Post-COVID-19 pulmonary fibrosis: Mechanisms, biomarkers, and therapeutic perspectives

Abstract

Post-COVID-19 pulmonary fibrosis (post-CPF) has emerged as a serious complication with profound implications for long-term respiratory health. This short review explores the multifactorial mechanisms underlying post-CPF, emphasising the role of oxidative stress, epithelial-to-mesenchymal transition (EMT), and dysregulated immune responses. Key signalling pathways, such as TGF-β, WNT, and Cadherin, are pivotal in fibrosis progression, offering potential therapeutic targets. Biomarkers, such as MUC4, KRT5, and ATP12A show promise for early detection and therapeutic targeting, as they share molecular features with idiopathic pulmonary fibrosis (IPF) and fibrotic interstitial lung diseases (f-ILDs), suggesting opportunities to repurpose antifibrotic therapies. Despite these advancements, significant gaps remain in understanding the cellular and molecular mechanisms underlying fibrosis progression, hindering effective management of post-CPF. Addressing these challenges through a targeted approach is critical to improving outcomes for survivors of severe COVID-19.

Keywords

diffuse alveolar damage / fibrotic biomarkers / immune dysregulation / post-COVID-19 pulmonary fibrosis / SARS-CoV-2

References

[1] BallL, Barisione E, MastracciL, et al. Extension of collagen deposition in COVID-19 post mortem lung samples and computed tomography analysis findings. Int J Mol Sci. 2021;22(14):7498.

[2] BharatA, Machuca TN, QuerreyM, et al. Early outcomes after lung transplantation for severe COVID-19: a series of the first consecutive cases from four countries. Lancet Respir Med. 2021;9(5):487-497.

[3] GulatiA, Lakhani P. Interstitial lung abnormalities and pulmonary fibrosis in COVID-19 patients: a short-term follow-up case series. Clin Imaging. 2021;77:180-186.

[4] FrischbutterS, DurekP, WitkowskiM, et al. Serum TGF-beta as a predictive biomarker for severe disease and fatality of COVID-19. Eur J Immunol. 2023;53(10):e2350433.

[5] PiP, ZengZ, ZengL, Han B, BaiX, XuS. Molecular mechanisms of COVID-19-induced pulmonary fibrosis and epithelial-mesenchymal transition. Front Pharmacol. 2023;14:1218059.

[6] DelpinoMV, Quarleri J. SARS-CoV-2 pathogenesis: imbalance in the renin-angiotensin system favors lung fibrosis. Front Cell Infect Microbiol. 2020;10:340.

[7] GuoX, WangXF. Signaling cross-talk between TGF-beta/BMP and other pathways. Cell Res. 2009;19(1):71-88.

[8] HirawatR, JainN, Aslam SaifiM, RachamallaM, GoduguC. Lung fibrosis: post-COVID-19 complications and evidences. Int Immunopharmacol. 2023;116:109418.

[9] Niayesh-MehrR, Kalantar M, BontempiG, et al. The role of epithelial-mesenchymal transition in pulmonary fibrosis: lessons from idiopathic pulmonary fibrosis and COVID-19. Cell Commun Signal. 2024;22(1):542.

[10] ZhangL, TangC, ZhangM, et al. Single cell meta-analysis of EndMT and EMT state in COVID-19. Front Immunol. 2022;13:976512.

[11] PandolfiL, Bozzini S, FrangipaneV, et al. Neutrophil extracellular traps induce the epithelial-mesenchymal transition: implications in post-COVID-19 fibrosis. Front Immunol. 2021;12:663303.

[12] StewartCA, GayCM, RamkumarK, et al. Lung cancer models reveal severe acute respiratory syndrome coronavirus 2–induced epithelial-to-mesenchymal transition contributes to coronavirus disease 2019 pathophysiology. Journal of Thoracic Oncology. 2021;16(11):1821-1839.

[13] WangY, WeiJ, DengH, Zheng L, YangH, LvX. The role of Nrf2 in pulmonary fibrosis: molecular mechanisms and treatment approaches. Antioxidants. 2022;11(9):1685.

[14] Perez-MiesB, Caniego-Casas T, BardiT, et al. Progression to lung fibrosis in severe COVID-19 patients: a morphological and transcriptomic study in postmortem samples. Front Med. 2022;9:976759.

[15] KooistraEJ, DahmK, van HerwaardenAE, et al. Molecular mechanisms and treatment responses of pulmonary fibrosis in severe COVID-19. Respir Res. 2023;24(1):196.

[16] ZhengZ, PengF, ZhouY. Pulmonary fibrosis: a short-or long-term sequelae of severe COVID-19? Chin Med J Pulm Crit Care Med. 2023;1(2):77-83.

[17] HuangL, YaoQ, GuX, et al. 1-year outcomes in hospital survivors with COVID-19: a longitudinal cohort study. Lancet. 2021;398(10302):747-758.

[18] KonopkaKE, PerryW, HuangT, Farver CF, MyersJL. Usual interstitial pneumonia is the most common finding in surgical lung biopsies from patients with persistent interstitial lung disease following infection with SARS-CoV-2. EClin Med. 2021;42:101209.

[19] BatahSS, Rodriguez-Herrera AJ, Faci do MarcoMJ, et al. Transcriptomic profiling reveals the dynamics of fibrotic progression-related gene expression into post-coronavirus disease 2019 pulmonary fibrosis. Clin Transl Med. 2024;14(11):e70088.

[20] AbdelgiedM, ZhouS, UhlK, et al. Increased expression of ATP12A in small airway epithelia of post-COVID-19 pulmonary fibrosis. Am J Respir Cell Mol Biol. 2024;70(6):527-530.

[21] CheonIS, LiC, SonYM, et al. Immune signatures underlying post-acute COVID-19 lung sequelae. Sci Immunol. 2021;6(65):eabk1741.

[22] GeorgePM, ReedA, DesaiSR, et al. A persistent neutrophil-associated immune signature characterizes post-COVID-19 pulmonary sequelae. Sci Transl Med. 2022;14(671):eabo5795.

[23] BinghamGC, Muehling LM, LiC, et al. High-dimensional comparison of monocytes and T cells in post-COVID and idiopathic pulmonary fibrosis. Front Immunol. 2023;14:1308594.

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2025 The Author(s). Clinical and Translational Discovery published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.