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Global T
Global Translational Medicineranslational Medicine Risk factors of idiopathic pulmonary fibrosis
Risk factors of idiopathic pulmonary fibrosis

of three microRNAs: miR199a-5p, miR199a-3p, and miR- pamrevlumab was found to reduce mortality and improve
214-3p, which are formed during DNM3OS splicing and lung function in patients taking this drug, as compared
enhance TGF-β1 signaling through TGF-β1/SMAD and with the placebo group .
[64]
TGF-β1/β-catenin pathway, leading to the development GLPG1690 is an inhibitor of autotoxin, an enzyme that
and progression of fibrosis . Inhibition of lncRNA ZFAS1 hydrolyses lysophosphatidylcholine to lysophosphatidic
[58]
resulted in a decrease in lipid peroxidation (LPO), TGF- acid, which has a profibrotic effect. Clinical trials of this
β1-activated migration of HFL1 fibroblasts, and a more inhibitor were terminated due to unsatisfactory safety
favorable course of bleomycin-induced pulmonary fibrosis profile .
[63]
in mice due to the sequestration of miR-150-5p, which has
[59]
inhibitory activity against SLC38A1 (LPO controller) . TD139 is an inhibitor of galectin-3, a profibrotic protein
Li et al. identified groups of genes whose co-expression receptor on the cell membrane of macrophages. This drug
[60]
[66]
is associated with both SARS-CoV-2 infection and the is undergoing phase 2b clinical trials .
development of IPF, while their expression is largely There are a number of drugs that could inhibit
regulated by m6A (N6-methyladenosine), which is one of the activity of TGF-β1, JAK 1, JAK 2, JAK 3, ROCK2,
the most common mRNA modifications in mammalian HSP47, JNK, NOX1, and NOX4 signaling pathways
cells. (drugs rhPTX-2/PRM-151, Jaktinib Dihydrochloride
Patients with IPF are more susceptible to COVID-19, Monohydrate, KD025/SLx-2119, ND-L02-s0201/
and patients who have had this infectious disease are at an BMS-986263, CC-90001, GKT137831, respectively).
increased risk of developing pulmonary fibrosis, which, in These drugs are undergoing phase 2 clinical trials. The
addition to gene expression features, is due to the presence promising treatment is the use of small interfering RNAs,
of immune cell infiltrate in the lung tissue, represented in particular TRK-250, which suppresses the expression of
by natural killer cells, mast cells, M2-macrophages, and the TGF-β1 gene (Phase 1 clinical trials). The possibility
gamma delta T (γδT) cells that secret profibrotic cytokines. of using monoclonal antibodies against ILs, lysyl oxidase,
The development of pulmonary fibrosis after COVID- integrins, and leukotriene antagonists for IPF therapy is
19 is also facilitated by high levels of IL-6, IL-1, TGF-β1, being studied [63,65] .
TNF-α, and other pro-inflammatory cytokines, which are Biomarkers to differentiate IPF patients from healthy
secreted as a result of viral infection [61,62] . people include Krebs von den Lungen (KL-6), a high-

4. IPF therapy and biomarkers molecular weight glycoprotein on the surface of alveolar
epithelium, chitinase-like protein (YKL40), surfactant
At present, two pharmacological drugs are used for proteins, mainly (SP)-A, -D, less -B, lysyl oxidase-like
the treatment of pulmonary fibrosis. However, they are proteins, and genetic markers, such as polymorphisms of
only able to slow down the progression of the disease. the MUC5B, TERT, and TERC genes. MMP1 and MMP7
Pirfenidone is a modified pyridine molecule that reduces are also prognostic markers; their concentration in the
collagen synthesis by fibroblasts, suppresses TGF-β1 and blood are correlated with the severity of the disease [65,67,68] .
TNF-α, and has an antifibrotic and antioxidant effect. Circulating immune cells can also be a biomarker of IPF; a
Nintedanib is an inhibitor of receptors with tyrosine kinase higher level of monocytes in blood is correlated with more
activity, namely receptors for endothelial growth factor 1 – severe IPF type and increased mortality risk .
[69]
3 (EGF 1 – 3), receptors for FGF 1 – 3, and platelet-derived
growth factor receptor a and b (PDGFRA, PDGFRB), 5. Conclusion
which suppresses proliferation, fibroblast migration, and The development of pulmonary fibrotic processes involves
differentiation into myofibroblasts. Both of them have been both genetic mechanisms (genes encoding signaling
proven to be effective during phase 3 clinical trials [63,64] . pathway proteins that activate fibroblast proliferation
Pentraxin 2 is one of the plasma acute phase proteins. and extracellular matrix synthesis) and non-genetic
It suppresses the transformation of monocytes into mechanisms (immune) featuring the secretion of TGF-β,
macrophages and fibrocytes, as well as inhibits the pro-inflammatory, and profibrotic cytokines. LncRNAs,
synthesis of TGF-β1. The level of pentraxin 2 is reduced in being an important epigenetic regulator, also contribute
patients with IPF; at present, the recombinant protein drug to the development of pulmonary fibrosis, including the
is at phase 3 clinical trials [63,65] . idiopathic variant, which is presented in the current review.
Pamrevlumab is a monoclonal antibody against At present, our research group is studying the role
connective tissue growth factor. The drug is now at phase 3 of lncRNAs TP53TG1, LINC00342, RP11-363E7.4 and
clinical trials. Based on earlier phases of the clinical trials, others in the pathogenesis of IPF and COVID-19-induced

Volume 1 Issue 2 (2022) 7 https://doi.org/10.36922/gtm.v1i2.107