Idiopathic Pulmonary Fibrosis: Current Pathogenetic Insights and Emerging Therapeutic Strategies

Jiying Lou

doi:10.54097/z5p20r16

Authors

Jiying Lou

DOI:

https://doi.org/10.54097/z5p20r16

Keywords:

Idiopathic Pulmonary Fibrosis, Idiopathic Interstitial Pneumonias, Pathogenetic Insights, Emerging Therapeutic Strategies

Abstract

Idiopathic interstitial pneumonias (IIPs) comprise a heterogeneous group of diffuse parenchymal lung disorders, with idiopathic pulmonary fibrosis (IPF) being the most prevalent subtype. Despite its rarity, IPF is associated with a high mortality rate, driving substantial research into its etiology, pathogenesis, diagnostic strategies, and therapeutic interventions. In recent years, multiple novel agents, including the anti-fibrotic candidate PRM-151, have been explored as potential treatments aimed at modifying disease progression and improving patient outcomes.

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References

[1] Agustí, A.G.N., Roca, J., Gea, J., Wagner, P.D., Xaubet, A. and Rodriguez-Roisin, R. (1991). Mechanisms of Gas-exchange Impairment in Idiopathic Pulmonary Fibrosis. American Review of Respiratory Disease, 143(2), pp.219–225. doi: https: // doi.org/10.1164/ajrccm/143.2.219.

[2] Bourke, S.J., Hawkins, T., Keavey, P.M., Gascoigne, A.D. and Corris, P.A. (1993). Ventilation perfusion radionuclide imaging in cryptogenic fibrosing alveolitis. Nuclear Medicine Communications, [online] 14(6), pp.454–464. doi: https:// doi. org/ 10.1097/00006231-199306000- 00008.

[3] Cortes-Telles, A., Forkert, L., O’Donnell, D.E. and Morán-Mendoza, O. (2014). Idiopathic Pulmonary Fibrosis: New Insights to Functional Characteristics at Diagnosis. Canadian Respiratory Journal, 21(3), pp.e55–e60. doi:https://doi.org/ 10.1155/2014/825606.

[4] Datta, A., Scotton, C.J. and Chambers, R.C. (2011). Novel therapeutic approaches for pulmonary fibrosis. British Journal of Pharmacology, 163(1), pp.141–172. doi: https://doi. org/10. 1111/ j.1476-5381.2011.01247. x.

[5] Esposito, D.B., Lanes, S., Donneyong, M., Holick, C.N., Lasky, J.A., Lederer, D., Nathan, S.D., O’Quinn, S., Parker, J. and Tran, T.N. (2015). Idiopathic Pulmonary Fibrosis in United States Automated Claims. Incidence, Prevalence, and Algorithm Validation. American Journal of Respiratory and Critical Care Medicine, 192(10), pp.1200–1207. doi: https://doi. org/10. 1164/ rccm.201504-0818oc.

[6] Finnerty, J.P., Ponnuswamy, A., Dutta, P., Abdelaziz, A. and Kamil, H. (2021). Efficacy of antifibrotic drugs, nintedanib and pirfenidone, in treatment of progressive pulmonary fibrosis in both idiopathic pulmonary fibrosis (IPF) and non-IPF: a systematic review and meta-analysis. BMC Pulmonary Medicine, 21(1). doi:https://doi. org/10. 1186/ s12890-021-01783-1.

[7] Gazdhar, A., Susuri, N., Hostettler, K., Gugger, M., Knudsen, L., Roth, M., Ochs, M. and Geiser, T. (2013). HGF Expressing Stem Cells in Usual Interstitial Pneumonia Originate from the Bone Marrow and Are Antifibrotic. PLoS ONE, [online] 8(6), p.e65453. doi:https:// doi.org/10. 1371/ journal. pone.0065453.

[8] Germano, D., Przemyslaw Blyszczuk, Valaperti, A., Kania, G., Dirnhofer, S., Landmesser, U., Lüscher, T.F., Hunziker, L., Zulewski, H. and Eriksson, U. (2009). Prominin-1/CD133+ Lung Epithelial Progenitors Protect from Bleomycin-induced Pulmonary Fibrosis. American Journal of Respiratory and Critical Care Medicine, 179(10), pp.939–949. doi: https:// doi.org/10.1164/rccm.200809-1390oc.

[9] Glass, D.S., Grossfeld, D., Renna, H.A., Agarwala, P., Spiegler, P., DeLeon, J. and Reiss, A.B. (2022). Idiopathic pulmonary fibrosis: Current and future treatment. The Clinical Respiratory Journal, 16(2), pp.84–96. doi:https:// doi.org/10.1111/ crj. 13466.

[10] Glassberg, M.K., Minkiewicz, J., Toonkel, R.L., Simonet, E.S., Rubio, G.A., DiFede, D., Shafazand, S., Khan, A., Pujol, M.V., LaRussa, V.F., Lancaster, L.H., Rosen, G.D., Fishman, J., Mageto, Y.N., Mendizabal, A. and Hare, J.M. (2017). Allogeneic Human Mesenchymal Stem Cells in Patients With Idiopathic Pulmonary Fibrosis via Intravenous Delivery (AETHER). Chest, [online] 151(5), pp.971–981. doi:https://doi. org/10.1016/j.chest.2016.10.061.

[11] Günther, A., Schmidt, R., Nix, F., Yabut-Perez, M., Guth, C., Rosseau, S., Siebert, C., Grimminger, F., Morr, H., Velcovsky, H.G. and Seeger, W. (1999). Surfactant abnormalities in idiopathic pulmonary fibrosis, hypersensitivity pneumonitis and sarcoidosis. The European Respiratory Journal, [online] 14(3), pp.565–573. doi:https://doi.org/10.1034/j.1399- 3003.1999. 14c 14.x.

[12] Hettiarachchi, S.U., Li, Y.-H., Roy, J., Zhang, F., Puchulu-Campanella, E., Lindeman, S.D., Madduri Srinivasarao, Konstantin Tsoyi, Liu, Z., Ayaub, E.A., Nickerson-Nutter, C., Rosas, I.O. and Low, P.S. (2020). Targeted inhibition of PI3 kinase/mTOR specifically in fibrotic lung fibroblasts suppresses pulmonary fibrosis in experimental models. Science Translational Medicine, 12(567). doi:https://doi.org/ 10.1126/ scitranslmed.aay3724.

[13] Hirani, N., MacKinnon, A.C., Nicol, L., Ford, P.J., Hans Thalsgaard Schambye, Anders Gorm Pedersen, Nilsson, U.J., Leffler, H., Sethi, T., Tantawi, S., Gravelle, L., Slack, R.J., Mills, R., Utsa Karmakar, Humphries, D., Zetterberg, F., Keeling, L., Paul, L., Molyneaux, P.L. and Li, F. (2021). Target inhibition of galectin-3 by inhaled TD139 in patients with idiopathic pulmonary fibrosis. 57(5), pp.2002559–2002559. doi:https://doi. org/ 10.1183/13993003.02559-2020.

[14] Jia, W., Wang, Z., Gao, C., Wu, J. and Wu, Q. (2021). Trajectory modeling of endothelial-to- mesenchymal transition reveals galectin-3 as a mediator in pulmonary fibrosis. Cell Death & Disease, [online] 12(4), p.327. doi: https:// doi.org/ 10. 1038/s41419-021-03603-0.

[15] Joehanes, R., Just, A.C., Marioni, R.E., Pilling, L.C., Reynolds, L.M., Mandaviya, P.R., Guan, W., Xu, T., Elks, C.E., Aslibekyan, S., Moreno-Macias, H., Smith, J.A., Brody, J.A., Dhingra, R., Yousefi, P., Pankow, J.S., Kunze, S., Shah, S.H., McRae, A.F. and Lohman, K. (2016). Epigenetic Signatures of Cigarette Smoking. Circulation: Cardiovascular Genetics, 9(5), pp.436–447. doi:https://doi. org/10.1161/ circgenetics. 116. 001506.

[16] Johkoh, T., Müller, N.L., Cartier, Y., Kavanagh, P.V., Hartman, T.E., Akira, M., Ichikado, K., Ando, M. and Nakamura, H. (1999). Idiopathic Interstitial Pneumonias: Diagnostic Accuracy of Thin-Section CT in 129 Patients. Radiology, 211 (2), pp.555–560. doi: https://doi.org/ 10.1148/ radiology. 211.2. r99ma01555.

[17] Jones, R.M., Hilldrup, S., Hope-Gill, B.D., Eccles, R. and Harrison, N.K. (2011). Mechanical induction of cough in Idiopathic Pulmonary Fibrosis. Cough, 7(1), p.2. doi: https://doi.org/ 10. 1186/1745-9974-7-2.

[18] Kaul, B., Lee, J.S., Zhang, N., Vittinghoff, E., Sarmiento, K., Collard, H.R. and Whooley, M.A. (2021). Epidemiology of Idiopathic Pulmonary Fibrosis Among U.S. Veterans, 2010 – 2019. Annals of the American Thoracic Society, Vol 19, No 2, pp 196–203. doi: https://doi.org/10.1513/annalsats.202103-295oc.

[19] Kaur, A., Mathai, S.K. and Schwartz, D.A. (2017). Genetics in Idiopathic Pulmonary Fibrosis Pathogenesis, Prognosis, and Treatment. Frontiers in Medicine, 4. doi: https:// doi.org/10. 3389/ fmed.2017.00154.

[20] Korfei, M., Ruppert, C., Mahavadi, P., Henneke, I., Markart, P., Koch, M., Lang, G., Fink, L., Bohle, R.-M., Seeger, W., Weaver, T.E. and Guenther, A. (2008). Epithelial Endoplasmic Reticulum Stress and Apoptosis in Sporadic Idiopathic Pulmonary Fibrosis. American Journal of Respiratory and Critical Care Medicine, 178(8), pp.838–846. doi:https://doi. org/ 10.1164/rccm.200802-313oc.

[21] Lawson, W.E., Grant, S., Ambrosini, V., Womble, K., Dawson, E., Lane , K., Markin, C., Renzoni, E., Lympany, P., Thomas, A., Roldan, J., Scott, T., Blackwell, T., Phillips, J. 3rd, Loyd, J. and du Bois, R. (2004). Genetic mutations in surfactant protein C are a rare cause of sporadic cases of IPF. Thorax, 59(11), pp.977–980. doi:https:// doi.org/10.1136/thx.2004.026336.

[22] Lipson, K.E., Wong, C., Teng, Y. and Spong, S. (2012). CTGF is a central mediator of tissue remodeling and fibrosis and its inhibition can reverse the process of fibrosis. Fibrogenesis & Tissue Repair, 5(S1). doi: https: //doi.org/ 10.1186/ 1755-1536-5-s1-s24.

[23] Liu, B., Yi, J., Yang, X., Liu, L., Lou, X., Zhang, Z., Qi, H., Wang, Z., Zou, J., Zhu, W.-G., Gu, W. and Luo, J. (2019). MDM2-mediated degradation of WRN promotes cellular senescence in a p53-independent manner. Oncogene, [online] 38(14), pp.2501–2515. doi:https://doi.org/10.1038/s41388-018-0605-5.

[24] Lopes, A.J., Capone, D., Mogami, R., Cunha, D.L. da, Melo, P.L. de and Jansen, J.M. (2007). Correlação dos achados tomográficos com parâmetros de função pulmonar na fibrose pulmonar idiopática em não fumantes. Jornal Brasileiro de Pneumologia, 33(6), pp.671–678. doi:https://doi.org/ 10. 1590/s1806-37132007000600010.

[25] Maher, T.M., Bendstrup, E., Dron, L., Langley, J., Smith, G., Khalid, J.M., Patel, H. and Kreuter, M. (2021). Global incidence and prevalence of idiopathic pulmonary fibrosis. Respiratory Research, 22(1). doi:https://doi.org/10.1186/s12931-021-01791-z.

[26] Mei, Q., Liu, Z., Zuo, H., Yang, Z. and Qu, J. (2022). Idiopathic Pulmonary Fibrosis: An Update on Pathogenesis. Frontiers in Pharmacology, 12:797292. doi: https:// doi.org/ 10.3389/ fphar. 2021. 797292.

[27] Mulugeta, S., Nureki, S.-I. and Beers, M.F. (2015). Lost after translation: insights from pulmonary surfactant for understanding the role of alveolar epithelial dysfunction and cellular quality control in fibrotic lung disease. American Journal of Physiology-Lung Cellular and Molecular Physiology, 309(6), pp.L507–L525. doi:https:// doi. org/ 10.1152/ ajplung. 00139. 2015.

[28] Murray, L.A., Chen, Q., Kramer, M.S., Hesson, D.P., Argentieri, R.L., Peng, X., Gulati, M., Homer, R.J., Russell, T., van Rooijen, N., Elias, J.A., Hogaboam, C.M. and Herzog, E.L. (2011). TGF-beta driven lung fibrosis is macrophage dependent and blocked by Serum amyloid P. The International Journal of Biochemistry & Cell Biology, [online] 43(1), pp.154–162. doi: https://doi.org/ 10. 1016/ j.biocel.2010.10.013.

[29] Nabhan, A.N., Brownfield, D.G., Harbury, P.B., Krasnow, M.A. and Desai, T.J. (2018). Single- cell Wnt signaling niches maintain stemness of alveolar type 2 cells. Science, 359(6380), pp. 1118–1123. doi:https://doi.org/10.1126/science.aam6603.

[30] Naik, P.K. and Moore, B.B. (2010). Viral infection and aging as cofactors for the development of pulmonary fibrosis. Expert Review of Respiratory Medicine, 4(6), pp.759–771. doi: https: //doi. org/10.1586/ers.10.73.

[31] Nakamura, Y. and Suda, T. (2015). Idiopathic Pulmonary Fibrosis: Diagnosis and Clinical Manifestations. Clinical Medicine Insights: Circulatory, Respiratory and Pulmonary Medicine, [online] 9s1(163–171), p.CCRPM.S39897. doi: https://doi.org/ 10.4137/ ccrpm. s39897.

[32] Nishimura, K., Kitaichi, M., Izumi, T., Nagai, S., Kanaoka, M. and Itoh, H. (1992). Usual interstitial pneumonia: histologic correlation with high-resolution CT. Radiology, 182(2), pp.337–342. doi: https://doi.org/10. 1148/ radiology. 182.2. 1732946.

[33] Ornatowski, W., Lu, Q., Yegambaram, M., Garcia, A.E., Zemskov, E.A., Maltepe, E., Fineman, J.R., Wang, T. and Black, S.M. (2020). Complex interplay between autophagy and oxidative stress in the development of pulmonary disease. Redox Biology, [online] 36, p.101679. doi: https://doi.org/10. 1016/j. redox. 2020. 101679.

[34] Ortiz, L.A., Gambelli, F., McBride, C., Gaupp, D., Baddoo, M., Kaminski, N. and Phinney, D.G. (2003). Mesenchymal stem cell engraftment in lung is enhanced in response to bleomycin exposure and ameliorates its fibrotic effects. Proceedings of the National Academy of Sciences, 100(14), pp.8407–8411. doi: https://doi.org/10.1073/pnas.1432929100.

[35] Pardo, A. and Selman, M. (2021). The Interplay of the Genetic Architecture, Aging, and Environmental Factors in the Pathogenesis of Idiopathic Pulmonary Fibrosis. American Journal of Respiratory Cell and Molecular Biology, 64(2), pp.163–172. doi: https: //doi. org/10.1165/rcmb.2020-0373ps.

[36] Patil, S.M. (2022). Epidemiology of Idiopathic Pulmonary Fibrosis. IntechOpen eBooks. doi:https: //doi. org/ 10.5772/ intechopen. 98482.

[37] Plantier, L., Cazes, A., Dinh-Xuan, A.-T., Bancal, C., Marchand-Adam, S. and Crestani, B.(2018). Physiology of the lung in idiopathic pulmonary fibrosis. European Respiratory Review, 27(147), p.170062. doi:https://doi.org/10. 1183/ 16000617. 0062-2017.

[38] Plantier, L., Debray, M.-P., Estellat, C., Flamant, M., Roy, C., Bancal, C., Borie, R., Israël-Biet, D., Mal, H., Crestani, B. and Delclaux, C. (2016). Increased volume of conducting airways in idiopathic pulmonary fibrosis is independent of disease severity: a volumetric capnography study. Journal of Breath Research, [online] 10(1), p.016005. doi:https:// doi.org/ 10.1088/1752- 7155/10/1/ 016005.

[39] Raghu, G., Chen, S.-Y., Yeh, W.-S., Maroni, B., Li, Q., Lee, Y.-C. and Collard, H.R. (2014). Idiopathic pulmonary fibrosis in US Medicare beneficiaries aged 65 years and older: incidence, prevalence, and survival, 2001–11. The Lancet Respiratory Medicine, 2(7), pp.566–572. doi: https:// doi. org/ 10.1016/s2213-2600(14) 70101-8

[40] Raghu, G., Collard, H.R., Egan, J.J., Martinez, F.J., Behr, J., Brown, K.K., Colby, T.V., Cordier, J.-F., Flaherty, K.R., Lasky, J.A., Lynch, D.A., Ryu, J.H., Swigris, J.J., Wells, A.U., Ancochea, J., Bouros, D., Carvalho, C., Costabel, U., Ebina, M. and Hansell, D.M. (2011). An Official ATS/ERS/JRS/ALAT Statement: Idiopathic Pulmonary Fibrosis: Evidence-based Guidelines for Diagnosis and Management. American Journal of Respiratory and Critical Care Medicine, 183(6), pp.788–824. doi:https:// doi.org/ 10.1164/ rccm.2009-040gl.

[41] Raghu, G., Nathan, S.D., Behr, J., Brown, K.K., Egan, J.J., Kawut, S.M., Flaherty, K.R., Martinez, F.J., Wells, A.U., Shao, L., Zhou, H., Henig, N., Szwarcberg, J., Gillies, H., Montgomery, A.B. and O’Riordan, T.G. (2015). Pulmonary hypertension in idiopathic pulmonary fibrosis with mild-to-moderate restriction. European Respiratory Journal, 46(5), pp.1370–1377. doi:https://doi.org/10.1183/13993003.01537-2014.

[42] Raghu, G., van den Blink, B., Hamblin, M.J., Brown, A.W., Golden, J.A., Ho, L.A., Wijsenbeek, M.S., Vasakova, M., Pesci, A., Antin-Ozerkis, D.E., Meyer, K.C., Kreuter, M., Santin-Janin, H., Mulder, G.-J., Bartholmai, B., Gupta, R. and Richeldi, L. (2018). Effect of Recombinant Human Pentraxin 2 vs Placebo on Change in Forced Vital Capacity in Patients With Idiopathic Pulmonary Fibrosis. JAMA, [online] 319(22), p.2299. doi: https:// doi.org/ 10. 1001/jama.2018.6129.

[43] Richeldi, L., Fernández Pérez, E.R., Costabel, U., Albera, C., Lederer, D.J., Flaherty, K. R.,Ettinger, N., Perez, R., Scholand, M.B., Goldin, J., Peony Yu, K.-H., Neff, T., Porter, S., Zhong, M., Gorina, E., Kouchakji, E. and Raghu, G. (2020). Pamrevlumab, an anti-connective tissue growth factor therapy, for idiopathic pulmonary fibrosis (PRAISE): a phase 2, randomised, double-blind, placebo-controlled trial. The Lancet. Respiratory Medicine, [online] 8(1), pp.25–33. doi: https:// doi. org/ 10.1016/S2213-2600(19)30262-0.

[44] Romero, Y., Bueno, M., Ramirez, R., Álvarez, D., Sembrat, J.C., Goncharova, E.A., Rojas, M., Selman, M., Mora, A.L. and Pardo, A. (2016). mTORC 1 activation decreases autophagy in aging and idiopathic pulmonary fibrosis and contributes to apoptosis resistance in IPF fibroblasts. Aging Cell, 15(6), pp.1103–1112. doi:https://doi.org/10.1111/acel.12514.

[45] Ryerson, C.J., Urbania, T.H., Richeldi, L., Mooney, J.J., Lee, J.S., Jones, K.D., Elicker, B.M., Koth, L.L., King, T.E., Wolters, P.J. and Collard, H.R. (2012). Prevalence and prognosis of unclassifiable interstitial lung disease. European Respiratory Journal, 42(3), pp.750–757. doi: https://doi.org/ 10. 1183/ 090 31936.00131912.

[46] Sakamoto, S., Muramatsu, Y., Satoh, K., Ishida, F., Kikuchi, N., Sano, G., Sugino, K., Isobe, K., Takai, Y. and Homma, S. (2015). Effectiveness of combined therapy with pirfenidone and inhaled N-acetylcysteine for advanced idiopathic pulmonary fibrosis: A case-control study. Respirology, 20(3), pp.445–452. doi:https://doi.org/ 10. 1111/resp.12477.

[47] Selman, M., Martinez, F.J. and Pardo, A. (2019). Why Does an Aging Smoker’s Lung Develop Idiopathic Pulmonary Fibrosis and Not Chronic Obstructive Pulmonary Disease? American Journal of Respiratory and Critical Care Medicine, 199(3), pp.279–285. doi:https://doi.org/10.1164/rccm.201806-1166pp.

[48] Sgalla, G., Iovene, B., Calvello, M., Ori, M., Varone, F. and Richeldi, L. (2018). Idiopathic pulmonary fibrosis: pathogenesis and management. Respiratory Research, 19(1). doi:https://doi.org/10.1186/s12931-018-0730-2.

[49] Snetselaar, R., van Batenburg, A.A., van Oosterhout, M.F.M., Kazemier, K.M., Roothaan, S.M., Peeters, T., van der Vis, J.J., Goldschmeding, R., Grutters, J.C. and van Moorsel, C.H.M. (2017). Short telomere length in IPF lung associates with fibrotic lesions and predicts survival. PLOS ONE, 12(12), p.e0189467. doi:https://doi.org/10.1371/journal.pone.0189467.

[50] Spagnolo, P., Kropski, J.A., Jones, M.G., Lee, J.S., Rossi, G., Karampitsakos, T., Maher, T.M., Tzouvelekis, A. and Ryerson, C.J. (2021). Idiopathic pulmonary fibrosis: Disease mechanisms and drug development. Pharmacology & Therapeutics, 222, p.107798. doi:https://doi.org/ 10.1016/j. pharmthera. 2020.107798.

[51] Steele, M.P., Speer, M.C., Loyd, J.E., Brown, K.K., Herron, A., Slifer, S.H., Burch, L.H., Wahidi, M.M., Phillips, J.A., Sporn, T.A., McAdams, H.P., Schwarz, M.I. and Schwartz, D.A. (2005). Clinical and pathologic features of familial interstitial pneumonia. American Journal of Respiratory and Critical Care Medicine, [online] 172(9), pp.1146–1152. doi:https://doi.org/10.1164/rccm.200408-1104OC.

[52] Strongman, H., Kausar, I. and Maher, T.M. (2018). Incidence, Prevalence, and Survival of Patients with Idiopathic Pulmonary Fibrosis in the UK. Advances in Therapy, 35(5), pp.724–736. doi: https://doi.org/10.1007/s12325-018-0693-1.

[53] Tabaj, G.C., Fernandez, C.F., Sabbagh, E. and Leslie, K.O. (2015). Histopathology of the idiopathic interstitial pneumonias (IIP): A review. Respirology, 20(6), pp.873–883. doi: https://doi.org/10.1111/resp.12551.

[54] Tsakiri, K.D., Cronkhite, J.T., Kuan, P.J., Xing, C., Raghu, G., Weissler, J.C., Rosenblatt, R.L., Shay, J.W. and Garcia, C.K. (2007). Adult-onset pulmonary fibrosis caused by mutations in telomerase. Proceedings of the National Academy of Sciences, 104(18), pp.7552–7557. doi: https://doi. org/10. 1073/ pnas. 0701009104.

[55] Tsukui, T., Sun, K., Wetter, J., Wilson-Kanamori, J., Hazelwood, L.A., Henderson, N.C., Adams, T., Schupp, J.C., Poli, S., Rosas, I.O., Kaminski, N., Matthay, M.A., Wolters, P.J. and Sheppard, D. (2020). Collagen-producing lung cell atlas identifies multiple subsets with distinct localization and relevance to fibrosis. Nature Communications, 11(1). doi: https://doi.org/10.1038/s41467-020-15647-5.

[56] Usmani, O.S., Biddiscombe, M.F., Yang, S., Meah, S., Oballa, E., Simpson, J.K., Fahy, W.A., Marshall, R.P., Lukey, P.T. and Maher, T.M. (2018). The topical study of inhaled drug (salbutamol) delivery in idiopathic pulmonary fibrosis. Respiratory Research, 19 (1). doi: https://doi. org/10. 1186/ s12 931-018-0732- 0.

[57] Wells, A., King, A.J., Rubens, M.B., Cramer, D.W., du, M. and Hansell, D.M. (1997). Lone cryptogenic fibrosing alveolitis: a functional-morphologic correlation based on extent of disease on thin-section computed tomography. American Journal of Respiratory and Critical Care Medicine, 155(4), pp.1367–1375. doi:https:// doi.org/10. 1164/ ajrccm.155.4.9105081.

[58] Wipff, P.-J., Rifkin, D.B., Meister, J.-J. and Hinz, B. (2007). Myofibroblast contraction activates latent TGF-β1 from the extracellular matrix. Journal of Cell Biology, 179(6), pp.1311–1323. doi: https://doi.org/10.1083/jcb.200704042.

[59] Wu, H., Yu, Y., Huang, H., Hu, Y., Fu, S., Wang, Z., Shi, M., Zhao, X., Yuan, J., Li, J., Yang, X., Bin, E., Wei, D., Zhang, H., Zhang, J., Yang, C., Cai, T., Dai, H., Chen, J. and Tang, N. (2020). Progressive Pulmonary Fibrosis Is Caused by Elevated Mechanical Tension on Alveolar Stem Cells. Cell, 180(1), pp.107-121.e17. doi:https://doi.org/10.1016/j.cell.2019.11.027.

[60] Xia, H., Diebold, D., Nho, R., Perlman, D., Kleidon, J., Kahm, J., Avdulov, S., Peterson, M., Nerva, J., Bitterman, P. and Henke, C. (2008). Pathological integrin signaling enhances proliferation of primary lung fibroblasts from patients with idiopathic pulmonary fibrosis. The Journal of Experimental Medicine, [online] 205(7), pp.1659–1672. doi: https://doi. org/10.1084/jem.20080001.

[61] Yoshihara, T., Nanri, Y., Nunomura, S., Yamaguchi, Y., Feghali-Bostwick, C., Ajito, K., Murakami, S., M`awatari, M. and Izuhara, K. (2020). Periostin plays a critical role in the cell cycle in lung fibroblasts. Respiratory Research, 21(1). doi:https:// doi.org/ 10.1186/s12931-020-1299-0.