AccScience Publishing / GTM / Volume 1 / Issue 2 / DOI: 10.36922/gtm.v1i2.107
Cite this article
Journal Browser
Volume | Year
News and Announcements
View All

Genetic and non-genetic risk factors of idiopathic pulmonary fibrosis: A review

Shamil R. Zulkarneev1 Rustem H. Zulkarneev1* Gulnaz Faritovna Korytina2,3 Irshat A. Gibadullin4 Arthur M. Avzaletdinov4 Zhihui Niu5 Jiayu Guo5 Yulia Genadievna Aznabaeva1 Guzel M. Nurtdinova1 Naufal Shamilevich Zagidullin1
Show Less
1 Department of Internal Diseases, Bashkir State Medical University, Ufa, 450008, Russian Federation
2 Institute of Biochemistry and Genetics - Subdivision of the Ufa Federal Research Centre of the Russian Academy of Sciences, IBG UFRC RAS, Laboratory of Physiological Genetics, Ufa, 450054, Russian Federation
3 Department of Biology, Bashkir State Medical University, Ufa, 450008, Russian Federation
4 Department of Hospital Surgery, Bashkir State Medical University, Republic of Bashkortostan, Ufa, 450008, Russian Federation
5 Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang 150081, China
Global Translational Medicine 2022, 1(2), 107
Submitted: 22 May 2022 | Accepted: 2 September 2022 | Published: 26 September 2022
© 2022 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( )

Idiopathic pulmonary fibrosis (IPF) is the most common form of fibrosis of internal organs. The etiology and pathogenesis of IPF are still not well understood. However, a growing line of evidence shows that both genetic and non-genetic factors contribute to IPF development. The release of pro-inflammatory cytokines activates the immune cells. The enhanced synthesis of interleukins and cytokines, especially transforming growth factor β1 leads to the proliferation of fibroblasts, increased extracellular matrix formation, and epithelial-mesenchymal transformation of the lung tissue. These pathological changes could lead to fibrosis. Polymorphisms of genes responsible for the function of mucociliary clearance (MUC5B), telomerases (TERT, TERC), as well as signaling pathway related-genes such as Sonic hedgehog, Wnt, and some other genes are also risk factors for IPF development. Epigenetic regulatory mechanisms, such as methylation and acetylation of DNA and histones, may also influence the development and progression of this disease. At present, the role of non-coding RNAs, in particular long non-coding RNAs (lncRNA) in the development of fibrotic processes, is actively studied. LncRNA is an RNA that is longer than 200 base pairs and does not code for any proteins. LncRNAs perform various functions in the cell, from nuclear compartmentation to epigenetic regulation of gene expression and post-translational modification of proteins. In this review, we present the important aspects in the pathogenesis of IPF.

Long non-coding RNAs
Idiopathic pulmonary fibrosis
COVID-19-induced pulmonary fibrosis
Grant of Russian Scientific Foundation 22-25-00019

Wynn TA, Ramalingam TR, 2012, Mechanisms of fibrosis: Therapeutic translation for fibrotic disease. Nat Med, 18: 1028–1040.


Rockey DC, Bell PD, Hill JA, 2015, Fibrosis a common pathway to organ injury and failure. N Engl J Med, 372: 1138–1149. 


Zhao X, Sun J, Chen Y, et al., 2018, LncRNA PFAR promotes lung fibroblast activation and fibrosis by targeting miR-138 to regulate the YAP1-twist axis. Mol Ther, 26: 2206–2217.


Yan W, Wu Q, Yao W, et al., 2017, MiR-503 modulates epithelial-mesenchymal transition in silica-induced pulmonary fibrosis by targeting PI3K p85 and is sponged by lncRNA MALAT1. Sci Rep, 7: 11313.


Richeldi L, Collard HR, Jones MG, 2017, Idiopathic pulmonary fibrosis. Lancet, 389:1941–1952.


Lederer DJ, Martinez FJ, 2018, Idiopathic pulmonary fibrosis. N Engl J Med, 378: 1811–1823.


Martinez FJ, Collard HR, Pardo A, et al., 2017, Idiopathic pulmonary fibrosis. Nat Rev Dis Primers, 3: 17074.


Hirahara K, Aoki A, Morimoto Y, et al., 2019, The immunopathology of lung fibrosis: Amphiregulin-producing pathogenic memory T helper-2 cells control the airway fibrotic responses by inducing eosinophils to secrete osteopontin. Semin Immunopathol, 41: 339–348.


Henderson NC, Rieder F, Wynn TA, 2020, Fibrosis: From mechanisms to medicines. Nature, 587: 555–566.


Chanda D, Otoupalova E, Smith SR, et al., 2019, Developmental pathways in the pathogenesis of lung fibrosis. Mol Aspects Med, 65: 56–69.


Zhu L, Fu X, Chen X, et al., 2017, M2 macrophages induce EMT through the TGF-β/Smad2 signaling pathway. Cell Biol Int, 41: 960–968.


Kugler MC, Joyner AL, Loomis CA, et al., 2015, Sonic hedgehog signaling in the lung. From development to disease. Am J Respir Cell Mol Biol, 52: 1-13.


Yang IV, Pedersen BS, Rabinovich E, et al., 2014, Relationship of DNA methylation and gene expression in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med, 190: 1263–1272.


Bechtel W, McGoohan S, Zeisberg EM, et al., 2010, Methylation determines fibroblast activation and fibrogenesis in the kidney. Nat Med, 16: 544–550.


Xu X, Tan X, Tampe B, et al., 2015, Epigenetic balance of aberrant Rasal1 promoter methylation and hydroxymethylation regulates cardiac fibrosis. Cardiovasc Res, 105: 279–291.


Pastore F, Bhagwat N, Pastore A, et al., 2020, PRMT5 inhibition modulates E2F1 methylation and gene-regulatory networks leading to therapeutic efficacy in JAK2V617F-mutant MPN. Cancer Discov, 10: 1742–1757.


Coward WR, Brand OJ, Pasini A, et al., 2018, Interplay between EZH2 and G9a regulates CXCL10 gene repression in idiopathic pulmonary fibrosis. Am J Respir Cell Mol Biol, 58: 449–460.


Wang Y, Zhang L, Huang T, et al., 2022, The methyl- CpG-binding domain 2 facilitates pulmonary fibrosis by orchestrating fibroblast to myofibroblast differentiation. Eur Respir J, 27: 2003697. 


Yang IV, Pedersen BS, Rabinovich E, et al., 2014, Relationship of DNA methylation and gene expression in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med, 190: 1263–1272.


Sanders YY, Pardo A, Selman M, et al., 2008, Thy-1 promoter hypermethylation: A novel epigenetic pathogenic mechanism in pulmonary fibrosis. Am J Respir Cell Mol Biol, 39: 610–618.


Sun L, Xu A, Li M, et al., 2021, Effect of methylation status of lncRNA-MALAT1 and MicroRNA-146a on pulmonary function and expression level of COX2 in patients with chronic obstructive pulmonary disease. Front Cell Dev Biol, 9: 667624.


Cisneros J, Hagood J, Checa M, et al., 2012, Hypermethylation-mediated silencing of p14(ARF) in fibroblasts from idiopathic pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol, 303: L295–L303.


Zhou J, Yi Z, Fu Q, 2019, Dynamic decreased expression and hypermethylation of secreted frizzled-related protein 1 and 4 over the course of pulmonary fibrosis in mice. Life Sci, 218: 241–252.


Elkouris M, Kontaki H, Stavropoulos A, et al., 2016, SET9- mediated regulation of TGF-β signaling links protein methylation to pulmonary fibrosis. Cell Rep, 15: 2733–2744.


Jiang Y, Xiang C, Zhong F, et al., 2021, Histone H3K27 methyltransferase EZH2 and demethylase JMJD3 regulate hepatic stellate cells activation and liver fibrosis. Theranostics, 11: 361–378.


Irifuku T, Doi S, Sasaki K, et al., 2016, Inhibition of H3K9 histone methyltransferase G9a attenuates renal fibrosis and retains klotho expression. Kidney Int, 89: 147–157. 


Müller D, Győrffy B, 2022, DNA methylation-based diagnostic, prognostic, and predictive biomarkers in colorectal cancer. Biochim Biophys Acta Rev Cancer, 1877: 188722.


Zhang X, Liu H, Zhou JQ, et al., 2022, Modulation of H4K16Ac levels reduces pro-fibrotic gene expression and mitigates lung fibrosis in aged mice. Theranostics, 12: 530–541.


Schuetze KB, McKinsey TA, Long CS, 2014, Targeting cardiac fibroblasts to treat fibrosis of the heart: Focus on HDACs. J Mol Cell Cardiol, 70: 100–107.


Li M, Zheng Y, Yuan H, et al., 2017, Effects of dynamic changes in histone acetylation and deacetylase activity on pulmonary fibrosis. Int Immunopharmacol, 52: 272–280. 


Zheng Q, Lei Y, Hui S, et al., 2022, HDAC3 promotes pulmonary fibrosis by activating NOTCH1 and STAT1 signaling and up-regulating inflammasome components AIM2 and ASC. Cytokine, 153: 155842. 


Saito S, Zhuang Y, Suzuki T, et al., 2019, HDAC8 inhibition ameliorates pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol, 316: L175–L186.


Kim S, Lim JH, Woo CH, 2013, ERK5 inhibition ameliorates pulmonary fibrosis via regulating Smad3 acetylation. Am J Pathol, 183: 1758–1768.


Barnes PJ, Adcock IM, Ito K, 2005, Histone acetylation and deacetylation: Importance in inflammatory lung diseases. Eur Respir J, 25: 552–563.


Peng WX, Koirala P, Mo YY, 2017, LncRNA-mediated regulation of cell signaling in cancer. Oncogene, 36: 5661– 5667.


Zhang P, Wu W, Chen Q, et al., 2019, Non-coding RNAs and their integrated networks. J Integr Bioinform, 16: 20190027.


Ferrè F, Colantoni A, Helmer-Citterich M, 2016, Revealing protein-lncRNA interaction. Brief Bioinform, 17: 106–116. 


Hulshoff MS, Del Monte-Nieto G, Kovacic J, et al., 2019, Non-coding RNA in endothelial-to-mesenchymal transition. Cardiovasc Res, 115: 1716–1731. 


Bridges MC, Daulagala AC, Kourtidis A, 2021, LNCcation: lncRNA localization and function. J Cell Biol, 220: e202009045.


Wang J, Su Z, Lu S, et al., 2018, LncRNA HOXA-AS2 and its molecular mechanisms in human cancer. Clin Chim Acta, 485: 229–233.


Xing C, Sun SG, Yue ZQ, et al., 2021, Role of lncRNA LUCAT1 in cancer. Biomed Pharmacother, 134: 111158. 


Lu Q, Guo Q, Xin M, 2021, LncRNA TP53TG1 promotes the growth and migration of hepatocellular carcinoma cells via activation of ERK signaling. Noncoding RNA, 7: 52. 


Wang H, Zhang Z, Zhang Y, et al., 2021, Long non-coding RNA TP53TG1 upregulates SHCBP1 to promote retinoblastoma progression by sponging miR-33b. Cell Transplant, 30: 9636897211025223. 


Zhang Y, Yang H, Du Y, et al., 2019, Long noncoding RNA TP53TG1 promotes pancreatic ductal adenocarcinoma development by acting as a molecular sponge of microRNA-96. Cancer Sci, 110: 2760–2772. 


Liu R, Yang X, 2021, LncRNA LINC00342 promotes gastric cancer progression by targeting the miR-545-5p/CNPY2 axis. BMC Cancer, 21: 1163.


Shen P, Qu L, Wang J, et al., 2021, LncRNA LINC00342 contributes to the growth and metastasis of colorectal cancer via targeting miR-19a-3p/NPEPL1 axis. Cancer Cell Int, 21:105. 


Chen QF, Kong JL, Zou SC, et al., 2019, LncRNA LINC00342 regulated cell growth and metastasis in non-small cell lung cancer via targeting miR-203a-3p. Eur Rev Med Pharmacol Sci, 23: 7408–7418. 


Lv D, Tan L, Ma H, et al., 2020, WITHDRAWN: LINC00342 promotes thyroid carcinoma progression by targeting miR- 384/CHMP5 pathway. Pathol Res Pract, 223: 153272. 


Chen C, Wang X, Liu T, et al., 2020, Overexpression of long non-coding RNA RP11-363E7.4 inhibits proliferation and invasion in gastric cancer. Cell Biochem Funct, 38: 921–931. 


Jiang X, Ning Q, 2020, The mechanism of lncRNA H19 in fibrosis and its potential as novel therapeutic target. Mech Ageing Dev, 188: 111243. 


Poulet C, Njock MS, Moermans C, et al., 2020, Exosomal long non-coding RNAs in lung diseases. Int J Mol Sci, 21: 3580. 


Xiao T, Zou Z, Xue J, et al., 2021, LncRNA H19-mediated M2 polarization of macrophages promotes myofibroblast differentiation in pulmonary fibrosis induced by arsenic exposure. Environ Pollut, 268: 115810. 


Zhang S, Chen H, Yue D, et al., 2021, Long non-coding RNAs: Promising new targets in pulmonary fibrosis. J Gene Med, 23: e3318. 


Gao Y, Zhang J, Liu Y, et al., 2017, Regulation of TERRA on telomeric and mitochondrial functions in IPF pathogenesis. BMC Pulm Med, 17: 163. 


Li Y, Sun W, Pan H, et al., 2021, LncRNA-PVT1 activates lung fibroblasts via miR-497-5p and is facilitated by FOXM1. Ecotoxicol Environ Saf, 213: 112030. 


Lin S, Zhang R, Xu L, et al., 2020, LncRNA Hoxaas3 promotes lung fibroblast activation and fibrosis by targeting miR-450b-5p to regulate runx1. Cell Death Dis, 11: 706. 


Li X, Yu T, Shan H, et al., 2018, LncRNA PFAL promotes lung fibrosis through CTGF by competitively binding miR- 18a. FASEB J, 32: 5285–5297. 


Savary G, Dewaeles E, Diazzi S, et al., 2019, The long noncoding RNA DNM3OS Is a reservoir of fibromirs with major functions in lung fibroblast response to TGF-β and pulmonary fibrosis. Am J Respir Crit Care Med, 200: 184–198. 


Yang Y, Tai W, Lu N, et al., 2020, LncRNA ZFAS1 promotes lung fibroblast-to-myofibroblast transition and ferroptosis via functioning as a ceRNA through miR-150-5p/SLC38A1 axis. Aging (Albany, NY), 12: 9085–9102. 


Li X, Peng C, Zhu Z, et al., 2021, The networks of m6A-SARS-CoV-2 related genes and immune infiltration patterns in idiopathic pulmonary fibrosis. Aging (Albany, NY), 13: 6273–6288. 


Zhang C, Wu Z, Li JW, et al., 2020, Discharge may not be the end of treatment: Pay attention to pulmonary fibrosis caused by severe COVID-19. J Med Virol, 93: 1378–1386. 


George PM, Wells AU, Jenkins RG, 2020, Pulmonary fibrosis and COVID-19: The potential role for antifibrotic therapy. Lancet Respir Med, 8: 807–815. 


Spagnolo P, Kropski JA, Jones MG, et al., 2021, Idiopathic pulmonary fibrosis: Disease mechanisms and drug development. Pharmacol Ther, 222: 107798. 


Glass DS, Grossfeld D, Renna HA, et al., 2022, Idiopathic pulmonary fibrosis: Current and future treatment. Clin Respir J, 16: 84–96. 


Somogyi V, Chaudhuri N, Torrisi SE, et al., 2019, The therapy of idiopathic pulmonary fibrosis: What is next? Eur Respir Rev, 28: 190021. 


Hirani N, MacKinnon AC, Nicol L, et al., 2021, Target inhibition of galectin-3 by inhaled TD139 in patients with idiopathic pulmonary fibrosis. Eur Respir J, 57: 2002559. 


Guiot J, Moermans C, Henket M, et al., 2017, Blood biomarkers in idiopathic pulmonary fibrosis. Lung, 195: 273–280. 


Drakopanagiotakis F, Wujak L, Wygrecka M, et al., 2018, Biomarkers in idiopathic pulmonary fibrosis. Matrix Biol, 68–69: 404–421. 


Kreuter M, Lee JS, Tzouvelekis A, et al., 2021, Monocyte count as a prognostic biomarker in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med, 204: 74–81.

Conflict of interest
None of the authors has conflicts of interest to report with regard to this manuscript.
Back to top
Global Translational Medicine, Electronic ISSN: 2811-0021 Published by AccScience Publishing