulmonary fibrosis. The
Journal of Experimental Medicine 208 (7):1339–50. doi: 10.1084/
jem.20110551.
Xu, S., B.-P. Tian, L.-H. Zhang, W. Hua, L.-X. Xia, Z.-H. Chen, W.
Li, and H.-H. Shen. 2013. Prevention of allergic airway hyperres-
ponsiveness and remodeling in mice by Astragaliradix Antiasthmatic
decoction. BMC Complementary and Alternative Medicine 13:369.
doi: 10.1186/1472-6882-13-369.
Yao, Y., Y. Yuan, Z. Lu, Y. Ma, Y. Xie, M. Wang, F. Liu, C. Zhu, and
C. Lin. 2021. Effects of Nervilia fordii extract on pulmonary fibro-
sis through TGF-β/Smad signaling pathway. Frontiers in Pharmacology
12:659627. doi: 10.3389/FPHAR.2021.659627.
Ye, L., H. Wang, H. Li, H. Liu, T. Lv, Y. Song, and F. Zhang. 2019.
Eosinophil peroxidase over-expression predicts the clinical outcome
of patients with primary lung adenocarcinoma. Journal of Cancer
10 (4):1032–8. doi: 10.7150/jca.24314.
Yhee, J. Y., J. Im, and R. S. Nho. 2016. Advanced therapeutic strategies
for chronic lung disease using nanoparticle-based drug delivery.
Journal of Clinical Medicine 5 (9):82. doi: 10.3390/jcm5090082.
Zhou, H.-X., X.-M. Ou, Y.-J. Tang, L. Wang, and Y.-L. Feng. 2015.
Advanced chronic obstructive pulmonary disease: Innovative and
integrated management approaches. Chinese Medical Journal 128
(21):2952–9. doi: 10.4103/0366-6999.168073.
Zhou, M. X., G. H. Li, B. Sun, Y. W. Xu, A. L. Li, Y. R. Li, D. M.
Ren, X. N. Wang, X. Sen Wen, H. X. Lou, et  al. 2018. Identification
of novel Nrf2 activators from Cinnamomum chartophyllum H.W.
Li and their potential application of preventing oxidative insults in
human lung epithelial cells. Redox Biology 14:154–163. doi: 10.1016/j.
redox.2017.09.004.
Zoratti, E. M., and G. T. O’Connor. 2020. New therapeutic strategies
for asthma. JAMA 323 (6):517–8. doi: 10.1001/jama.2019.19985.