Page 66 - GTM-1-2

Global Translational Medicine Risk factors of idiopathic pulmonary fibrosis

1. Introduction 2. Non-genetic factors in the development

Fibrosis is a pathological process of wound healing in and progression of IPF
which connective tissue replaces the normal parenchymal 2.1. Risk factors and pathogenesis
tissue by increasing extracellular matrix synthesis and
proliferation of fibroblasts. This leads to a considerable Approximately 1/3 of new IPF cases and the progression
level of tissue remodeling and formation of permanent scar cases are etiologically linked to non-genetic factors. The
on tissues and organs, contributing to the remodeling of main risk factors for IPF are older age, male sex, smoking,
organ and damages to its histo- and cyto-architecture. In and living in unfavorable environmental surroundings.
clinical setting, signs of functional disorders or even organ Aging of type 1 alveolocytes and fibroblasts, metabolic
failure could be observed in patients with this condition. dysfunction of cellular proteins, and damage of subcellular
[6]
In short, fibrosis is the outcome of chronic inflammation, structures are potential risk factors of lung tissue fibrosis .
frequent tissue damage followed by proliferation processes, Such alterations lead to the release of mediators from
systemic connective tissue diseases, autoimmune diseases, epithelium, endothelium and connective tissue cells that
tissue necrosis, and atrophy due to ischemia and metabolic activate immunocompetent cells, such as polymorphic
disorders [1,2] . nuclear leukocytes, lymphocytes, monocytes, and
macrophages (Figure 1). When the vascular wall is impaired
Idiopathic pulmonary fibrosis (IPF) is a chronic and the blood coagulation cascade is activated, factor X is
progressive lung disease characterized by the destruction able to induce the differentiation of lung myofibroblasts,
of the acinar structure, the growth of the extracellular and thrombin (factor II) activates the production of the
matrix, and other properties of the fibrotic disease, and is chemokine (C-C motif) ligand 2, along with low molecular
histologically similar to interstitial pneumonia. Respiratory weight hyaluronic acid (LMWHA) and inflammatory
failure develops in patients with IPF, which in some cases mediators, such as interleukin (IL)-1β, IL-6, IL-25, IL-33,
could be fatal. IPF shares some similarities with COVID-19- which are chemoattractant for myelocytes and monocytes
induced pulmonary fibrosis. However, the mechanisms of the that could further differentiate into macrophages .
[8]
occurrence of both IPF and COVID-19-induced pulmonary
fibrosis are poorly understood. Of particular scientific 2.2. The role of macrophages in fibrosis
interest are the mechanisms that are somehow associated development
with the function of long non-coding RNA (lncRNA), the Under the influence of LMWHA, interferon gamma (IFN-γ),
role of which in the occurrence and progression of fibrotic ligands of toll-like receptors, macrophages are activated along
processes in various organs is being actively studied [3,4] . the classical pathway. The secreted active forms of nitrogen,
The discovery of new lncRNA-associated molecular oxygen, tumor necrosis factor alpha (TNF-α) and IL-1β are
mechanisms that are responsible for the pathogenesis of IPF strong tissue pro-inflammatory agents. IL-1β is responsible
and COVID-19-induced pulmonary fibrosis would facilitate for the transition of epithelial cells to mesenchymal cells, as
the development of diagnostic systems for predicting the
risk and severity of the disease and the formulation of well as for the induction of myofibroblasts. TNF-α stimulates
therapeutic measures which can target key pathogenic the expression of IL-6, an autocrine stimulator of fibroblast
factor with minimal side effects. growth. There is also an alternative pathway for macrophage
activation, which is induced by granulocyte-macrophage
IPF is the most common form of visceral fibrosis. colony-stimulating factor, IL-4, and IL-13. As a result, the
According to meta-analyses, the incidence of IPF in Europe expression of the enzyme arginase-1 (Arg1) increases, as
and North America is 3 – 9 cases/100,000 population per demonstrated in in vitro and murine experiments. This leads
year (according to other sources, up to 18 cases ), whereas to the increase of L-proline concentration, which is necessary
[5]
<4 cases/100,000 population per year were reported in for the synthesis of collagen fibers .
[9]
South America and East Asia. The prevalence of the disease
in North America is 10 – 60 cases/100,000 population per 2.3. The role of other immune cells in fibrosis
year. In total, there are about 3 million patients with IPF development
worldwide, while there is an increase in the number of Fibroblast growth factor (FGF)-2, FGF-10, FGF-9, and
patient visits to hospitals and the frequency of deaths. In FGF-18 may also contribute to the development of IPF .
[10]
addition, IPF is more common in men, with a median age The role of eosinophils in the development of pulmonary
of 65 years [6,7] . fibrosis in allergy as well as IPF is attributed to their ability
The goal of the review is to summarize the genetic and to synthesize transforming growth factor beta 1 (TGF-β1)
non-genetic risk factors that contribute to IPF development and IL-13, which was confirmed in a study on mice [8,9] .
and the role of lncRNA in this disease. According to a meta-analysis by Wynn and Ramalingam ,
[1]

Volume 1 Issue 2 (2022) 2 https://doi.org/10.36922/gtm.v1i2.107