Interstitial lung diseases (ILDs) is a large and heterogeneous group of disorders with a variable degree of lung inflammation and lung fibrosis. In some ILDs, we can observe a progressive-fibrosing phenotype-PF-ILD (e.g., idiopathic pulmonary fibrosis, fibrotic phenotype of hypersensitivity pneumonitis, familial lung fibrosis, etc.). Lung fibrosis is characterized by overgrowth, stiffening, and scarring of tissues due to excess deposition of extracellular matrix. In some patients suffering from PF-ILD, progression and fatal outcomes occur despite treatment. Therefore, there is a great need for the development of lung fibrosis models that will help to understand and recapitulate the etiopathogenesis of the disease and may thus serve as tools for unraveling its underlying profibrotic mechanisms and potential therapeutic targets. In this review, we summarize ILD etiopathogenesis, current and novel therapeutic options, and discuss in vivo, ex vivo, and in vitro near-to-native lung fibrosis models, which help to elucidate specific processes within ILD pathophysiology.

Department of Histology and Embryology Faculty of Medicine Masaryk University Kamenice 753 5 625 00 Brno Czech Republic

Department of Respiratory Diseases and Tuberculosis University Hospital Brno and Faculty of Medicine Masaryk University Jihlavská 20 625 00 Brno Czech Republic

International Clinical Research Center St Anne's University Hospital Brno Czech Republic

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Mehal WZ, Iredale J, Friedman SL. Scraping fibrosis: expressway to the core of fibrosis. Nat Med. 2011;17:552–3. PubMed DOI PMC

Yanagi S, Tsubouchi H, Miura A, Matsumoto N, Nakazato M. Breakdown of epithelial barrier integrity and overdrive activation of alveolar epithelial cells in the pathogenesis of acute respiratory distress syndrome and lung fibrosis. BioMed Res Int. 2015;2015:573210. 10.1155/2015/573210. PubMed DOI PMC

Phan THG, Paliogiannis P, Nasrallah GK, Giordo R, Eid AH, Fois AG, et al. Emerging cellular and molecular determinants of idiopathic pulmonary fibrosis. Cell Mol Life Sci. 2021;78:2031–57. PubMed DOI PMC

Yao C, Guan X, Carraro G, Parimon T, Liu X, Huang G, et al. Senescence of alveolar type 2 cells drives progressive pulmonary fibrosis. Am J Respir Crit Care Med. 2021;203:707–17. PubMed DOI PMC

Raghu G, Remy-Jardin M, Richeldi L, Thomson CC, Inoue Y, Johkoh T, et al. Idiopathic pulmonary fibrosis (an update) and progressive pulmonary fibrosis in adults. An official ATS/ERS/JRS/ALAT clinical practice guideline. Am J Respir Crit Care Med. 2022;205:e18-e47. PubMed DOI PMC

Martinez FJ, Collard HR, Pardo A, Raghu G, Richeldi L, Selman M, et al. Idiopathic pulmonary fibrosis. Nat Rev Dis Primers. 2017;3:17074. PubMed DOI

Barros A, Oldham J, Noth I. Genetics of idiopathic pulmonary fibrosis. Am J Med Sci. 2019;357(5):379–83. 10.1016/j.amjms.2019.02.009. PubMed DOI PMC

Doubková M, Staňo Kozubík K, Radová L, Pešová M, Trizuljak J, Pál K, et al. A novel germline mutation of the SFTPA1 gene in familial interstitial pneumonia. Hum Genome Var. 2019;6:12. PubMed DOI PMC

Doubkova M, Kriegova E, Littnerova S, Schneiderova P, Sterclova M, Bartos V, et al. DSP rs2076295 variants influence nintedanib and pirfenidone outcomes in idiopathic pulmonary fibrosis: a pilot study. Ther Adv Respir Dis. 2021;15:17534666211042528. PubMed DOI PMC

Cocconcelli E, Biondini D, Bernardinello N, Baraldo S, Lococo S, Andreotti G, et al. Association between MUC5B rs35705950 genotype and response to antifibrotic treatment in patients with Idiopathic Pulmonary Fibrosis (IPF). Eur Respir J. 2020;56:735.

Caliskan C, Seeliger B, Jäger B, Fuge J, Welte T, Terwolbeck O, et al. Genetic variation in CCL18 gene influences CCL18 expression and correlates with survival in Idiopathic Pulmonary Fibrosis—Part B. J Clin Med. 2020;9(6):1993. 10.3390/jcm9061993. PubMed DOI PMC

Šelb J, Osolnik K, Kern I, Korošec P, Rijavec M. Utility of telomerase gene mutation testing in patients with Idiopathic Pulmonary Fibrosis in routine practice. Cells. 2022;11(3):372. 10.3390/cells11030372. PubMed DOI PMC

Karampitsakos T, Juan-Guardela BM, Tzouvelekis A, Herazo-Maya JD. Precision medicine advances in idiopathic pulmonary fibrosis. EBioMedicine. 2023;95:104766. 10.1016/j.ebiom.2023.104766. PubMed DOI PMC

Jensen K, Nizamutdinov D, Guerrier M, Afroze S, Dostal D, Glaser S. General mechanisms of nicotine-induced fibrogenesis. FASEB J. 2012;26(12):4778–87. 10.1096/fj.12-206458. PubMed DOI PMC

Fughelli P, Stella A, Sterpetti AV. Marcello Malpighi (1628–1694). Circ Res. 2019;124:1430–2. PubMed DOI

Travaglini KJ, Nabhan AN, Penland L, Sinha R, Gillich A, Sit RV, et al. A molecular cell atlas of the human lung from single-cell RNA sequencing. Nature. 2020;587(7835):619–25. 10.1038/s41586-020-2922-4. PubMed DOI PMC

Zhu W, Tan C, Zhang J. Alveolar epithelial type 2 cell dysfunction in idiopathic pulmonary fibrosis. Lung. 2022;200(5):539–47. 10.1007/s00408-022-00571-w. PubMed DOI

Volpe MC, Ciucci G, Zandomenego G, Vuerich R, Ring NAR, Vodret S, et al. Flt1 produced by lung endothelial cells impairs ATII cell transdifferentiation and repair in pulmonary fibrosis. Cell Death Dis. 2023;14(7):437. 10.1038/s41419-023-05962-2. PubMed DOI PMC

Selman M, Pardo A. Revealing the pathogenic and aging-related mechanisms of the enigmatic idiopathic pulmonary fibrosis. An integral model. Am J Respir Crit Care Med. 2014;189:1161–72. PubMed DOI

Mason RJ, Williams MC. Type II alveolar cell. Defender of the alveolus. Am Rev Respir Dis. 1977;115:81–91. PubMed

Verleden SE, Tanabe N, McDonough JE, Vasilescu DM, Xu F, Wuyts WA, et al. Small airways pathology in idiopathic pulmonary fibrosis: a retrospective cohort study. Lancet Respir Med. 2020;8(6):573–84. 10.1016/S2213-2600(19)30356-X. PubMed DOI PMC

Ikezoe K, Hackett TL, Peterson S, Prins D, Hague CJ, Murphy D, et al. Small airway reduction and fibrosis is an early pathologic feature of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2021;204:1048–59. PubMed DOI

Stancil IT, Michalski JE, Schwartz DA. An airway-centric view of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2022;206:410–6. PubMed DOI PMC

Adams TS, Schupp JC, Poli S, Ayaub EA, Neumark N, Ahangari F, et al. Single-cell RNA-seq reveals ectopic and aberrant lung-resident cell populations in idiopathic pulmonary fibrosis. Sci Adv. 2020;6:eaba1983. PubMed DOI PMC

Chilosi M, Poletti V, Murer B, Lestani M, Cancellieri A, Montagna L, et al. Abnormal re-epithelialization and lung remodeling in idiopathic pulmonary fibrosis: the role of deltaN-p63. Lab Invest. 2002;82(10):1335–45. 10.1097/01.lab.0000032380.82232.67. PubMed DOI

Reynaud P, Ahmed E, Serre I, Knabe L, Bommart S, Suehs C, et al. Club cell loss as a feature of bronchiolization in ILD. Front Immunol. 2021;12:630096. 10.3389/fimmu.2021.630096. PubMed DOI PMC

Spagnolo P, Distler O, Ryerson CJ, Tzouvelekis A, Lee JS, Bonella F, et al. Mechanisms of progressive fibrosis in connective tissue disease (CTD)-associated interstitial lung diseases (ILDs). Ann Rheum Dis. 2021;80(2):143. 10.1136/annrheumdis-2020-217230. PubMed DOI PMC

Celada LJ, Kropski JA, Herazo-Maya JD, Luo W, Creecy A, Abad AT, et al. PD-1 up-regulation on CD4(+) T cells promotes pulmonary fibrosis through STAT3-mediated IL-17A and TGF-β1 production. Sci Transl Med. 2018;10:eaar8356. PubMed DOI PMC

Morse C, Tabib T, Sembrat J, Buschur KL, Bittar HT, Valenzi E, et al. Proliferating SPP1/MERTK-expressing macrophages in idiopathic pulmonary fibrosis. Eur Respir J. 2019;54:1802441. PubMed DOI PMC

Yang X, Liu Z, Zhou J, Guo J, Han T, Liu Y, et al. SPP1 promotes the polarization of M2 macrophages through the Jak2/Stat3 signaling pathway and accelerates the progression of idiopathic pulmonary fibrosis. Int J Mol Med. 2024;54:89. PubMed DOI PMC

Zhou B-W, Liu H-M, Xu F, Jia X-H. The role of macrophage polarization and cellular crosstalk in the pulmonary fibrotic microenvironment: a review. Cell Commun Signal. 2024;22:172. PubMed DOI PMC

Selman M, Pardo A. When things go wrong: exploring possible mechanisms driving the progressive fibrosis phenotype in interstitial lung diseases. Eur Respir J. 2021;58:2004507. PubMed DOI

Phan SH, Kunkel SL. Lung cytokine production in bleomycin-induced pulmonary fibrosis. Exp Lung Res. 1992;18(1):29–43. 10.3109/01902149209020649. PubMed DOI

Zhang K, Gharaee-Kermani M, McGarry B, Remick D, Phan SH. TNF-alpha-mediated lung cytokine networking and eosinophil recruitment in pulmonary fibrosis. J Immunol. 1997;158(2):954–9. 10.4049/jimmunol.158.2.954. PubMed DOI

Smith RE, Strieter RM, Phan SH, Lukacs N, Kunkel SL. TNF and IL-6 mediate MIP-1alpha expression in bleomycin-induced lung injury. J Leukoc Biol. 1998;64:528–36. PubMed DOI

Lee JM, Yoshida M, Kim MS, Lee JH, Baek AR, Jang AS, et al. Involvement of alveolar epithelial cell necroptosis in idiopathic pulmonary fibrosis pathogenesis. Am J Respir Cell Mol Biol. 2018;59:215–24. PubMed DOI

Ye X, Zhang M, Gu H, Liu M, Zhao Y, Shi Y, et al. Animal models of acute exacerbation of pulmonary fibrosis. Respir Res. 2023;24:296. PubMed DOI PMC

Song L, Li K, Chen H, Xie L. Cell cross-talk in alveolar microenvironment: from lung injury to fibrosis. Am J Respir Cell Mol Biol. 2024;71:30–42. PubMed DOI PMC

Lingampally A, Truchi M, Shi X, Zhou Y, Vasquez-Pacheco E, Panagiotidis GD, et al. Unraveling alveolar fibroblast and activated myofibroblast heterogeneity and differentiation trajectories during lung fibrosis development and resolution in young and old mice. Aging Cell. 2025;24:e14503. PubMed DOI PMC

Liu X, Dai K, Zhang X, Huang G, Lynn H, Rabata A, et al. Multiple fibroblast subtypes contribute to matrix deposition in pulmonary fibrosis. Am J Respir Cell Mol Biol. 2023;69:45–56. PubMed DOI PMC

Tsukui T, Wolters PJ, Sheppard D. Alveolar fibroblast lineage orchestrates lung inflammation and fibrosis. Nature. 2024;631:627–34. PubMed DOI PMC

Habermann AC, Gutierrez AJ, Bui LT, Yahn SL, Winters NI, Calvi CL, et al. Single-cell RNA sequencing reveals profibrotic roles of distinct epithelial and mesenchymal lineages in pulmonary fibrosis. Sci Adv. 2020;6:eaba1972. PubMed DOI PMC

Phillips RJ, Burdick MD, Hong K, Lutz MA, Murray LA, Xue YY, et al. Circulating fibrocytes traffic to the lungs in response to CXCL12 and mediate fibrosis. J Clin Invest. 2004;114:438–46. PubMed DOI PMC

Kramann R, Schneider RK, DiRocco DP, Machado F, Fleig S, Bondzie PA, et al. Perivascular Gli1+ progenitors are key contributors to injury-induced organ fibrosis. Cell Stem Cell. 2015;16:51–66. PubMed DOI PMC

King TE Jr., Pardo A, Selman M. Idiopathic pulmonary fibrosis. Lancet. 2011;378(9807):1949–61. 10.1016/S0140-6736(11)60052-4. PubMed DOI

Herrera J, Henke CA, Bitterman PB. Extracellular matrix as a driver of progressive fibrosis. J Clin Invest. 2018;128(1):45–53. 10.1172/JCI93557. PubMed DOI PMC

Tang VW. Collagen, stiffness, and adhesion: the evolutionary basis of vertebrate mechanobiology. Mol Biol Cell. 2020;31(17):1823–34. 10.1091/mbc.E19-12-0709. PubMed DOI PMC

Upagupta C, Shimbori C, Alsilmi R, Kolb M. Matrix abnormalities in pulmonary fibrosis. Eur Respir Rev. 2018;27(148):180033. 10.1183/16000617.0033-2018. PubMed DOI PMC

Wipff PJ, Rifkin DB, Meister JJ, Hinz B. Myofibroblast contraction activates latent TGF-beta1 from the extracellular matrix. J Cell Biol. 2007;179:1311–23. PubMed DOI PMC

Thannickal VJ, Henke CA, Horowitz JC, Noble PW, Roman J, Sime PJ, et al. Matrix biology of idiopathic pulmonary fibrosis: a workshop report of the national heart, lung, and blood institute. Am J Pathol. 2014;184:1643–51. PubMed DOI PMC

Nguyen XX, Nishimoto T, Takihara T, Mlakar L, Bradshaw AD, Feghali-Bostwick C. Lysyl oxidase directly contributes to extracellular matrix production and fibrosis in systemic sclerosis. Am J Physiol Lung Cell Mol Physiol. 2021;320(1):L29-l40. 10.1152/ajplung.00173.2020. PubMed DOI PMC

Nizamoglu M, Alleblas F, Koster T, Borghuis T, Vonk JM, Thomas MJ, et al. Three dimensional fibrotic extracellular matrix directs microenvironment fiber remodeling by fibroblasts. Acta Biomater. 2024;177:118–31. 10.1016/j.actbio.2024.02.008. PubMed DOI

Chuliá-Peris L, Carreres-Rey C, Gabasa M, Alcaraz J, Carretero J, Pereda J. Matrix metalloproteinases and their inhibitors in pulmonary fibrosis: EMMPRIN/CD147 comes into play. Int J Mol Sci. 2022;23(13):6894. 10.3390/ijms23136894. PubMed DOI PMC

Burgess JK, Gosens R. Mechanotransduction and the extracellular matrix: key drivers of lung pathologies and drug responsiveness. Biochem Pharmacol. 2024;228:116255. 10.1016/j.bcp.2024.116255. PubMed DOI

Ratnasingham M, Bradding P, Roach KM. The role of TRP channels in lung fibrosis: mechanisms and therapeutic potential. Int J Biochem Cell Biol. 2025;180:106728. 10.1016/j.biocel.2024.106728. PubMed DOI

Samanta A, Hughes TET, Moiseenkova-Bell VY. Transient receptor potential (TRP) channels. Subcell Biochem. 2018;87:141–65. PubMed DOI PMC

Roach KM, Bradding P. Ca(2+) signalling in fibroblasts and the therapeutic potential of K(Ca)3.1 channel blockers in fibrotic diseases. Br J Pharmacol. 2020;177:1003–24. PubMed DOI PMC

Rahaman SO, Grove LM, Paruchuri S, Southern BD, Abraham S, Niese KA, et al. TRPV4 mediates myofibroblast differentiation and pulmonary fibrosis in mice. J Clin Invest. 2014;124:5225–38. PubMed DOI PMC

Hofmann K, Fiedler S, Vierkotten S, Weber J, Klee S, Jia J, et al. Classical transient receptor potential 6 (TRPC6) channels support myofibroblast differentiation and development of experimental pulmonary fibrosis. Biochimica et Biophysica Acta (BBA). 2017;1863(2):560–8. 10.1016/j.bbadis.2016.12.002. PubMed DOI

Haak AJ, Tan Q, Tschumperlin DJ. Matrix biomechanics and dynamics in pulmonary fibrosis. Matrix Biol. 2018;73:64–76. 10.1016/j.matbio.2017.12.004. PubMed DOI PMC

Parker MW, Rossi D, Peterson M, Smith K, Sikström K, White ES, et al. Fibrotic extracellular matrix activates a profibrotic positive feedback loop. J Clin Invest. 2014;124:1622–35. PubMed DOI PMC

Nizamoglu M, de Hilster RHJ, Zhao F, Sharma PK, Borghuis T, Harmsen MC, et al. An in vitro model of fibrosis using crosslinked native extracellular matrix-derived hydrogels to modulate biomechanics without changing composition. Acta Biomater. 2022;147:50–62. 10.1016/j.actbio.2022.05.031. PubMed DOI

Vicens-Zygmunt V, Estany S, Colom A, Montes-Worboys A, Machahua C, Sanabria AJ, et al. Fibroblast viability and phenotypic changes within glycated stiffened three-dimensional collagen matrices. Respir Res. 2015;16(1):82. 10.1186/s12931-015-0237-z. PubMed DOI PMC

Brown AC, Fiore VF, Sulchek TA, Barker TH. Physical and chemical microenvironmental cues orthogonally control the degree and duration of fibrosis-associated epithelial-to-mesenchymal transitions. J Pathol. 2013;229(1):25–35. 10.1002/path.4114. PubMed DOI PMC

Kim KK, Wei Y, Szekeres C, Kugler MC, Wolters PJ, Hill ML, et al. Epithelial cell alpha3beta1 integrin links beta-catenin and Smad signaling to promote myofibroblast formation and pulmonary fibrosis. J Clin Invest. 2009;119:213–24. PubMed PMC

Ba J, Zheng C, Lai Y, He X, Pan Y, Zhao Y, et al. High matrix stiffness promotes senescence of type II alveolar epithelial cells by lysosomal degradation of lamin A/C in pulmonary fibrosis. Respir Res. 2025;26(1):128. 10.1186/s12931-025-03201-0. PubMed DOI PMC

Froese AR, Shimbori C, Bellaye PS, Inman M, Obex S, Fatima S, et al. Stretch-induced activation of transforming growth factor-β1 in pulmonary fibrosis. Am J Respir Crit Care Med. 2016;194:84–96. PubMed DOI

Wellman TJ, Mondoñedo JR, Davis GS, Bates JHT, Suki B. Topographic distribution of idiopathic pulmonary fibrosis: a hybrid physics- and agent-based model. Physiol Meas. 2018;39(6):064007. 10.1088/1361-6579/aaca86. PubMed DOI PMC

Hall JK, Bates JHT, Casey DT, Bartolák-Suki E, Lutchen KR, Suki B. Front Netw Physiol. 2023;3:1124223. PubMed PMC

Cogno N, Bauer R, Durante M. A 3D agent-based model of lung fibrosis. Symmetry. 2022;14:90. PubMed DOI PMC

Hall JK, Bates JHT, Krishnan R, Kim JH, Deng Y, Lutchen KR, et al. Elucidating the interaction between stretch and stiffness using an agent-based spring network model of progressive pulmonary fibrosis. Front Netw Physiol. 2024;4:1396383. PubMed DOI PMC

Wilson CL, Stephenson SE, Higuero JP, Feghali-Bostwick C, Hung CF, Schnapp LM. Characterization of human PDGFR-β-positive pericytes from IPF and non-IPF lungs. Am J Physiol Lung Cell Mol Physiol. 2018;315(6):L991–1002. 10.1152/ajplung.00289.2018. PubMed DOI PMC

Garrison AT, Bignold RE, Wu X, Johnson JR. Pericytes: the lung-forgotten cell type. Front Physiol. 2023;14:1150028. PubMed DOI PMC

Sava P, Ramanathan A, Dobronyi A, Peng X, Sun H, Ledesma-Mendoza A, et al. Human pericytes adopt myofibroblast properties in the microenvironment of the IPF lung. JCI Insight. 2017;2(24):e96352. 10.1172/jci.insight.96352. PubMed DOI PMC

Yamaguchi M, Hirai S, Tanaka Y, Sumi T, Tada M, Takahashi H, et al. Pericyte-myofibroblast transition in the human lung. Biochem Biophys Res Commun. 2020;528(2):269–75. 10.1016/j.bbrc.2020.05.091. PubMed DOI

Bradley J, O'Shea P, Wrench C, Mattsson J, Paulin R, Overed-Sayer C, Rosenberg L, Olsson H, Gianni D. A secretome screen in primary human lung fibroblasts identifies FGF9 as a novel regulator of cellular senescence. SLAS Discov. 2025;32:100223. PubMed

Lei Y, Zhong C, Zhang J, Zheng Q, Xu Y, Li Z, et al. Senescent lung fibroblasts in idiopathic pulmonary fibrosis facilitate non-small cell lung cancer progression by secreting exosomal MMP1. Oncogene. 2025;44(11):769–81. 10.1038/s41388-024-03236-5. PubMed DOI PMC

Enomoto Y, Katsura H, Fujimura T, Ogata A, Baba S, Yamaoka A, et al. Autocrine TGF-β-positive feedback in profibrotic AT2-lineage cells plays a crucial role in non-inflammatory lung fibrogenesis. Nat Commun. 2023;14(1):4956. 10.1038/s41467-023-40617-y. PubMed DOI PMC

Xie T, Liang J, Stripp B, Noble PW. Cell-cell interactions and communication dynamics in lung fibrosis. Chin Med J Pulm Crit Care Med. 2024;2:63–71. PubMed PMC

Weng S, Zuo J, Mo J, Ye L. Cellular senescence-related gene signatures in idiopathic pulmonary fibrosis: insights from bioinformatics. Front Immunol. 2025;16:1557848. PubMed DOI PMC

Álvarez D, Cárdenes N, Sellarés J, Bueno M, Corey C, Hanumanthu VS, et al. IPF lung fibroblasts have a senescent phenotype. Am J Physiol Lung Cell Mol Physiol. 2017;313:L1164-l1173. PubMed DOI PMC

Blokland KEC, Waters DW, Schuliga M, Read J, Pouwels SD, Grainge CL, et al. Senescence of IPF lung fibroblasts disrupt alveolar epithelial cell proliferation and promote migration in wound healing. Pharmaceutics. 2020;24:389. PubMed DOI PMC

Wang Y, Guo Z, Ma R, Wang J, Wu N, Fan Y, et al. Prognostic predictive characteristics in patients with fibrosing interstitial lung disease: a retrospective cohort study. Front Pharmacol. 2022;13:924754. 10.3389/fphar.2022.924754. PubMed DOI PMC

Lee JS, La J, Aziz S, Dobrinskikh E, Brownell R, Jones KD, et al. Molecular markers of telomere dysfunction and senescence are common findings in the usual interstitial pneumonia pattern of lung fibrosis. Histopathology. 2021;79:67–76. PubMed DOI PMC

Hoffman TW, van der Vis JJ, van der Smagt JJ, Massink MPG, Grutters JC, van Moorsel CHM. Pulmonary fibrosis linked to variants in the ACD gene, encoding the telomere protein TPP1. Eur Respir J. 2019;54:1900809. PubMed DOI

Newman DR, Sills WS, Hanrahan K, Ziegler A, Tidd KM, Cook E, et al. Expression of WNT5A in idiopathic pulmonary fibrosis and its control by TGF-β and WNT7B in human lung fibroblasts. J Histochem Cytochem. 2016;64:99–111. PubMed DOI PMC

Mullenbrock S, Liu F, Szak S, Hronowski X, Gao B, Juhasz P, et al. Systems analysis of transcriptomic and proteomic profiles identifies novel regulation of fibrotic programs by miRNAs in pulmonary fibrosis fibroblasts. Genes. 2018;9:588. PubMed DOI PMC

McDonough JE, Ahangari F, Li Q, Jain S, Verleden SE, Herazo-Maya J, et al. Transcriptional regulatory model of fibrosis progression in the human lung. JCI Insight. 2019;4(22):e131597. 10.1172/jci.insight.131597. PubMed DOI PMC

Zhang J, Muise ES, Han S, Kutchukian PS, Costet P, Zhu Y, et al. Molecular profiling reveals a common metabolic signature of tissue fibrosis. Cell Rep Med. 2020;1(4):100056. 10.1016/j.xcrm.2020.100056. PubMed DOI PMC

Zheng P, Sun S, Wang J, Cheng ZJ, Lei KC, Xue M, et al. Integrative omics analysis identifies biomarkers of idiopathic pulmonary fibrosis. Cell Mol Life Sci. 2022;79:66. PubMed DOI PMC

Ruan P, Todd JL, Zhao H, Liu Y, Vinisko R, Soellner JF, et al. Integrative multi-omics analysis reveals novel idiopathic pulmonary fibrosis endotypes associated with disease progression. Respir Res. 2023;24(1):141. 10.1186/s12931-023-02435-0. PubMed DOI PMC

Sivakumar P, Ammar R, Thompson JR, Luo Y, Streltsov D, Porteous M, et al. Integrated plasma proteomics and lung transcriptomics reveal novel biomarkers in idiopathic pulmonary fibrosis. Respir Res. 2021;22(1):273. 10.1186/s12931-021-01860-3. PubMed DOI PMC

Kinnula VL, Fattman CL, Tan RJ, Oury TD. Oxidative stress in pulmonary fibrosis: a possible role for redox modulatory therapy. Am J Respir Crit Care Med. 2005;172:417–22. PubMed DOI PMC

Ruwanpura SM, Thomas BJ, Bardin PG. Pirfenidone: molecular mechanisms and potential clinical applications in lung disease. Am J Respir Cell Mol Biol. 2020;62:413–22. PubMed DOI

Ma Z, Zhao C, Chen Q, Yu C, Zhang H, Zhang Z, et al. Antifibrotic effects of a novel pirfenidone derivative in vitro and in vivo. Pulm Pharmacol Ther. 2018;53:100–6. 10.1016/j.pupt.2018.10.006. PubMed DOI

Hirano A, Kanehiro A, Ono K, Ito W, Yoshida A, Okada C, et al. Pirfenidone modulates airway responsiveness, inflammation, and remodeling after repeated challenge. Am J Res Cell Mol Biol. 2006;35:366–77. PubMed DOI PMC

Gurujeyalakshmi G, Hollinger MA, Giri SN. Pirfenidone inhibits PDGF isoforms in bleomycin hamster model of lung fibrosis at the translational level. Am J Physiol. 1999;276:L311-318. PubMed

Wollin L, Maillet I, Quesniaux V, Holweg A, Ryffel B. Antifibrotic and anti-inflammatory activity of the tyrosine kinase inhibitor nintedanib in experimental models of lung fibrosis. J Pharmacol Exp Ther. 2014;349(2):209–20. 10.1124/jpet.113.208223. PubMed DOI

Hostettler KE, Zhong J, Papakonstantinou E, Karakiulakis G, Tamm M, Seidel P, et al. Anti-fibrotic effects of nintedanib in lung fibroblasts derived from patients with idiopathic pulmonary fibrosis. Respir Res. 2014;15(1):157. 10.1186/s12931-014-0157-3. PubMed DOI PMC

Crinò L, Metro G. Therapeutic options targeting angiogenesis in nonsmall cell lung cancer. Eur Respir Rev. 2014;23(131):79–91. 10.1183/09059180.00008913. PubMed DOI PMC

Renzoni EA. Neovascularization in idiopathic pulmonary fibrosis: too much or too little? Am J Respir Crit Care Med. 2004;169(11):1179–80. 10.1164/rccm.2403006. PubMed DOI

Roach KM, Castells E, Dixon K, Mason S, Elliott G, Marshall H, et al. Evaluation of pirfenidone and nintedanib in a human lung model of fibrogenesis. Front Pharmacol. 2021;12:679388. 10.3389/fphar.2021.679388. PubMed DOI PMC

Reininger D, Wolf F, Mayr CH, Wespel SL, Laufhaeger N, Geillinger-Kästle K, Dick A, Gantner F, Nickolaus P, Herrmann FE. Insights into the Cellular and Molecular Mechanisms Behind the Antifibrotic Effects of Nerandomilast. Am J Respir Cell Mol Biol. 2025. Online ahead of print. PubMed PMC

Maher TM, Assassi S, Azuma A, Cottin V, Hoffmann-Vold AM, Kreuter M, et al. Nerandomilast in patients with progressive pulmonary fibrosis. N Engl J Med. 2025;392(22):2203–14. 10.1056/NEJMoa2503643. PubMed DOI

Richeldi L, Azuma A, Cottin V, Kreuter M, Maher TM, Martinez FJ, et al. Nerandomilast in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2025;392:2193–202. PubMed DOI

Sun H, Zhu Y, Pan H, Chen X, Balestrini JL, Lam TT, et al. Netrin-1 regulates fibrocyte accumulation in the decellularized fibrotic sclerodermatous lung microenvironment and in bleomycin-induced pulmonary fibrosis. Arthritis Rheumatol. 2016;68(5):1251–61. 10.1002/art.39575. PubMed DOI PMC

Rajasekharan S, Kennedy TE. The netrin protein family. Genome Biol. 2009;10:239. PubMed DOI PMC

van der Velden JL, Wagner DE, Lahue KG, Abdalla ST, Lam YW, Weiss DJ, et al. TGF-β1-induced deposition of provisional extracellular matrix by tracheal basal cells promotes epithelial-to-mesenchymal transition in a c-Jun NH(2)-terminal kinase-1-dependent manner. Am J Physiol Lung Cell Mol Physiol. 2018;314(6):L984-l997. 10.1152/ajplung.00053.2017. PubMed DOI PMC

Mattos W, Khalil N, Spencer LG, Bonella F, Folz RJ, Rolf JD, et al. Phase 2, double-blind, placebo-controlled trial of a c-Jun N-terminal kinase inhibitor in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2024;210:435–43. PubMed DOI

Roach KM, Sutcliffe A, Matthews L, Elliott G, Newby C, Amrani Y, et al. A model of human lung fibrogenesis for the assessment of anti-fibrotic strategies in idiopathic pulmonary fibrosis. Sci Rep. 2018;8(1):342. 10.1038/s41598-017-18555-9. PubMed DOI PMC

Derseh HB, Dewage SNV, Perera KUE, Pagel CN, Koumoundouros E, Organ L, et al. K(Ca)3.1 channel blockade attenuates microvascular remodelling in a large animal model of bleomycin-induced pulmonary fibrosis. Sci Rep. 2019;9:19893. PubMed DOI PMC

Senicapoc in Patients with Worsening Fibrotic Interstitial Lung Disease [https://trial.medpath.com/clinical-trial/4b33d331b2774e26/nct06714123-senicapoc-fibrotic-ild-ipf-prevention]

Vats A, Chaturvedi P. The regenerative power of stem cells. Treating bleomycin-induced lung fibrosis. Stem Cells Cloning. 2023;16:43–59. PubMed PMC

Miceli V, Pampalone M, Vella S, Carreca AP, Amico G, Conaldi PG. Comparison of immunosuppressive and angiogenic properties of human amnion-derived mesenchymal stem cells between 2D and 3D culture systems. Stem Cells Int. 2019;2019:7486279. 10.1155/2019/7486279. PubMed DOI PMC

Shu J, He X, Li H, Liu X, Qiu X, Zhou T, et al. The beneficial effect of human amnion mesenchymal cells in inhibition of inflammation and induction of neuronal repair in EAE mice. J Immunol Res. 2018;2018:5083797. 10.1155/2018/5083797. PubMed DOI PMC

Decaris ML, Schaub JR, Chen C, Cha J, Lee GG, Rexhepaj M, et al. Dual inhibition of αvβ6 and αvβ1 reduces fibrogenesis in lung tissue explants from patients with IPF. Respir Res. 2021;22(1):265. 10.1186/s12931-021-01863-0. PubMed DOI PMC

Birker-Robaczewska M, Boucher M, Ranieri G, Poirey S, Studer R, Freti D, et al. The novel lysophosphatidic acid receptor 1-selective antagonist, ACT-1016-0707, has unique binding properties that translate into effective antifibrotic and anti-inflammatory activity in different models of pulmonary fibrosis. J Pharmacol Exp Ther. 2025;392(3):103396. 10.1016/j.jpet.2025.103396. PubMed DOI

Hay M, Thomas DW, Craighead JL, Economides C, Rosenthal J. Clinical development success rates for investigational drugs. Nat Biotechnol. 2014;32:40–51. PubMed DOI

Sedláková V, Kloučková M, Garlíková Z, Vašíčková K, Jaroš J, Kandra M, et al. Options for modeling the respiratory system: inserts, scaffolds and microfluidic chips. Drug Discov Today. 2019;24(4):971–82. 10.1016/j.drudis.2019.03.006. PubMed DOI

Yanagihara T, Chong SG, Vierhout M, Hirota JA, Ask K, Kolb M. Current models of pulmonary fibrosis for future drug discovery efforts. Expert Opin Drug Discov. 2020;15(8):931–41. 10.1080/17460441.2020.1755252. PubMed DOI

Sundarakrishnan A, Chen Y, Black LD, Aldridge BB, Kaplan DL. Engineered cell and tissue models of pulmonary fibrosis. Adv Drug Deliv Rev. 2018;129:78–94. 10.1016/j.addr.2017.12.013. PubMed DOI

Moeller A, Ask K, Warburton D, Gauldie J, Kolb M. The bleomycin animal model: A useful tool to investigate treatment options for idiopathic pulmonary fibrosis? Int J Biochem Cell Biol. 2008;40(3):362–82. 10.1016/j.biocel.2007.08.011. PubMed DOI PMC

Chua F, Gauldie J, Laurent GJ. Pulmonary fibrosis: searching for model answers. Am J Respir Cell Mol Biol. 2005;33(1):9–13. 10.1165/rcmb.2005-0062TR. PubMed DOI

Sundarakrishnan A, Zukas H, Coburn J, Bertini BT, Liu Z, Georgakoudi I, et al. Bioengineered in vitro tissue model of fibroblast activation for modeling pulmonary fibrosis. ACS Biomater Sci Eng. 2019;5(5):2417–29. 10.1021/acsbiomaterials.8b01262. PubMed DOI

Basil MC, Morrisey EE. Lung regeneration: a tale of mice and men. Semin Cell Dev Biol. 2020;100:88–100. 10.1016/j.semcdb.2019.11.006. PubMed DOI PMC

Schrier DJ, Kunkel RG, Phan SH. The role of strain variation in murine bleomycin-induced pulmonary fibrosis. Am J Respir Crit Care Med. 1983;127:63–6. PubMed

Raghu G. Idiopathic pulmonary fibrosis. Lessons from clinical trials over the past 25 years. Eur Respir J. 2017;50:1701209. PubMed DOI

Fregonese L, Eichler I. The future of the development of medicines in idiopathic pulmonary fibrosis. BMC Med. 2015;13(1):239. 10.1186/s12916-015-0480-7. PubMed DOI PMC

Jenkins RG, Moore BB, Chambers RC, Eickelberg O, Königshoff M, Kolb M, et al. An official American Thoracic Society workshop report. Use of animal models for the preclinical assessment of potential therapies for pulmonary fibrosis. Am J Respir Cell Mol Biol. 2017;56:667–79. PubMed DOI PMC

Ishida Y, Kuninaka Y, Mukaida N, Kondo T. Immune mechanisms of pulmonary fibrosis with bleomycin. Int J Mol Sci. 2023;24(4):3149. 10.3390/ijms24043149. PubMed DOI PMC

Adamson IY, Bowden DH. Bleomycin-induced injury and metaplasia of alveolar type 2 cells. Relationship of cellular responses to drug presence in the lung. Am J Pathol. 1979;96:531–44. PubMed PMC

Kolb P, Upagupta C, Vierhout M, Ayaub E, Bellaye PS, Gauldie J, et al. The importance of interventional timing in the bleomycin model of pulmonary fibrosis. Eur Respir J. 2020;55(6):1901105. 10.1183/13993003.01105-2019. PubMed DOI

Karvonen RL, Fernandez-Madrid F, Maughan RL, Palmer KC, Fernandez-Madrid I. An animal model of pulmonary radiation fibrosis with biochemical, physiologic, immunologic, and morphologic observations. Radiat Res. 1987;111(1):68–80. 10.2307/3577022. PubMed DOI

Sime PJ, Xing Z, Graham FL, Csaky KG, Gauldie J. Adenovector-mediated gene transfer of active transforming growth factor-beta1 induces prolonged severe fibrosis in rat lung. J Clin Invest. 1997;100(4):768–76. 10.1172/JCI119590. PubMed DOI PMC

Sime PJ, Marr RA, Gauldie D, Xing Z, Hewlett BR, Graham FL, et al. Transfer of tumor necrosis factor-alpha to rat lung induces severe pulmonary inflammation and patchy interstitial fibrogenesis with induction of transforming growth factor-beta1 and myofibroblasts. Am J Pathol. 1998;153:825–32. PubMed DOI PMC

Kolb M, Margetts PJ, Anthony DC, Pitossi F, Gauldie J. Transient expression of IL-1beta induces acute lung injury and chronic repair leading to pulmonary fibrosis. J Clin Invest. 2001;107:1529–36. PubMed DOI PMC

Nureki SI, Tomer Y, Venosa A, Katzen J, Russo SJ, Jamil S, et al. Expression of mutant Sftpc in murine alveolar epithelia drives spontaneous lung fibrosis. J Clin Invest. 2018;128(9):4008–24. 10.1172/JCI99287. PubMed DOI PMC

Povedano JM, Martinez P, Flores JM, Mulero F, Blasco MA. Mice with pulmonary fibrosis driven by telomere dysfunction. Cell Rep. 2015;12(2):286–99. 10.1016/j.celrep.2015.06.028. PubMed DOI

Hancock LA, Hennessy CE, Solomon GM, Dobrinskikh E, Estrella A, Hara N, et al. Muc5b overexpression causes mucociliary dysfunction and enhances lung fibrosis in mice. Nat Commun. 2018;9:5363. PubMed DOI PMC

Young LR, Pasula R, Gulleman PM, Deutsch GH, McCormack FX. Susceptibility of Hermansky-Pudlak mice to bleomycin-induced type II cell apoptosis and fibrosis. Am J Respir Cell Mol Biol. 2007;37:67–74. PubMed DOI PMC

Korogi Y, Gotoh S, Ikeo S, Yamamoto Y, Sone N, Tamai K, et al. In vitro disease modeling of Hermansky-Pudlak syndrome type 2 using human induced pluripotent stem cell-derived alveolar organoids. Stem Cell Reports. 2019;12(3):431–40. 10.1016/j.stemcr.2019.01.014. PubMed DOI PMC

Habiel DM, Espindola MS, Coelho AL, Hogaboam CM. Modeling idiopathic pulmonary fibrosis in humanized severe combined immunodeficient mice. Am J Pathol. 2018;188(4):891–903. 10.1016/j.ajpath.2017.12.020. PubMed DOI PMC

Geng Y, Liu X, Liang J, Habiel DM, Kulur V, Coelho AL, et al. PD-L1 on invasive fibroblasts drives fibrosis in a humanized model of idiopathic pulmonary fibrosis. JCI insight. 2019;4(6):e125326. 10.1172/jci.insight.125326. PubMed DOI PMC

Liu Y, Wu W, Cai C, Zhang H, Shen H, Han Y. Patient-derived xenograft models in cancer therapy: technologies and applications. Signal Transduct Target Ther. 2023;8(1):160. 10.1038/s41392-023-01419-2. PubMed DOI PMC

Russell W, Burch R. The principles of humane experimental technique. London: Methuen & Co. Ltd.; 1959.

Koziol-White C, Gebski E, Cao G, Panettieri RA Jr. Precision cut lung slices: an integrated ex vivo model for studying lung physiology, pharmacology, disease pathogenesis and drug discovery. Respir Res. 2024;25(1):231. 10.1186/s12931-024-02855-6. PubMed DOI PMC

Alsafadi HN, Staab-Weijnitz CA, Lehmann M, Lindner M, Peschel B, Königshoff M, et al. An ex vivo model to induce early fibrosis-like changes in human precision-cut lung slices. Am J Physiol Lung Cell Mol Physiol. 2017;312(6):L896-l902. 10.1152/ajplung.00084.2017. PubMed DOI

Lehmann M, Buhl L, Alsafadi HN, Klee S, Hermann S, Mutze K, et al. Differential effects of Nintedanib and Pirfenidone on lung alveolar epithelial cell function in ex vivo murine and human lung tissue cultures of pulmonary fibrosis. Respir Res. 2018;19(1):175. 10.1186/s12931-018-0876-y. PubMed DOI PMC

Ihara H, Mitsuishi Y, Kato M, Takahashi F, Tajima K, Hayashi T, et al. Nintedanib inhibits epithelial-mesenchymal transition in A549 alveolar epithelial cells through regulation of the TGF-β/Smad pathway. Respir Investig. 2020;58(4):275–84. 10.1016/j.resinv.2020.01.003. PubMed DOI

Togami K, Yamaguchi K, Chono S, Tada H. Evaluation of permeability alteration and epithelial–mesenchymal transition induced by transforming growth factor-β1 in A549, NCI-H441, and Calu-3 cells: development of an in vitro model of respiratory epithelial cells in idiopathic pulmonary fibrosis. J Pharmacol Toxicol Methods. 2017;86:19–27. 10.1016/j.vascn.2017.02.023. PubMed DOI

Li D, Zhang X, Song Z, Zhao S, Huang Y, Qian W, et al. Advances in common in vitro cellular models of pulmonary fibrosis. Immunol Cell Biol. 2024;102:557–69. PubMed DOI

Vancheri C. Common pathways in idiopathic pulmonary fibrosis and cancer. Eur Respir Rev. 2013;22:265–72. PubMed DOI PMC

Vásquez-Pacheco E, Marega M, Lingampally A, Fassy J, Truchi M, Goth K, et al. Highlighting fibroblast plasticity in lung fibrosis: the WI-38 cell line as a model for investigating the myofibroblast and lipofibroblast switch. Theranostics. 2024;14:3603–22. PubMed DOI PMC

Watts KL, Cottrell E, Hoban PR, Spiteri MA. RhoA signaling modulates cyclin D1 expression in human lung fibroblasts; implications for idiopathic pulmonary fibrosis. Respir Res. 2006;7:88. PubMed DOI PMC

Liang G, Zhang Y. Embryonic stem cell and induced pluripotent stem cell: an epigenetic perspective. Cell Res. 2013;23:49–69. PubMed DOI PMC

Ermolaeva M, Neri F, Ori A, Rudolph KL. Cellular and epigenetic drivers of stem cell ageing. Nat Rev Mol Cell Biol. 2018;19:594–610. PubMed DOI

Kotasová H, Capandová M, Pelková V, Dumková J, Koledová Z, Remšík J, et al. Expandable lung epithelium differentiated from human embryonic stem cells. Tissue Eng Regen Med. 2022;19:1033–50. PubMed DOI PMC

Schruf E, Schroeder V, Le HQ, Schönberger T, Raedel D, Stewart EL, et al. Recapitulating idiopathic pulmonary fibrosis related alveolar epithelial dysfunction in a human iPSC-derived air-liquid interface model. FASEB J. 2020;34:7825–46. PubMed DOI

Ptasinski V, Monkley SJ, Öst K, Tammia M, Alsafadi HN, Overed-Sayer C, et al. Modeling fibrotic alveolar transitional cells with pluripotent stem cell-derived alveolar organoids. Life Sci Alliance. 2023;6(8):e202201853. 10.26508/lsa.202201853. PubMed DOI PMC

Portakal T, Havlíček V, Herůdková J, Pelková V, Gruntová T, Çakmakci RC, et al. Lipopolysaccharide induces retention of E-cadherin in the endoplasmic reticulum and promotes hybrid epithelial-to-mesenchymal transition of human embryonic stem cells-derived expandable lung epithelial cells. Inflamm Res. 2025;74:82. PubMed DOI PMC

Kawase E, Nakatsuji N. Development of substrates for the culture of human pluripotent stem cells. Biomater Sci. 2023;11:2974–87. PubMed DOI

Blanc P, Coste K, Pouchin P, Azaïs J-M, Blanchon L, Gallot D, et al. A role for mesenchyme dynamics in mouse lung branching morphogenesis. PLoS ONE. 2012;7(7):e41643. 10.1371/journal.pone.0041643. PubMed DOI PMC

Franzdóttir SR, Axelsson IT, Arason AJ, Baldursson Ó, Gudjonsson T, Magnusson MK. Airway branching morphogenesis in three dimensional culture. Respir Res. 2010;11:162. PubMed DOI PMC

Sakai T, Larsen M, Yamada KM. Fibronectin requirement in branching morphogenesis. Nature. 2003;423:876–81. PubMed DOI

Smithmyer ME, Sawicki LA, Kloxin AM. Hydrogel scaffolds as in vitro models to study fibroblast activation in wound healing and disease. Biomater Sci. 2014;2:634–50. PubMed DOI PMC

Barosova H, Maione AG, Septiadi D, Sharma M, Haeni L, Balog S, et al. Use of EpiAlveolar Lung Model to predict fibrotic potential of multiwalled carbon nanotubes. ACS Nano. 2020;14:3941–56. PubMed DOI

Barron SL, Wyatt O, O’Connor A, Mansfield D, Suzanne Cohen E, Witkos TM, et al. Modelling bronchial epithelial-fibroblast cross-talk in idiopathic pulmonary fibrosis (IPF) using a human-derived in vitro air liquid interface (ALI) culture. Sci Rep. 2024;14:240. PubMed DOI PMC

Hagiwara M, Peng F, Ho C-M. In vitro reconstruction of branched tubular structures from lung epithelial cells in high cell concentration gradient environment. Sci Rep. 2015;5:8054. PubMed DOI PMC

Kolanko E, Cargnoni A, Papait A, Silini AR, Czekaj P, Parolini O. The evolution of in vitro models of lung fibrosis: promising prospects for drug discovery. Eur Respir Rev. 2024;33(171):230127. 10.1183/16000617.0127-2023. PubMed DOI PMC

Sant S, Johnston PA. The production of 3D tumor spheroids for cancer drug discovery. Drug Discov Today Technol. 2017;23:27–36. 10.1016/j.ddtec.2017.03.002. PubMed DOI PMC

Henry E, Cores J, Hensley MT, Anthony S, Vandergriff A, de Andra JB, et al. Adult lung spheroid cells contain progenitor cells and mediate regeneration in rodents with bleomycin-induced pulmonary fibrosis. Stem Cells Transl Med. 2015;4:1265–74. PubMed DOI PMC

Surolia R, Li FJ, Wang Z, Li H, Liu G, Zhou Y, et al. 3D pulmospheres serve as a personalized and predictive multicellular model for assessment of antifibrotic drugs. JCI Insight. 2017;2(2):e91377. 10.1172/jci.insight.91377. PubMed DOI PMC

Lancaster MA, Knoblich JA. Organogenesis in a dish: modeling development and disease using organoid technologies. Science. 2014;345:1247125. PubMed DOI

Wilkinson DC, Alva-Ornelas JA, Sucre JM, Vijayaraj P, Durra A, Richardson W, et al. Development of a three-dimensional bioengineering technology to generate lung tissue for personalized disease modeling. Stem Cells Transl Med. 2017;6(2):622–33. 10.5966/sctm.2016-0192. PubMed DOI PMC

Strikoudis A, Cieślak A, Loffredo L, Chen YW, Patel N, Saqi A, et al. Modeling of fibrotic lung disease using 3D organoids derived from human pluripotent stem cells. Cell Rep. 2019;27:3709-3723.e3705. PubMed DOI PMC

Blumer S, Khan P, Artysh N, Plappert L, Savic S, Knudsen L, et al. The use of cultured human alveolar basal cells to mimic honeycomb formation in idiopathic pulmonary fibrosis. Respir Res. 2024;25:26. PubMed DOI PMC

Vazquez‐Armendariz AI, Heiner M, El Agha E, Salwig I, Hoek A, Hessler MC, et al. Multilineage murine stem cells generate complex organoids to model distal lung development and disease. EMBO J. 2020;39(21):e103476. 10.15252/embj.2019103476. PubMed DOI PMC

Yamamoto Y, Gotoh S, Korogi Y, Seki M, Konishi S, Ikeo S, et al. Long-term expansion of alveolar stem cells derived from human iPS cells in organoids. Nat Methods. 2017;14:1097–106. PubMed DOI

Yang Q, Li M, Xiao Z, Feng Y, Lei L, Li S. A new perspective on precision medicine. The power of digital organoids. Biomater Res. 2025;29:0171. PubMed DOI PMC

Coggan H, Weeden CE, Pearce P, Dalwadi MP, Magness A, Swanton C, et al. An agent-based modelling framework to study growth mechanisms in EGFR-L858R mutant cell alveolar type II cells. R Soc Open Sci. 2024;11(7):240413. 10.1098/rsos.240413. PubMed DOI PMC

Sedlakova V, Ruel M, Suuronen EJ. Therapeutic use of bioengineered materials for myocardial infarction. In: Edited by Alarcon EI, Ahumada M, editors. Nanoengineering Materials for Biomedical Uses. Cham: Springer International Publishing; 2019. p. 161–193.

Drury JL, Mooney DJ. Hydrogels for tissue engineering: scaffold design variables and applications. Biomaterials. 2003;24(24):4337–51. 10.1016/S0142-9612(03)00340-5. PubMed DOI

Dunsmore SE. Treatment of COPD: a matrix perspective. Int J Chron Obstruct Pulmon Dis. 2008;3:113–22. PubMed DOI PMC

Berhan A, Harris T, Jaffar J, Jativa F, Langenbach S, Lönnstedt I, et al. Cellular microenvironment stiffness regulates eicosanoid production and signaling pathways. Am J Respir Cell Mol Biol. 2020;63:819–30. PubMed DOI

Zhang Q, Wang P, Fang X, Lin F, Fang J, Xiong C. Collagen gel contraction assays: from modelling wound healing to quantifying cellular interactions with three-dimensional extracellular matrices. Eur J Cell Biol. 2022;101(3):151253. 10.1016/j.ejcb.2022.151253. PubMed DOI

Travis JA, Hughes MG, Wong JM, Wagner WD, Geary RL. Hyaluronan enhances contraction of collagen by smooth muscle cells and adventitial fibroblasts: role of CD44 and implications for constrictive remodeling. Circ Res. 2001;88(1):77–83. 10.1161/01.RES.88.1.77. PubMed DOI

Grinnell F, Petroll WM. Cell motility and mechanics in three-dimensional collagen matrices. Annu Rev Cell Dev Biol. 2010;26:335–61. PubMed DOI

Asano S, Ito S, Takahashi K, Furuya K, Kondo M, Sokabe M, et al. Matrix stiffness regulates migration of human lung fibroblasts. Physiol Rep. 2017;5(9):e13281. 10.14814/phy2.13281. PubMed DOI PMC

Matera DL, DiLillo KM, Smith MR, Davidson CD, Parikh R, Said M, et al. Microengineered 3D pulmonary interstitial mimetics highlight a critical role for matrix degradation in myofibroblast differentiation. Sci Adv. 2020;6:eabb5069. PubMed DOI PMC

Vijayaraj P, Minasyan A, Durra A, Karumbayaram S, Mehrabi M, Aros CJ, et al. Modeling progressive fibrosis with pluripotent stem cells identifies an anti-fibrotic small molecule. Cell Rep. 2019;29:3488-3505.e3489. PubMed DOI PMC

Capandova M, Sedlakova V, Vorac Z, Kotasova H, Dumkova J, Moran L, et al. Using polycaprolactone nanofibers for the proof-of-concept construction of the alveolar-capillary interface. J Biomed Mater Res A. 2025;113(1):e37824. 10.1002/jbm.a.37824. PubMed DOI

Garlíková Z, Silva AC, Rabata A, Potěšil D, Ihnatová I, Dumková J, et al. Generation of a close-to-native in vitro system to study lung cells-extracellular matrix crosstalk. Tissue Eng Part C Methods. 2018;24(1):1–13. 10.1089/ten.tec.2017.0283. PubMed DOI

Gilpin SE, Guyette JP, Gonzalez G, Ren X, Asara JM, Mathisen DJ, et al. Perfusion decellularization of human and porcine lungs: bringing the matrix to clinical scale. J Heart Lung Transplant. 2014;33(3):298–308. 10.1016/j.healun.2013.10.030. PubMed DOI

Rosmark O, Kadefors M, Dellgren G, Karlsson C, Ericsson A, Lindstedt S, et al. Alveolar epithelial cells are competent producers of interstitial extracellular matrix with disease relevant plasticity in a human in vitro 3D model. Sci Rep. 2023;13(1):8801. 10.1038/s41598-023-35011-z. PubMed DOI PMC

Pouliot RA, Link PA, Mikhaiel NS, Schneck MB, Valentine MS, Kamga Gninzeko FJ, et al. Development and characterization of a naturally derived lung extracellular matrix hydrogel. J Biomed Mater Res A. 2016;104(8):1922–35. 10.1002/jbm.a.35726. PubMed DOI PMC

Dabaghi M, Saraei N, Carpio MB, Nanduri V, Ungureanu J, Babi M, et al. A robust protocol for decellularized human lung bioink generation amenable to 2D and 3D lung cell culture. Cells. 2021;10(6):1538. 10.3390/cells10061538. PubMed DOI PMC

de Hilster RHJ, Sharma PK, Jonker MR, White ES, Gercama EA, Roobeek M, et al. Human lung extracellular matrix hydrogels resemble the stiffness and viscoelasticity of native lung tissue. Am J Physiol Lung Cell Mol Physiol. 2020;318(4):L698-l704. 10.1152/ajplung.00451.2019. PubMed DOI PMC

Fernandez Davila JG, Singh AK, Moore DW, Kim J, Khan JA, Lemma M, et al. Pulmonary matrix-derived hydrogels from patients with idiopathic pulmonary fibrosis induce a proinflammatory state in lung fibroblasts in vitro. Mol Biol Cell. 2024;35:ar114. PubMed DOI PMC

Petrou CL, D’Ovidio TJ, Bölükbas DA, Tas S, Brown RD, Allawzi A, et al. Clickable decellularized extracellular matrix as a new tool for building hybrid-hydrogels to model chronic fibrotic diseases in vitro. J Mater Chem B. 2020;8(31):6814–26. 10.1039/D0TB00613K. PubMed DOI PMC

Saleh KS, Hewawasam R, Šerbedžija P, Blomberg R, Noreldeen SE, Edelman B, et al. Engineering Hybrid-Hydrogels Comprised of Healthy or Diseased Decellularized Extracellular Matrix to Study Pulmonary Fibrosis. Cell Mol Bioeng. 2022;15(5):505–19. 10.1007/s12195-022-00726-y. PubMed DOI PMC

Balestrini JL, Gard AL, Gerhold KA, Wilcox EC, Liu A, Schwan J, et al. Comparative biology of decellularized lung matrix: implications of species mismatch in regenerative medicine. Biomaterials. 2016;102:220–30. 10.1016/j.biomaterials.2016.06.025. PubMed DOI PMC

Hoffman E, Song Y, Zhang F, Asarian L, Downs I, Young B, et al. Regional and disease-specific glycosaminoglycan composition and function in decellularized human lung extracellular matrix. Acta Biomater. 2023;168:388–99. PubMed DOI PMC

Asmani M, Velumani S, Li Y, Wawrzyniak N, Hsia I, Chen Z, et al. Fibrotic microtissue array to predict anti-fibrosis drug efficacy. Nat Commun. 2018;9(1):2066. 10.1038/s41467-018-04336-z. PubMed DOI PMC

Booth AJ, Hadley R, Cornett AM, Dreffs AA, Matthes SA, Tsui JL, et al. Acellular normal and fibrotic human lung matrices as a culture system for in vitro investigation. Am J Respir Crit Care Med. 2012;186(9):866–76. 10.1164/rccm.201204-0754OC. PubMed DOI PMC

Ahadian S, Civitarese R, Bannerman D, Mohammadi MH, Lu R, Wang E, et al. Organ-On-A-Chip Platforms: a convergence of advanced materials, cells, and microscale technologies. Adv Healthc Mater. 2018;7(2):1700506. 10.1002/adhm.201700506. PubMed DOI

Huh D, Matthews BD, Mammoto A, Montoya-Zavala M, Hsin HY, Ingber DE. Reconstituting organ-level lung functions on a chip. Science. 2010;328(5986):1662–8. 10.1126/science.1188302. PubMed DOI PMC

Huh D, Leslie DC, Matthews BD, Fraser JP, Jurek S, Hamilton GA, et al. A human disease model of drug toxicity-induced pulmonary edema in a lung-on-a-chip microdevice. Sci Transl Med. 2012;4:159ra147. PubMed DOI PMC

Herland A, Maoz BM, Das D, Somayaji MR, Prantil-Baun R, Novak R, et al. Quantitative prediction of human pharmacokinetic responses to drugs via fluidically coupled vascularized organ chips. Nat Biomed Eng. 2020;4(4):421–36. 10.1038/s41551-019-0498-9. PubMed DOI PMC

Bovard D, Sandoz A, Luettich K, Frentzel S, Iskandar A, Marescotti D, et al. A lung/liver-on-a-chip platform for acute and chronic toxicity studies. Lab Chip. 2018;18(24):3814–29. 10.1039/C8LC01029C. PubMed DOI

Kannan RR, Singh N, Przekwas A. A compartment-quasi-3D multiscale approach for drug absorption, transport, and retention in the human lungs. Int J Numer Meth Biomed Eng. 2018;34:e2955. PubMed DOI PMC

Shen C, Yang H, She W, Meng Q. A microfluidic lung-on-a-chip based on biomimetic hydrogel membrane. Biotechnol Bioeng. 2023;120(7):2027–38. 10.1002/bit.28426. PubMed DOI

Xia J, Dong R, Fang Y, Guo J, Xiong Z, Zhang T, et al. A micro-lung chip with macrophages for targeted anti-fibrotic therapy. Biofabrication. 2025;17(2):025020. PubMed DOI

Felder M, Trueeb B, Stucki AO, Borcard S, Stucki JD, Schnyder B, et al. Impaired wound healing of alveolar lung epithelial cells in a breathing lung-on-a-chip. Front Bioeng Biotechnol. 2019;7:3. 10.3389/fbioe.2019.00003. PubMed DOI PMC

Doryab A, Taskin MB, Stahlhut P, Groll J, Schmid O. Real-time measurement of cell mechanics as a clinically relevant readout of an in vitro lung fibrosis model established on a bioinspired basement membrane. Adv Mater. 2022;34(41):2205083. 10.1002/adma.202205083. PubMed DOI