Facing Forward: Science and Arts in

Respiratory Medicine
FR
Real World Evidence of Vitamin D and Glutathione
FABRIKAM RESIDENCES
Use in Respiratory Disease
Fathiyah Isbaniah
Department Pulmonology and Respiratory Medicine
Faculty of Medicine, University of Indonesia
Jakarta, February 2022
Introduction
• A seco-steroid hormone important in bone mineralization and
calcium homeostasis
• May play a role in multiple chronic diseases such as cancer,
autoimmune diseases, infections, cardiovascular disorders and
respiratory system
• A large cross-sectional study of the U.S. population in the NHANES III
 Higher vitamin D concentrations  better lung function
• Vitamin D improves lung function  regulating inflammation,
inducing antimicrobial peptides, and/or its action on muscle
• Asthma, COPD, cystic fibrosis, and respiratory infections
• ↓ maternal vitamin D status during pregnancy or during early
childhood  ↑ the risk of asthma and wheezing
• Vitamin D deficiency has been associated with ↓ lung function
in COPD and CF patients
• Studies have shown an association between vitamin D
deficiency and infections such as Mycobacterium tuberculosis
and upper respiratory tract infections
• The majority of these studies : cross-sectional by design, with
only a limited number of prospective randomized clinical trials
Mechanisms of Action of Pulmonary Vitamin D
• The bronchial epithelium and immune cells can convert the
circulating precursor 25-dihydroxyvita- min D3 (25(OH)D3) to local
active 1,25(OH)D3
• 1,25(OH)D3 ↓ production of inflammatory cytokines (such as
interleukin-8 (IL-8)) and chemokines (leucocyte attracting CXCL10)
from stimulated epithelial cells by modulating the nuclear factor κB
axis
• Vitamin D promotes innate immune responses essential for the early
protection against pathogens  enhancing the synthesis of
antimicrobial peptides such as cathelicidin and other vitamin D
regulated molecules with antibacterial, antimycobacterial and
antiviral actions
• Vitamin D promotes autophagy, the cellular digestion of
intracellular macro- molecules and inclusions, in parenchymal and
mononuclear immune cells
• Vitamin D ↓ expression of costimulatory molecules  positive T-
cell receptor signalling, and pro-inflammatory cytokines (eg, IL-
12) by antigen-presenting cells, ↓ their ability to promote
adaptive immune responses
• Vitamin D also regulates adaptive lymphocyte responses,
inhibiting lymphocyte proliferation and cytokine production in
pro-inflammatory T helper 1 (Th1) and Th17 responses
• ↑ levels of local 1,25(OH)D3 during the immune response to
a bronchial infection will boost innate immune responses and
then regulate adaptive responses to prevent an excessive
response
• Vitamin D insufficiency is thought to lead to more severe
exacerbations in asthma and COPD as a result of an impaired
innate response to the pathogen  by an excessive adaptive
immune response with ↑ production of inflammatory
cytokines and ↑ bronchial inflammation
The Role of Vitamin D in Respiratory Diseases
Acute Lung Injury
•Characteristics of acute lung injury are ↑ vascular leakage, pulmonary edema,
diffuse pulmonary infiltrates, reduced lung compliance, and release of
proinflammatory mediators
•Hongguang Nie et al. study reported the effect of vitamin-D on augmentation of
alveolar fluid clearance and ultimately ameliorating edema by alleviating
epithelial Na+ channel activity
•Juon Kong et al. experimental study provided an evidence that Vit D/VDR
signalling attenuate acute lung injury induced by LPS by targeting Ang-2-Tie-2
signalling and renin-angiotensin pathway
•Jun Xu et al. investigated the function of vitamin-D in alleviating LPS induce ALI
via regulation of the renin-angiotensin system (RAS).
•Shi et al. demonstrated the protective effect of vitamin-D by maintaining the
integrity of the epithelial barrier
Pneumonia
•Mamani et al. patients with Vit D deficiency might develop more severe
CAP, after that they have spent long duration in hospitals and ICU
•Huang et al. patients having low Vit D and acute ischemic stroke upon
admission to the hospital are more likely to get stroke-associated
pneumonia  the risk of Pneumonia increases as Vit D level ↓
•Tsujino et al, the annihilation of IL-1 and expression of SPP1 in these cells
 Vit D intake might prevent interstitial pneumonia by inhibiting
pulmonary fibrosis
•In some retrospective studies vitamin-D levels have been found to be
correlated with the development and progression of Pneumonia but they
are inconclusive
Cystic and Pulmonary Fibrosis
•Vit D deficiency is linked with pulmonary fibrosis and lung function
impairment, but the underlying mechanism is still unknown
•Studies show that 90% of CF cases have Vit D deficiency
•Study recommended Vit D supplementation in CF patients with P.
aeruginosa infection because of its anti- inflammatory effects through a
reduction in IL-17A and IL-23
•Vit D with DNA damaging agents may be used as an antifibrogenic agent
for pulmonary fibrosis
•Study shows an increase in Vit D serum levels can decrease pulmonary
exacerbations
Asthma
•Mohammed et al. found that exogenous administration of Vit D might help
to improve response to glucocorticoids in certain genetically predisposed
asthma patients
•An experimental study shows ↓ in the serum IL-17A levels and elevation of
IL-10 levels in asthma patients upon Vit D supplementation
•Administration of vitamin-D in a murine model of asthma inhibits airway
inflammation, ↓ IL4 level, hindrance in T-cell migration, and ↓ the
inflammatory response
•Experimental study found that Vit D supplementation ↓ airway remodelling
by downregulation of Wnt/β-catenin signalling pathway
•A group of researchers found alleviation in airway inflammation of
neutrophilic asthma in mouse on Vit D supplementation via transcriptional
alternation of interleukin-17A
Chronic Obstructive Pulmonary Disease (COPD)
•COPD  an inflammatory disorder of the pulmonary system, is a chronic
respiratory disease characterized by persistent breathing problems, airflow
limitation, and aberrant inflammation
•Aberrant inflammation  the activation of innate and adaptive immune
defence cells, and structural cells (epithelial and endothelial cells)  chronic
inflammation
•Activated inflammatory pathways  secretion of proinflammatory cytokines
such as Interleukin-1β (IL1β), IL6, IL8, TNF- α, and chemokines (monocyte
chemoattractant protein-1 (MCP1)  aggregation of more neutrophils,
monocyte and T-lymphocyte immune defence cells into the lung tissue
chronic inflammation
• Immune defence cells: neutrophils, macrophages and alveolar epithelial cells
release micropeptides such as cathelicidin, defensin β2  promotes the
death of invading bacteria and viruses  impaired phagocytosis of apoptotic
cells and increase bacterial load  impairment in lung tissue facilitate
colonization of bacteria and viruses in lower affected respiratory tract 
worsening of the disease
• A deficient level of Vit D  progression of pathogenic processes 
inflammation modulation, excessive oxidative stress, ↑ expression of
proteases, impaired host defence, and lung airways remodelling
• Leuhouck et al., supplementation of vitamin-D significantly ↓ the number of
exacerbations in severely Vit D deficient COPD patients
• Emphysema develops early in VDR knockout mice due to ↑ in
production of several matrix metalloproteinases (MMP2, MMP9, and
MMP12) and leads to imbalance in protease/antiprotease expression
• Vitamin-D also inhibits TGF-b1 signalling pathway responsible for
fibrosis in COPD
• Vitamin-D stimulated Nrf2 expression  improves the phagocytotic
potential of alveolar macrophages in COPD patients
• Double-blind placebo control randomized clinical trial  oral
administration of vitamin-D ↓ COPD exacerbation and improves FEV1
in severe COPD patients
the pathways which are involved in COPD pathogenesis and vitamin-D
involvement in modulating all these pathways to ameliorate COPD
Tuberculosis
•The first in vitro studies looking at vitamin D and M. tuberculosis were published
in the 1980s  adding 1,25D to M. tuberculosis-infected human monocytes and
macrophages reduced the intracellular bacterial load
•Series of observational studies suggesting that individuals with low 25D levels are
more susceptible to M. tuberculosis infection and often have a more severe course
of disease
•Case-control studies have also found an association between VDR polymorphisms
and susceptibility to tuberculosis, in particular, in individuals with low 25D levels
•A vitamin D-induced antimicrobial peptide (cathelicidin)  as a key role.
•Study of peripheral blood monocytes infected with recombinant mycobacteria,
vitamin D strongly induced cathelicidin mRNA and reduced the growth of
mycobacteria in a dose-dependent fashion
• Study showed a direct correlation between serum 25D levels and monocyte
expression of cathelicidin following treatment with TLR 2/1 and TLR 4 ligands
• Strong interrelation of seasonal variations in serum levels of Vit D and
incidence of TB has been demonstrated by two epidemiological studies.
• A metanalysis study : ↑ risk of TB, associated with ↓ Vit D status
• Immunomodulatory actions  inclusive of stimulation of innate antimicrobial
effector responses and anti- inflammatory pathways
• Activated Vit D stimulates cathelicidin and IFN γ mediated, oxidative species
induced, and phagolysosome promoting antimicrobial activity of macrophages
against Mycobacterium tuberculosis
• Rook et al. the first evidence of Vit D mediated immunity against
Mycobacterium tuberculosis  proliferation of macrophages ↓ upon
their treatment with Vit D and was further ↓ upon addition of cytokine,
IFN-g, and CYP27B1 (macrophage stimulator)
• Liu et al. demonstrated an increased in vitro and in vivo expression of
VDR and CYP27B1 after sensing Mycobacterium tuberculosis via
TLR2/1
• Macrophages possess Vit D VDRs on its surface and interactions
between macrophages and Mycobacterium tuberculosis enhance the
expression of 1-α-hydroxylase (CYP27B1), VDR, and cathelicidin via
activating Toll-like receptor I &II  Vit D induces the production of
cathelicidin and β-defensin 2(antimicrobial peptides)  recruits
monocytes, neutrophils, and T cells to the site of infection and exerts
immunomodulatory effects
• Studies have shown that Vit D treatment of PBMCs ↓ the expression of
MMP-7, MMP-9, and MMP-10, along with ↑ in expression of TIMP-1 
abrogating tissue damage and symptomatic relief during infection
• Vit D deficiency ↑ the susceptibility of patients to TB along with the risk of
conversion of latent to the active state of the disease  suggesting its use as
a prophylaxis in patients with latent TB
Vitamin-D mediated immune response against Mycobacterium tuberculosis infection
Initial clinical associations and early trials
suggest that vitamin D may be beneficial as an
adjunctive treatment to the traditional therapy
in patients with TB; however, additional
randomized trials need to be con- ducted to
clarify the role of vitamin D.
Gluthatione
• Glutathione is a potent antioxidant compound and detoxifying agent that
is produced in the cytoplasm of every cell of the human body
• Concentrated in the kidneys and in mucosal secretions of the intestinal
lining and lungs. It is present inside cells and in extracellular fluids
• Glutathione is a tripeptide molecule, composed of the amino acids
glutamate, cysteine, and glycine
• GSH contains a thiol group (—SH), making it an effective electron donor
to neutralize lipid peroxides, hydrogen peroxide, and other reactive
oxygen species
• GSSH is then recycled back to GSH with help from the enzyme glutathione
reductase and electrons donated from the reduced form of nicotinamide
adenine dinucleotide phosphate (NADPH)
Lung Diseases associated with glutathione deficiency
 Thank You.
FR
FABRIKAM RESIDENCES
fathiyahisbaniah

fathiyah21@gmail.com