新型冠状病毒感染后肺纤维化的机制及治疗进展_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

季辰菲 , 陶媛 ,  吉宁飞

南京医科大学第一附属医院呼吸与危重症医学科（江苏南京 210029）;

Corresponding author：

吉宁飞, Email: jiningfei@163.com

Keywords：

DOI：

10.7507/1671-6205.202504075

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1.	Aslan A, Aslan C, Zolbanin NM, et al. Acute respiratory distress syndrome in COVID-19: possible mechanisms and therapeutic management. Pneumonia(Nathan), 2021, 13(1): 14.
2.	Ambardar SR, Hightower SL, Huprikar NA, et al. Post-COVID-19 pulmonary fibrosis: novel sequelae of the current pandemic. J Clin Med, 2021, 10(11): 2452.
3.	Hirawat R, Jain N, Aslam Saifi M, et al. Lung fibrosis: post-COVID-19 complications and evidences. Int Immunopharmacol, 2023, 116: 109418.
4.	O'Reilly S. Pulmonary fibrosis in COVID-19: mechanisms, consequences and targets. QJM, 2023, 116(9): 750-754.
5.	Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell, 2020, 181(2): 271-280. e8.
6.	Li X, Geng M, Peng Y, et al. Molecular immune pathogenesis and diagnosis of COVID-19. J Pharm Anal, 2020, 10(2): 102-108.
7.	Wynn TA, Ramalingam TR. Mechanisms of fibrosis: therapeutic translation for fibrotic disease. Nat Med, 2012, 18(7): 1028-1040.
8.	Xia X. Domains and functions of spike protein in SARS-cov-2 in the context of vaccine design. Viruses, 2021, 13(1): 109.
9.	Thannickal VJ, Toews GB, White ES, et al. Mechanisms of pulmonary fibrosis. Annu Rev Med, 2004, 55: 395-417.
10.	Lei X, Dong X, Ma R, et al. Activation and evasion of type I interferon responses by SARS-CoV-2. Nat Commun, 2020, 11(1): 3810.
11.	Yuen CK, Lam J , Wong WM, et al. SARS-CoV-2 nsp13, nsp14, nsp15 and orf6 function as potent interferon antagonists. Emerg Microbes Infect, 2020, 9(1): 1418-1428.
12.	Khanmohammadi S, Rezaei N. Role of toll-like receptors in the pathogenesis of COVID-19. J Med Virol, 2021, 93(5): 2735-2739.
13.	Vaz de Paula CB, de Azevedo MLV, Nagashima S, et al. IL-4/IL-13 remodeling pathway of COVID-19 lung injury. Sci Rep, 2020, 10(1): 18689.
14.	Wendisch D, Dietrich O, Mari T, et al. SARS-CoV-2 infection triggers profibrotic macrophage responses and lung fibrosis. Cell, 2021, 184(26): 6243-6261. e27.
15.	Donlan AN, Mallawaarachchi I, Sasson JM, et al. Dupilumab use is associated with protection from coronavirus disease 2019 mortality: a retrospective analysis. Clin Infect Dis, 2023, 76(1): 148-151.
16.	Ferreira-Gomes M, Kruglov A, Durek P, et al. SARS-CoV-2 in severe COVID-19 induces a TGF-β-dominated chronic immune response that does not target itself. Nat Commun, 2021, 12(1): 1961.
17.	Choi EY, Park HH, Kim H, et al. Wnt5a and Wnt11 as acute respiratory distress syndrome biomarkers for severe acute respiratory syndrome coronavirus 2 patients. Eur Respir J, 2020, 56(5): 2001531.
18.	Vallée A, Lecarpentier Y. TGF-β in fibrosis by acting as a conductor for contractile properties of myofibroblasts. Cell Biosci, 2019, 9(1): 98.
19.	Garcia G Jr, Jeyachandran AV, Wang Y, et al. Hippo signaling pathway activation during SARS-CoV-2 infection contributes to host antiviral response. PLOS Biology, 2022, 20(11): e3001851.
20.	Inui N, Sakai S, Kitagawa M. Molecular pathogenesis of pulmonary fibrosis, with focus on pathways related to TGF-β and the ubiquitin-proteasome pathway. International Journal of Molecular Sciences, 2021, 22(11): 6107.
21.	Tsuji S, Minami S, Hashimoto R, et al. SARS-CoV-2 infection triggers paracrine senescence and leads to a sustained senescence-associated inflammatory response. Nature Aging, 2022, 2(2): 115-124.
22.	Lee S, Yu Y, Trimpert J, et al. Virus-induced senescence is a driver and therapeutic target in COVID-19. Nature, 2021, 599(7884): 283-289.
23.	Parimon T, Hohmann MS, Yao C. Cellular senescence: Pathogenic mechanisms in lung fibrosis. International journal of molecular sciences, 2021, 22(12): 6214.
24.	McGroder CF, Zhang D, Choudhury MA, et al. Pulmonary fibrosis 4 months after COVID-19 is associated with severity of illness and blood leucocyte telomere length. Thorax, 2021, 76(12): 1242-1245.
25.	Guiot J, Henket M, Remacle C, et al. Systematic review of overlapping microRNA patterns in COVID-19 and idiopathic pulmonary fibrosis. Respiratory Research, 2023, 24(1): 112.
26.	Shu Y, He L, Liu C. Impact of anti-fibrotic medications on post-COVID-19 pulmonary fibrosis: a systematic review and meta-analysis. International Journal of Infectious Diseases, 2024, 147: 107193.
27.	Banerjee T, Das M, Mitra K. The effect of pirfenidone on pulmonary function parameters in post recovery COVID-19 patients with pulmonary fibrosis compared to placebo in a government medical college, west bengal. Biomedicine, 2022, 42(5): 1005-1007.
28.	Mohamed R H, Abdel hay N H, Fawzy N M, et al. Targeting mevalonate pathway by zoledronate ameliorated pulmonary fibrosis in a rat model: promising therapy against post-COVID-19 pulmonary fibrosis. Fundamental & Clinical Pharmacology, 2024, 38(4): 703-717.
29.	Hirani N, MacKinnon AC, Nicol L, et al. Target inhibition of galectin-3 by inhaled TD139 in patients with idiopathic pulmonary fibrosis. European Respiratory Journal, 2021, 57(5): 2002559.
30.	Mizera J, Genzor S, Sova M, et al. The effectiveness of glucocorticoid treatment in post-COVID-19 pulmonary involvement. Pneumonia, 2024, 16(1): 2.
31.	Myall KJ, Mukherjee B, Castanheira AM, et al. Persistent post–COVID-19 interstitial lung disease. An observational study of corticosteroid treatment. Annals of the American Thoracic Society, 2021, 18(5): 799-806.
32.	Tan HX, Wong CK, Yik WF, et al. Post COVID-19 organizing pneumonia treated with mycophenolate mofetil. Respirology Case Reports, 2022, 10(11): e01042.
33.	Kobayashi T, Tanaka K, Fujita T, et al. Bidirectional role of IL-6 signal in pathogenesis of lung fibrosis. Respiratory Research, 2015, 16(1): 99.
34.	Cojocaru E, Cojocaru T, Pînzariu GM, et al. Perspectives on post-COVID-19 pulmonary fibrosis treatment. Journal of Personalized Medicine, 2024, 14(1): 51.
35.	Zhu Y, Tchkonia T, Pirtskhalava T, et al. The achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell, 2015, 14(4): 644-58.
36.	Nambiar A, Kellogg D, Justice J, et al. Senolytics dasatinib and quercetin in idiopathic pulmonary ﬁbrosis: results of a phase I, single-blind, single-center, randomized, placebo-controlled pilot trial on feasibility and tolerability. EBioMedicine, 2023, 90: 104481.
37.	Shen M, Fu J, Zhang Y, et al. A novel senolytic drug for pulmonary fibrosis: BTSA1 targets apoptosis of senescent myofibroblasts by activating BAX. Aging Cell, 2024, 23(9): e14229.
38.	Reyes NS, Krasilnikov M, Allen NC, et al. Sentinel p16INK4a+ cells in the basement membrane form a reparative niche in the lung. Science, 2022, 378(6616): 192-201.
39.	Chen L, Qu J, Kalyani FS, et al. Mesenchymal stem cell-based treatments for COVID-19: Status and future perspectives for clinical applications. Cellular and Molecular Life Sciences, 2022, 79(3): 142.
40.	Liu J, Peng D, You J, et al. Type 2 alveolar epithelial cells differentiated from human umbilical cord mesenchymal stem cells alleviate mouse pulmonary fibrosis through β-catenin-regulated cell apoptosis. Stem Cells and Development, 2021, 30(13): 660-670.
41.	Avanzini MA, Mura M, Percivalle E, et al. Human mesenchymal stromal cells do not express ACE2 and TMPRSS2 and are not permissive to SARS-CoV-2 infection. Stem Cells Translational Medicine, 2021, 10(4): 636-642.
42.	Wan Q, Zhang X, Zhou D, et al. Inhaled nano-based therapeutics for pulmonary fibrosis: Recent advances and future prospects. Journal of Nanobiotechnology, 2023, 21(1): 215.
43.	Ndebele RT, Yao Q, Shi YN, et al. Progress in the application of nano- and micro-based drug delivery systems in pulmonary drug delivery. BIO Integration, 2022, 3(2).
44.	Asati S, Sahu A, Jain A. Nanotoxicity: the dark side of nanoformulations. Current Nanotoxicity and Prevention, 2021, 1(1): 6-25.
45.	Jacobs SS, Krishnan JA, Lederer DJ, et al. Home oxygen therapy for adults with chronic lung disease. An official American thoracic society clinical practice guideline. American Journal of Respiratory and Critical Care Medicine, 2020, 202(10): e121-e141.
46.	Visca D, Centis R, Pontali E, et al. Clinical standards for diagnosis, treatment and prevention of post-COVID-19 lung disease. The International Journal of Tuberculosis and Lung Disease, 2023, 27(10): 729-741.
47.	Leong SW, Bos S, Lordan L, et al. Lung transplantation for interstitial lung disease: evolution over three decades. BMJ Open Respir Res, 2023, 10(1): e001387.
48.	Mi X. Clinical characteristics and outcomes of lung transplantation in patients with severe COVID-19 infection: a systematic review and meta-analysis. Int J Infect Dis, 2024, 147: 107176.

1. Aslan A, Aslan C, Zolbanin NM, et al. Acute respiratory distress syndrome in COVID-19: possible mechanisms and therapeutic management. Pneumonia(Nathan), 2021, 13(1): 14.
2. Ambardar SR, Hightower SL, Huprikar NA, et al. Post-COVID-19 pulmonary fibrosis: novel sequelae of the current pandemic. J Clin Med, 2021, 10(11): 2452.
3. Hirawat R, Jain N, Aslam Saifi M, et al. Lung fibrosis: post-COVID-19 complications and evidences. Int Immunopharmacol, 2023, 116: 109418.
4. O'Reilly S. Pulmonary fibrosis in COVID-19: mechanisms, consequences and targets. QJM, 2023, 116(9): 750-754.
5. Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell, 2020, 181(2): 271-280. e8.
6. Li X, Geng M, Peng Y, et al. Molecular immune pathogenesis and diagnosis of COVID-19. J Pharm Anal, 2020, 10(2): 102-108.
7. Wynn TA, Ramalingam TR. Mechanisms of fibrosis: therapeutic translation for fibrotic disease. Nat Med, 2012, 18(7): 1028-1040.
8. Xia X. Domains and functions of spike protein in SARS-cov-2 in the context of vaccine design. Viruses, 2021, 13(1): 109.
9. Thannickal VJ, Toews GB, White ES, et al. Mechanisms of pulmonary fibrosis. Annu Rev Med, 2004, 55: 395-417.
10. Lei X, Dong X, Ma R, et al. Activation and evasion of type I interferon responses by SARS-CoV-2. Nat Commun, 2020, 11(1): 3810.
11. Yuen CK, Lam J , Wong WM, et al. SARS-CoV-2 nsp13, nsp14, nsp15 and orf6 function as potent interferon antagonists. Emerg Microbes Infect, 2020, 9(1): 1418-1428.
12. Khanmohammadi S, Rezaei N. Role of toll-like receptors in the pathogenesis of COVID-19. J Med Virol, 2021, 93(5): 2735-2739.
13. Vaz de Paula CB, de Azevedo MLV, Nagashima S, et al. IL-4/IL-13 remodeling pathway of COVID-19 lung injury. Sci Rep, 2020, 10(1): 18689.
14. Wendisch D, Dietrich O, Mari T, et al. SARS-CoV-2 infection triggers profibrotic macrophage responses and lung fibrosis. Cell, 2021, 184(26): 6243-6261. e27.
15. Donlan AN, Mallawaarachchi I, Sasson JM, et al. Dupilumab use is associated with protection from coronavirus disease 2019 mortality: a retrospective analysis. Clin Infect Dis, 2023, 76(1): 148-151.
16. Ferreira-Gomes M, Kruglov A, Durek P, et al. SARS-CoV-2 in severe COVID-19 induces a TGF-β-dominated chronic immune response that does not target itself. Nat Commun, 2021, 12(1): 1961.
17. Choi EY, Park HH, Kim H, et al. Wnt5a and Wnt11 as acute respiratory distress syndrome biomarkers for severe acute respiratory syndrome coronavirus 2 patients. Eur Respir J, 2020, 56(5): 2001531.
18. Vallée A, Lecarpentier Y. TGF-β in fibrosis by acting as a conductor for contractile properties of myofibroblasts. Cell Biosci, 2019, 9(1): 98.
19. Garcia G Jr, Jeyachandran AV, Wang Y, et al. Hippo signaling pathway activation during SARS-CoV-2 infection contributes to host antiviral response. PLOS Biology, 2022, 20(11): e3001851.
20. Inui N, Sakai S, Kitagawa M. Molecular pathogenesis of pulmonary fibrosis, with focus on pathways related to TGF-β and the ubiquitin-proteasome pathway. International Journal of Molecular Sciences, 2021, 22(11): 6107.
21. Tsuji S, Minami S, Hashimoto R, et al. SARS-CoV-2 infection triggers paracrine senescence and leads to a sustained senescence-associated inflammatory response. Nature Aging, 2022, 2(2): 115-124.
22. Lee S, Yu Y, Trimpert J, et al. Virus-induced senescence is a driver and therapeutic target in COVID-19. Nature, 2021, 599(7884): 283-289.
23. Parimon T, Hohmann MS, Yao C. Cellular senescence: Pathogenic mechanisms in lung fibrosis. International journal of molecular sciences, 2021, 22(12): 6214.
24. McGroder CF, Zhang D, Choudhury MA, et al. Pulmonary fibrosis 4 months after COVID-19 is associated with severity of illness and blood leucocyte telomere length. Thorax, 2021, 76(12): 1242-1245.
25. Guiot J, Henket M, Remacle C, et al. Systematic review of overlapping microRNA patterns in COVID-19 and idiopathic pulmonary fibrosis. Respiratory Research, 2023, 24(1): 112.
26. Shu Y, He L, Liu C. Impact of anti-fibrotic medications on post-COVID-19 pulmonary fibrosis: a systematic review and meta-analysis. International Journal of Infectious Diseases, 2024, 147: 107193.
27. Banerjee T, Das M, Mitra K. The effect of pirfenidone on pulmonary function parameters in post recovery COVID-19 patients with pulmonary fibrosis compared to placebo in a government medical college, west bengal. Biomedicine, 2022, 42(5): 1005-1007.
28. Mohamed R H, Abdel hay N H, Fawzy N M, et al. Targeting mevalonate pathway by zoledronate ameliorated pulmonary fibrosis in a rat model: promising therapy against post-COVID-19 pulmonary fibrosis. Fundamental & Clinical Pharmacology, 2024, 38(4): 703-717.
29. Hirani N, MacKinnon AC, Nicol L, et al. Target inhibition of galectin-3 by inhaled TD139 in patients with idiopathic pulmonary fibrosis. European Respiratory Journal, 2021, 57(5): 2002559.
30. Mizera J, Genzor S, Sova M, et al. The effectiveness of glucocorticoid treatment in post-COVID-19 pulmonary involvement. Pneumonia, 2024, 16(1): 2.
31. Myall KJ, Mukherjee B, Castanheira AM, et al. Persistent post–COVID-19 interstitial lung disease. An observational study of corticosteroid treatment. Annals of the American Thoracic Society, 2021, 18(5): 799-806.
32. Tan HX, Wong CK, Yik WF, et al. Post COVID-19 organizing pneumonia treated with mycophenolate mofetil. Respirology Case Reports, 2022, 10(11): e01042.
33. Kobayashi T, Tanaka K, Fujita T, et al. Bidirectional role of IL-6 signal in pathogenesis of lung fibrosis. Respiratory Research, 2015, 16(1): 99.
34. Cojocaru E, Cojocaru T, Pînzariu GM, et al. Perspectives on post-COVID-19 pulmonary fibrosis treatment. Journal of Personalized Medicine, 2024, 14(1): 51.
35. Zhu Y, Tchkonia T, Pirtskhalava T, et al. The achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell, 2015, 14(4): 644-58.
36. Nambiar A, Kellogg D, Justice J, et al. Senolytics dasatinib and quercetin in idiopathic pulmonary ﬁbrosis: results of a phase I, single-blind, single-center, randomized, placebo-controlled pilot trial on feasibility and tolerability. EBioMedicine, 2023, 90: 104481.
37. Shen M, Fu J, Zhang Y, et al. A novel senolytic drug for pulmonary fibrosis: BTSA1 targets apoptosis of senescent myofibroblasts by activating BAX. Aging Cell, 2024, 23(9): e14229.
38. Reyes NS, Krasilnikov M, Allen NC, et al. Sentinel p16INK4a+ cells in the basement membrane form a reparative niche in the lung. Science, 2022, 378(6616): 192-201.
39. Chen L, Qu J, Kalyani FS, et al. Mesenchymal stem cell-based treatments for COVID-19: Status and future perspectives for clinical applications. Cellular and Molecular Life Sciences, 2022, 79(3): 142.
40. Liu J, Peng D, You J, et al. Type 2 alveolar epithelial cells differentiated from human umbilical cord mesenchymal stem cells alleviate mouse pulmonary fibrosis through β-catenin-regulated cell apoptosis. Stem Cells and Development, 2021, 30(13): 660-670.
41. Avanzini MA, Mura M, Percivalle E, et al. Human mesenchymal stromal cells do not express ACE2 and TMPRSS2 and are not permissive to SARS-CoV-2 infection. Stem Cells Translational Medicine, 2021, 10(4): 636-642.
42. Wan Q, Zhang X, Zhou D, et al. Inhaled nano-based therapeutics for pulmonary fibrosis: Recent advances and future prospects. Journal of Nanobiotechnology, 2023, 21(1): 215.
43. Ndebele RT, Yao Q, Shi YN, et al. Progress in the application of nano- and micro-based drug delivery systems in pulmonary drug delivery. BIO Integration, 2022, 3(2).
44. Asati S, Sahu A, Jain A. Nanotoxicity: the dark side of nanoformulations. Current Nanotoxicity and Prevention, 2021, 1(1): 6-25.
45. Jacobs SS, Krishnan JA, Lederer DJ, et al. Home oxygen therapy for adults with chronic lung disease. An official American thoracic society clinical practice guideline. American Journal of Respiratory and Critical Care Medicine, 2020, 202(10): e121-e141.
46. Visca D, Centis R, Pontali E, et al. Clinical standards for diagnosis, treatment and prevention of post-COVID-19 lung disease. The International Journal of Tuberculosis and Lung Disease, 2023, 27(10): 729-741.
47. Leong SW, Bos S, Lordan L, et al. Lung transplantation for interstitial lung disease: evolution over three decades. BMJ Open Respir Res, 2023, 10(1): e001387.
48. Mi X. Clinical characteristics and outcomes of lung transplantation in patients with severe COVID-19 infection: a systematic review and meta-analysis. Int J Infect Dis, 2024, 147: 107176.

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Latest Articles新型冠状病毒感染后肺纤维化的机制及治疗进展

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