Pulmonary fibrosis

Introduction 
Pulmonary fibrosis is a lung disease that is refractory to treatment and carries a
high mortality rate. It includes a heterogeneous group of lung disorders
characterized by the progressive and irreversible destruction of lung architecture
caused by scar formation that ultimately leads to organ malfunction, disruption of
gas exchange, and death from respiratory failure. Idiopathic pulmonary fibrosis
(IPF), a particularly severe form of pulmonary fibrosis with unknown etiology has
a life expectancy of 2–6 year after diagnosis. Lung fibrosis can also develop after
viral infections and after exposure to radiotherapy, chemotherapeutic drugs, and
aerosolized environmental toxins. It also occurs in some bone marrow transplant
recipients suffering from chronic graft versus host disease and in a subset of
individuals with chronic inflammatory diseases like scleroderma and rheumatoid
arthritis [1].

Epidemiology
It is remarkably that the clinical results of pulmonary fibrosis (PF) were usually
observed in patients with severe acute respiratory syndrome and Middle Eastern
respiratory syndrome. Bilateral extensive lung damage and diffuse damage to
alveoli and cells is a risky factor, as it disrupts lung recovery in patients who have
suffered coronavirus. Patients with a higher risk of PF are, as a rule, elderly men,
active smokers with underlying diseases, including diabetes mellitus, lung and
cardiovascular diseases.

Statistics on the spread of the disease may vary among the population of different
ethnic groups and countries. Nevertheless, a large number of studies have shown
that the frequency and prevalence of IPF is increasing and older people are at risk.
Special “case-control” studies have determined that a number of factors increase
the likelihood of this disease. For example, cigarette smoking, exposure to metal
and wood dust, exposure to silica and agriculture are the causative agents of IPF
[2].

A recent study collecting data from US Medicare beneficiaries aged 65 years or

older between 2001 and 2011 has shown much higher rates than previously
described. In the observed period incidence has remained stable, whereas
prevalence appears on the rise. In the UK, a first study reported an incidence of 4.6
per 100 000/year by retrieving cases from a longitudinal primary care database
between 1991 and 2003. A higher incidence of 7.4 per 100 000/year has been
reported in a follow-up study using data from same database (but slightly different
methods for case inclusion) for theperiod of 2000–2009. Importantly, both studies
have showed an increase of incidence rates throughout the observed periods [3].
Pathogenesis
The pathogenesis of pulmonary fibrosis originates after damage to the alveolar
epithelial cells (AECs). Damaged AECs can induce the relevant inflammatory cells
to secrete inflammatory factors. These inflammatory factors can stimulate the
transition of bone marrow (BM) fibrocytes to lung fibroblasts, accelerate the EMT
process, induce the transition of AECs to lung fibroblasts, and promote the
transition of lung fibroblasts to myofibroblasts. Myofibroblasts can secrete a large
amount of collagen, which further accelerates the progression of pulmonary
fibrosis [4].

Repair of damaged tissues is a critical process for survival, because it replaces

dead and injured cells through a biological mechanism. But an unregulated
recovery process can lead to the occurrence of a permanent fibrotic "scar". A
fibrotic scar is a seal resulting from excessive accumulation of extracellular matrix
components in the area of tissue damage. Such components include hyaluronic
acid, fibronectin, proteoglycans and interstitial collagens. Consequently,
fibrogenesis can be called an uncontrolled wound healing reaction [1].

Wound repair has four distinct stages that include a clotting/coagulation phase, an
inflammatory phase, a fibroblast migration/proliferation phase, and a final
remodeling phase where normal tissue architecture is restored. At the earliest
stages after tissue damage, epithelial and/or endothelial cells secrete inflammatory
mediators that initiate a cascade of antifibrinolytic coagulation. As a result of this
response, blood clotting and the development of temporary ECM are triggered.
Platelet aggregation and subsequent degranulation, in turn, contribute to the
expansion of blood vessels and increase permeability. This makes it possible to
effectively attract inflammatory cells (for example, neutrophils, macrophages,
lymphocytes and eosinophils) to the site of damage. The most common
inflammatory cells at the earliest stages of wound healing are neutrophils, but after
the degranulation process they are quickly replaced by macrophages. During the
initial phase of leukocyte migration, activated macrophages and neutrophils
disinfect the wound and kill excess organisms. Inflammatory cells secrete proteins
that are responsible for the onset of proliferation and recruitment of fibroblasts.
The activated fibroblasts then turn into myofibroblasts and secrete smooth muscle
actin for ECM components. At the fourth stage, myofibroblasts create conditions
for reducing wound tightening, and epithelial/endothelial cells divide and move
along a temporary matrix to regenerate damaged tissue. However, in some cases,
scars form on the site of wounds. This happens when the wound is severe, the
stimulus continues to function or the healing process is not controlled, which
explains the complex nature of pulmonary fibrosis. Many types of pulmonary
fibrosis retain most of the inflammatory component throughout the entire period of
the disease. However, IPF is a special form of the disease that shows the
progressive development of the disease without the presence of significant
inflammation. In this case, it has been hypothesized that intrinsic defects in the
wound healing response involving lung epithelial cells and fibroblasts contribute to
the progression of fibrosis [1].

Clinical presentations
The symptoms of pulmonary fibrosis have individual manifestations in each
person. For example, some patients may notice a gradual and slow deterioration of
breathing, while others may face a severe form of pulmonary fibrosis in the early
stages of the disease. Symptoms of acute exacerbation include severe shortness of
breath, fatigue, unreasonable weight loss, dry cough, aching pains in muscles and
joints.
Cough and dyspnoea — common symptoms in patients with IPF — have proven
difficult to treat. Symptoms, including cough, fatigue and, in particu lar, exertional
dyspnoea (and their downstream effects) drive much of the quality of life (QOL)
impairment. Mental anguish and dependence on others generated by living with a
progres sive, incurable disease contribute as well. Among patients, there are
myriad ‘QOL phenotypes’: cough, fatigue and emotional well-being inevitably
burden some patients more than others [5].

Diagnosis
The diagnosis of IPF often requires a multidisciplinary approach, involving
pulmonologists, radiologists, and pathologists experienced in the field of
interstitial lung diseases. When diagnosing this disease, you need to make sure of
the characteristic signs of fibrosis and distinguish it from a number of other lung
diseases. That is, it is necessary to exclude a pattern that refers to the usual
interstitial forms of pneumonia. This type of lung disease differs from pulmonary
fibrosis in that it occurs as a result of exposure to the environment or medications.
Serological evaluation for connective tissue diseases is recommended, even in the
absence of signs or symptoms of such diseases. Blood samples and
bronchoalveolar flushing fluid provide reliable biomarkers for differential
diagnosis or prediction of the outcome of pulmonary fibrosis. IPF has a
heterogeneous clinical course, and patients have a median survival of 2.5–3.5 years
after diagnosis. Worse prognosis is associated with old age (>70 years of age),
smoking history, low body-mass index, severe physio logical impair ment, large
radiological extent of disease, and pulmonary hypertension [6].

Many patients with IPF have a relatively slow clinical course and usually consult
doctors for months to years after the beginning of symptoms (cough and
progressive dyspnoea). At presentation, patients have decreased lung volumes and
capacities, with hypoxaemia at rest that worsens with exercise [6].

Diagnosis is made by a combination of clinical (worsening of dyspnoea within

days to few weeks), physiological (severe decrease of PaO2 in arterial blood), and
radiographical findings (bilateral ground-glass opacities and consolidation
superimposed on a pattern [6].
Treatment
Treatment of pulmonary fibrosis can be divided into two categories such as current
pharmacologic treatments and nonpharmacologic therapy.

Current pharmacologic treatments:

Two antifibrotic therapies have been approved for the treatment of IPF:
pirfenidone and nintedanib. Pirfenidone is a modified small pyridine molecule with
antifibrotic, anti-inflammatory and antioxidant properties [7].

Nintedanib is an intracellular tyrosine kinase inhibitor that binds to adenosine

triphosphate binding sites. As a result, signaling pathways associated with vascular
endothelial growth factor receptor, fibroblast growth factor receptor 1-3, and
platelet growth factor receptor α and β are suppressed. These effects on receptor
tyrosine kinases lead to a decrease in the activity of fibroblasts [7].

Thus, either nintedanib or pirfenidone are a good choice as the main treatment for
IPF inhibitors at present. On the one hand, these two drugs are able to slow down
the deterioration of the FVC and provide the patient with greater comfort for a
noticeably longer time. On the other hand, the use of these drugs can lead to high
out-of-pocket expenses without noticeable progress in treatment, to high mortality
within 3-5 years after diagnosis. Some patients may not respond to these drugs,
and in light of their cost and side effect profile, studies are being conducted to
determine when these tyrosine kinase inhibitors may be useless [7].

Nonpharmacologic therapy: lung transplantation

Some patients may have a particularly complex form of pulmonary fibrosis, which
requires mandatory surgical intervention. In such cases, lung transplantation may
be a viable treatment option for IPF. A key advantage compared with other modes
of treatment is that it is the only method to improve both symptoms and survival
time [7].

Determining the need for transplant is challenging, but in selecting IPF patients for
transplant, risk of mortality and likelihood of survival after transplantation are key
considerations. Furthermore, other comorbidities that may lead to complications
such as cardiac dysfunction, GERD, diabetes, and obesity must be taken into
account. Among the key criteria for placement on the transplant list are rapid
decline in FVC or DLCO, oxygen desaturation, or decrease in distance covered
during 6‐min walk test, pulmonary hypertension, or hospitalization due to
respiratory decline, pneumothorax, or acute exacerbation [7].

Summary
Pulmonary fibrosis is a serious disease associated with various inflammatory cell
types that lead to changes in the structure of the lungs, deterioration of gas
exchange and the manifestation of adverse symptoms. Nowadays, an effective
treatment has not yet been found to combat the frequent mortality due to this
disease. Therefore, it is important to study in detail the mechanism of cases when
wound healing becomes an uncontrolled biological process and leads to
progressive pulmonary fibrosis.
There is an urgent need for more attention and in‐depth research into development
of targeted treatments that prolong life and improve quality of life for persons with
IPF. Pirfenidone and nintedanib are the two antifibrotic agents currently available
for the treatment IPF. At this time, only lung transplant can alter its relentless
course. Novel treatments under evaluation include pentraxin, pamrevulmab
(monoclonal antibody against CTGF), and ATX inhibitors.

Gene and protein expression profiling is beginning to generate information on the

mechanisms that result in lung damage in IPF. The clinical and research
communities must come together to find better ways to regulate fibrotic and
inflammatory responses in the IPF lung [7].

References:

1. https://rupress.org/jem/article/208/7/1339/41120/Integrating-mechanisms-
of-pulmonary
2. https://pubmed.ncbi.nlm.nih.gov/28345383/
3. https://onlinelibrary.wiley.com/doi/epdf/10.1111/resp.12683
4. https://pubmed.ncbi.nlm.nih.gov/33312337/
5. https://www.nature.com/articles/nrdp201774
6. https://pubmed.ncbi.nlm.nih.gov/21719092/
7. https://pubmed.ncbi.nlm.nih.gov/35001525/