Lung Fibrosis after COVID-19: Treatment Prospects

Evgeny Bazdyrev, Polina Rusina, Maria Panova, Fedor Novikov, Ivan Grishagin, Vladimir Nebolsin, Evgeny Bazdyrev, Polina Rusina, Maria Panova, Fedor Novikov, Ivan Grishagin, Vladimir Nebolsin

Abstract

At the end of 2019, a highly contagious infection began its ominous conquest of the world. It was soon discovered that the disease was caused by a novel coronavirus designated as SARS-CoV-2, and the disease was thus abbreviated to COVID-19 (COVID). The global medical community has directed its efforts not only to find effective therapies against the deadly pathogen but also to combat the concomitant complications. Two of the most common respiratory manifestations of COVID are a significant reduction in the diffusing capacity of the lungs (DLCO) and the associated pulmonary interstitial damage. One year after moderate COVID, the incidence rate of impaired DLCO and persistent lung damage still exceeds 30%, and one-third of the patients have severe DLCO impairment and fibrotic lung damage. The persistent respiratory complications may cause substantial population morbidity, long-term disability, and even death due to the lung fibrosis progression. The incidence of COVID-induced pulmonary fibrosis caused by COVID can be estimated based on a 15-year observational study of lung pathology after SARS. Most SARS patients with fibrotic lung damage recovered within the first year and then remained healthy; however, in 20% of the cases, significant fibrosis progression was found in 5-10 years. Based on these data, the incidence rate of post-COVID lung fibrosis can be estimated at 2-6% after moderate illness. What is worse, there are reasons to believe that fibrosis may become one of the major long-term complications of COVID, even in asymptomatic individuals. Currently, despite the best efforts of the global medical community, there are no treatments for COVID-induced pulmonary fibrosis. In this review, we analyze the latest data from ongoing clinical trials aimed at treating post-COVID lung fibrosis and analyze the rationale for the current drug candidates. We discuss the use of antifibrotic therapy for idiopathic pulmonary fibrosis, the IN01 vaccine, glucocorticosteroids as well as the stromal vascular fraction for the treatment and rehabilitation of patients with COVID-associated pulmonary damage.

Keywords: COVID-19; deupirfenidone; nintedanib; pirfenidone; pulmonary fibrosis; rehabilitation; treamid.

Conflict of interest statement

The authors declare no conflict of interest.

References

    1. Bazdyrev E.D. Coronavirus disease: A global problem of the 21st century. Complex Issues Cardiovasc. Dis. 2020;9:6–16. doi: 10.17802/2306-1278-2020-9-2-6-16.
    1. Lechowicz K., Drożdżal S., Machaj F., Rosik J., Szostak B., Zegan-Barańska M., Biernawska J., Dabrowski W., Rotter I., Kotfis K. COVID-19: The potential treatment of pulmonary fibrosis associated with SARS-CoV-2 infection. JCM. 2020;9:1917. doi: 10.3390/jcm9061917.
    1. Li X., Shen C., Wang L., Majumder S., Zhang D., Deen M.J., Li Y., Qing L., Zhang Y., Chen C., et al. Pulmonary fibrosis and its related factors in discharged patients with new corona virus pneumonia: A cohort study. Respir. Res. 2021;22:203. doi: 10.1186/s12931-021-01798-6.
    1. Ali R.M.M., Ghonimy M.B.I. Post-COVID-19 pneumonia lung fibrosis: A worrisome sequelae in surviving patients. Egypt. J. Radiol. Nucl. Med. 2021;52:101. doi: 10.1186/s43055-021-00484-3.
    1. Wu X., Liu X., Zhou Y., Yu H., Li R., Zhan Q., Ni F., Fang S., Lu Y., Ding X., et al. 3-month, 6-month, 9-month, and 12-month respiratory outcomes in patients following COVID-19-related hospitalisation: A prospective study. Lancet Respir. Med. 2021;9:747–754. doi: 10.1016/S2213-2600(21)00174-0.
    1. Wells A.U., Devaraj A., Desai S.R. Interstitial lung disease after COVID-19 infection: A catalog of uncertainties. Radiology. 2021;299:E216–E218. doi: 10.1148/radiol.2021204482.
    1. Vadász I., Husain-Syed F., Dorfmüller P., Roller F.C., Tello K., Hecker M., Morty R.E., Gattenlöhner S., Walmrath H.-D., Grimminger F., et al. Severe organising pneumonia following COVID-19. Thorax. 2021;76:201–204. doi: 10.1136/thoraxjnl-2020-216088.
    1. Cottin V., Lafitte C., Sénéchal A., Traclet J. Interstitial lung disease after COVID-19. Am. J. Respir. Crit. Care Med. 2021;203:1314–1315. doi: 10.1164/rccm.202006-2466IM.
    1. Udwadia Z.F., Pokhariyal P.K., Tripathi A.K.R., Kohli A. Fibrotic interstitial lung disease occurring as sequelae of COVID-19 pneumonia despite concomitant steroids. Lung India. 2021;38:S61–S63. doi: 10.4103/lungindia.lungindia_533_20.
    1. Rai D., Kumar S., Sahay N. Post-COVID-19 pulmonary fibrosis: A case series and review of literature. J. Fam. Med. Prim. Care. 2021;10:2028. doi: 10.4103/jfmpc.jfmpc_2126_20.
    1. Tale S., Ghosh S., Meitei S.P., Kolli M., Garbhapu A.K., Pudi S. Post COVID-19 pneumonia pulmonary fibrosis. QJM. 2020;113:837–838. doi: 10.1093/qjmed/hcaa255.
    1. Lei P., Fan B., Mao J., Wei J., Wang P. The progression of computed tomographic (CT) images in patients with coronavirus disease (COVID-19) pneumonia: Running title: The CT progression of COVID-19 pneumonia. J. Infect. 2020;80:e30–e31. doi: 10.1016/j.jinf.2020.03.020.
    1. Fu Z., Tang N., Chen Y., Ma L., Wei Y., Lu Y., Ye K., Liu H., Tang F., Huang G., et al. CT features of COVID-19 patients with two consecutive negative RT-PCR tests after treatment. Sci. Rep. 2020;10:11548. doi: 10.1038/s41598-020-68509-x.
    1. Francone M., Iafrate F., Masci G.M., Coco S., Cilia F., Manganaro L., Panebianco V., Andreoli C., Colaiacomo M.C., Zingaropoli M.A., et al. Chest CT score in COVID-19 patients: Correlation with disease severity and short-term prognosis. Eur. Radiol. 2020:1–10. doi: 10.1007/s00330-020-07033-y.
    1. Vasarmidi E., Tsitoura E., Spandidos D.A., Tzanakis N., Antoniou K.M. Pulmonary fibrosis in the aftermath of the COVID-19 era (Review) Exp. Med. 2020;20:2557–2560. doi: 10.3892/etm.2020.8980.
    1. Rai D.K., Sharma P., Kumar R. Post covid 19 pulmonary fibrosis. Is it real threat? Indian J. Tuberc. 2021;68:330–333. doi: 10.1016/j.ijtb.2020.11.003.
    1. Combet M., Pavot A., Savale L., Humbert M., Monnet X. Rapid onset honeycombing fibrosis in spontaneously breathing patient with COVID-19. Eur. Respir. J. 2020;56:2001808. doi: 10.1183/13993003.01808-2020.
    1. Ahmad Alhiyari M., Ata F., Islam Alghizzawi M., Bint I Bilal A., Salih Abdulhadi A., Yousaf Z. Post COVID-19 fibrosis, an emerging complicationof SARS-CoV-2 infection. IDCases. 2021;23:e01041. doi: 10.1016/j.idcr.2020.e01041.
    1. Dadhwal R., Sharma M., Surani S. Restrictive lung disease in patients with subclinical coronavirus infection: Are we bracing ourselves for devastating sequelae? Cureus. 2021;13:e12501. doi: 10.7759/cureus.12501.
    1. Udwadia Z.F., Koul P.A., Richeldi L. Post-COVID lung fibrosis: The tsunami that will follow the earthquake. Lung India. 2021;38:S41–S47. doi: 10.4103/lungindia.lungindia_818_20.
    1. Chun H.J., Coutavas E., Pine A., Lee A.I., Yu V., Shallow M., Giovacchini C.X., Mathews A., Stephenson B., Que L.G., et al. Immuno-fibrotic drivers of impaired lung function in post-acute sequelae of SARS-CoV-2 infection (PASC) medRxiv. 2021 doi: 10.1101/2021.01.31.21250870.
    1. Zhou M., Yin Z., Xu J., Wang S., Liao T., Wang K., Li Y., Yang F., Wang Z., Yang G., et al. Inflammatory profiles and clinical features of COVID-19 survivors three months after discharge in Wuhan, China. J. Infect. Dis. 2021 doi: 10.1093/infdis/jiab181.
    1. Qin W., Chen S., Zhang Y., Dong F., Zhang Z., Hu B., Zhu Z., Li F., Wang X., Wang Y., et al. Diffusion capacity abnormalities for carbon monoxide in patients with COVID-19 at 3-month follow-up. Eur. Respir. J. 2021;58:2003677. doi: 10.1183/13993003.03677-2020.
    1. McDonald L.T. Healing after COVID-19: Are survivors at risk for pulmonary fibrosis? Am. J. Physiol. Lung Cell Mol. Physiol. 2021;320:L257–L265. doi: 10.1152/ajplung.00238.2020.
    1. Hui D.S., Joynt G.M., Wong K.T., Gomersall C.D., Li T.S., Antonio G., Ko F.W., Chan M.C., Chan D.P., Tong M.W., et al. Impact of severe acute respiratory syndrome (SARS) on pulmonary function, functional capacity and quality of life in a cohort of survivors. Thorax. 2005;60:401–409. doi: 10.1136/thx.2004.030205.
    1. Hui D.S., Wong K.T., Ko F.W., Tam L.S., Chan D.P., Woo J., Sung J.J.Y. The 1-year impact of severe acute respiratory syndrome on pulmonary function, exercise capacity, and quality of life in a cohort of survivors. Chest. 2005;128:2247–2261. doi: 10.1378/chest.128.4.2247.
    1. Wong K., Antonio G.E., Hui D.S.C., Ho C., Chan P., Ng W., Shing K., Wu A., Lee N., Yap F., et al. Severe acute respiratory syndrome: Thin-section computed tomography features, temporal changes, and clinicoradiologic correlation during the convalescent period. J. Comput. Assist. Tomogr. 2004;28:790–795. doi: 10.1097/00004728-200411000-00010.
    1. Zhang P., Li J., Liu H., Han N., Ju J., Kou Y., Chen L., Jiang M., Pan F., Zheng Y., et al. Correction: Long-term bone and lung consequences associated with hospital-acquired severe acute respiratory syndrome: A 15-year follow-up from a prospective cohort study. Bone Res. 2020;8:34. doi: 10.1038/s41413-020-00113-1.
    1. Ngai J.C., Ko F.W., Ng S.S., To K., Tong M., Hui D.S. The Long-term impact of severe acute respiratory syndrome on pulmonary function, exercise capacity and health status. Respirology. 2010;15:543–550. doi: 10.1111/j.1440-1843.2010.01720.x.
    1. Park W.B., Jun K.I., Kim G., Choi J.-P., Rhee J.-Y., Cheon S., Lee C.H., Park J.-S., Kim Y., Joh J.-S., et al. Correlation between pneumonia severity and pulmonary complications in middle east respiratory syndrome. J. Korean Med. Sci. 2018;33 doi: 10.3346/jkms.2018.33.e169.
    1. Rivera-Ortega P., Hayton C., Blaikley J., Leonard C., Chaudhuri N. Nintedanib in the management of idiopathic pulmonary fibrosis: Clinical trial evidence and real-world experience. Adv. Respir. Dis. 2018;12 doi: 10.1177/1753466618800618.
    1. George P.M., Wells A.U. Pirfenidone for the treatment of idiopathic pulmonary fibrosis. Expert Rev. Clin. Pharm. 2017;10:483–491. doi: 10.1080/17512433.2017.1295846.
    1. Home—. [(accessed on 5 August 2021)]; Available online:
    1. Efficacy and Safety of Nintedanib Ethanesulfonate Soft Capsule in the Treatment of Pulmonary Fibrosis in Patients with Moderate to Severe COVID-9(COVID 19): A Single-Center, Randomized, Placebo-Controlled Study. Tongji Hospital; Tongji, China: 2020. Identifier NCT04338802.
    1. Nintedanib for the Treatment of SARS-Cov-2 Induced Pulmonary Fibrosis. Assistance Publique—Hôpitaux de Paris; Paris, France: 2020. Identifier NCT04541680.
    1. Early Nintedanib Deployment in COVID-19 Interstitial Fibrosis. Icahn School of Medicine at Mount Sinai; New York, NY, USA: 2020. Identifier NCT04619680.
    1. A Randomized, Open-Label Study to Evaluate the Efficacy and Safety of Pirfenidone in Patients with Severe and Critical Novel Coronavirus Infection. Tongji Hospital; Tongji, China: 2020. Identifier NCT04282902.
    1. Phase-II Randomized Clinical Trial to Evaluate the Effect of Pirfenidone Compared to Placebo in Post-COVID19 Pulmonary Fibrosis. Institut d’Investigació Biomèdica de Bellvitge; Barcelona, Spain: 2020. Identifier NCT04607928.
    1. Multicenter, Randomized, Double-Blind, Placebo-Controlled Pilot Study of Treamid Efficacy and Safety in the Rehabilitation of Patients After COVID-19 Pneumonia. Pharmenterprises; Moscow, Russia: 2020. Identifier NCT04527354.
    1. A Phase 2 Randomized, Double-Blind, Placebo-Controlled Trial and Open Label Extension to Evaluate the Safety and Efficacy of Deupirfenidone (LYT-100) in Post-Acute COVID-19 Respiratory Disease. PureTech; Boston, MA, USA: 2020. Identifier NCT04652518.
    1. Effect of Collagen-Polyvinylpyrrolidone for the Treatment of Hyperinflammation and the Pulmonary Fibrosis in COVID-19 Patients. Double Blind Placebo-Controlled Pilot Trial. Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran; Mexico, Mexico: 2020. Identifier NCT04517162.
    1. Short Term Low Dose Corticosteroids for Management of Post COVID-19 Pulmonary Fibrosis. South Valley University; Qena, Egypt: 2020. Identifier NCT04551781.
    1. Multicenter, Open-Label Prospective Cohort Study of the Efficacy and Safety of the Inclusion of Longidaze in the Prevention and Treatment of Post-Inflammatory Pulmonary Fibrosis and Interstitial Lung Diseases Caused by COVID-19. NPO Petrovax; Moscow, Russia: 2020. Identifier NCT04645368.
    1. A Phase 2 Study of BIO 300 Oral Suspension in Discharged COVID-19 Patients. Humanetics Corporation; Edina, MN, USA: 2020. Identifier NCT04482595.
    1. Clinical Study of Tetrandrine Tablets Adjuvant Treatment with COVID-19. Henan Provincial People’s Hospital; Zhengzhou, China: 2020. Identifier NCT04308317.
    1. Jing F., Fan H., Zhao Z., Xing F., He Y., Liu C. The efficacy of treating pulmonary fibrosis and pulmonary function injury in COVID-19 with the fuzheng huayu tablets: A multicenter randomized controlled trial. J. Dev. Drugs. 2021;10:205
    1. Zhang C., Li J., Wu Z., Wang H., Que C., Zhao H., Wang G. Efficacy and safety of anluohuaxian in the treatment of rehabilitation patients with corona virus disease 2019-A multicenter, open, randomized controlled study. Trials. 2020;21:1–3. doi: 10.1186/s13063-020-04399-8.
    1. Use of CSVF for Residual Lung Damage (COPD/Fibrotic Lung Disease After Symptomatic COVID-19 Infection for Residual Pulmonary Injury or Post-Adult Respiratory Distress Syndrome Following Viral (SARS-Co-2) Infection. Black Tie Medical, Inc.; San Diego, CA, USA: 2020. Identifier NCT04326036.
    1. Phase Ib Controlled Exploratory Trial for Treatment of Fibrosing Interstitial Lung Disease Patients Secondary to SARS-CoV-2 Infection with IN01 Vaccine (COVINVAC) Instituto Oncológico Dr Rosell; Barcelona, Spain: 2020. Identifier NCT04537130.
    1. George P.M., Wells A.U., Jenkins R.G. Pulmonary fibrosis and COVID-19: The potential role for antifibrotic therapy. Lancet Respir. Med. 2020;8:807–815. doi: 10.1016/S2213-2600(20)30225-3.
    1. Wollin L., Wex E., Pautsch A., Schnapp G., Hostettler K.E., Stowasser S., Kolb M. Mode of Action of Nintedanib in the treatment of idiopathic pulmonary fibrosis. Eur. Respir. J. 2015;45:1434–1445. doi: 10.1183/09031936.00174914.
    1. Raghu G., Richeldi L. Current approaches to the management of idiopathic pulmonary fibrosis. Respir. Med. 2017;129:24–30. doi: 10.1016/j.rmed.2017.05.017.
    1. Yue X., Shan B., Lasky J.A. TGF-β: Titan of lung fibrogenesis. Curr. Enzyme Inhib. 2010;6 doi: 10.2174/157340810791233033.
    1. Margaritopoulos G.A., Vasarmidi E., Antoniou K.M. Pirfenidone in the treatment of idiopathic pulmonary fibrosis: An evidence-based review of its place in therapy. Core Evid. 2016;11:11–22. doi: 10.2147/CE.S76549.
    1. Wong A.W., Fidler L., Marcoux V., Johannson K.A., Assayag D., Fisher J.H., Hambly N., Kolb M., Morisset J., Shapera S., et al. Practical considerations for the diagnosis and treatment of fibrotic interstitial lung disease during the coronavirus disease 2019 pandemic. Chest. 2020;158:1069–1078. doi: 10.1016/j.chest.2020.04.019.
    1. Moore B.B., Moore T.A. Viruses in idiopathic pulmonary fibrosis. Etiology and exacerbation. Ann. Am. Thorac. Soc. 2015;12:S186–S192. doi: 10.1513/AnnalsATS.201502-088AW.
    1. Wootton S.C., Kim D.S., Kondoh Y., Chen E., Lee J.S., Song J.W., Huh J.W., Taniguchi H., Chiu C., Boushey H., et al. Viral infection in acute exacerbation of idiopathic pulmonary fibrosis. Am. J. Respir. Crit. Care Med. 2011;183:1698–1702. doi: 10.1164/rccm.201010-1752OC.
    1. Treatment with Pirfenidone for COVID-19 Related Severe ARDS an Open Label Pilot Trial. Soroka University Medical Center; Beer Sheva, Israel: 2020. Identifier NCT04653831.
    1. Tang N., Bai H., Chen X., Gong J., Li D., Sun Z. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J. Thromb. Haemost. 2020;18:1094–1099. doi: 10.1111/jth.14817.
    1. Guan W., Ni Z., Hu Y., Liang W., Ou C., He J., Liu L., Shan H., Lei C., Hui D.S.C., et al. Clinical characteristics of coronavirus disease 2019 in China. N. Engl. J. Med. 2020;382:1708–1720. doi: 10.1056/NEJMoa2002032.
    1. Skurikhin E., Nebolsin V., Widera D., Ermakova N., Pershina O., Pakhomova A., Krupin V., Pan E., Zhukova M., Novikov F., et al. Antifibrotic and regenerative effects of treamid in pulmonary fibrosis. Int. J. Mol. Sci. 2020;21:8380. doi: 10.3390/ijms21218380.
    1. National Center for Biotechnology Information PubChem Patent Summary for US-9504677-B2, Substituted N-aryl pyridinones. [(accessed on 16 August 2021)]; Available online: .
    1. Olmos-Zuñiga J.R., Silva-Martínez M., Jasso-Victoria R., Baltazares-Lipp M., Hernández-Jiménez C., Buendía-Roldan I., Jasso-Arenas J., Martínez-Salas A., Calyeca-Gómez J., Guzmán-Cedillo A.E., et al. Effects of pirfenidone and collagen-polyvinylpyrrolidone on macroscopic and microscopic changes, TGF-Β1 expression, and collagen deposition in an experimental model of tracheal wound healing. Biomed. Res. Int. 2017;2017:6471071. doi: 10.1155/2017/6471071.
    1. Furuzawa-Carballeda J., Krötzsch E., Barile-Fabris L., Alcalá M., Espinosa-Morales R. Subcutaneous administration of collagen-polyvinylpyrrolidone down regulates IL-1beta, TNF-Alpha, TGF-Beta1, ELAM-1 and VCAM-1 expression in scleroderma skin lesions. Clin. Exp. Derm. 2005;30:83–86. doi: 10.1111/j.1365-2230.2004.01691.x.
    1. Wilkinson E. RECOVERY Trial: The UK covid-19 study resetting expectations for clinical trials. BMJ. 2020;369 doi: 10.1136/bmj.m1626.
    1. Yu W., Guo F., Song X. Effects and Mechanisms of pirfenidone, prednisone and acetylcysteine on pulmonary fibrosis in rat idiopathic pulmonary fibrosis models. Pharm. Biol. 2017;55:450–455. doi: 10.1080/13880209.2016.1247879.
    1. Lam E., Sayedy N., Anjum F., Akella J., Iqbal J. TP47. TP047 COVID and ARDS Case Reports. American Thoracic Society; New York, NY, USA: 2021. Corticosteroid therapy in post-COVID-19 pulmonary fibrosis; p. A2429.
    1. Myall K.J., Mukherjee B., Castanheira A.M., Lam J.L., Benedetti G., Mak S.M., Preston R., Thillai M., Dewar A., Molyneaux P.L., et al. Persistent post–COVID-19 interstitial lung disease. An observational study of corticosteroid treatment. Ann. ATS. 2021;18:799–806. doi: 10.1513/AnnalsATS.202008-1002OC.
    1. Novikova L.N., Zakharova A.S., Dzadzua D.V., Baranova O.P., Korzina N.V., Speranskaya A.A., Gichkin A.Y., Kameneva M.Y., Sukhovskaya O.A. Effects of longidaza in patients with idiopathic pulmonary fibrosis. . 2011;6:50–54.
    1. BIO 300: A Promising Radiation Countermeasure under Advanced Development for Acute Radiation Syndrome and the Delayed Effects of Acute Radiation Exposure—PubMed. [(accessed on 6 August 2021)]; Available online:
    1. Jackson I.L., Zodda A., Gurung G., Pavlovic R., Kaytor M.D., Kuskowski M.A., Vujaskovic Z. BIO 300, a nanosuspension of genistein, mitigates pneumonitis/fibrosis following high-dose radiation exposure in the C57L/J murine model. Br. J. Pharm. 2017;174:4738–4750. doi: 10.1111/bph.14056.
    1. Para A.E., Bezjak A., Yeung I.W.T., Dyk J.V., Hill R.P. Effects of genistein following fractionated lung irradiation in mice. Radiother. Oncol. 2009;92:500–510. doi: 10.1016/j.radonc.2009.04.005.
    1. Ippolito E., Fiore M., Greco C., D’Angelillo R.M., Ramella S. COVID-19 and radiation induced pneumonitis: Overlapping clinical features of different diseases. Radiother. Oncol. 2020;148:201–202. doi: 10.1016/j.radonc.2020.04.009.
    1. Rios C.I., Cassatt D.R., Hollingsworth B.A., Satyamitra M.M., Tadesse Y.S., Taliaferro L.P., Winters T.A., DiCarlo A.L. Commonalities between COVID-19 and radiation injury. Radiat. Res. 2021;195:1–24. doi: 10.1667/RADE-20-00188.1.
    1. Costela-Ruiz V.J., Illescas-Montes R., Puerta-Puerta J.M., Ruiz C., Melguizo-Rodríguez L. SARS-CoV-2 infection: The role of cytokines in COVID-19 disease. Cytokine Growth Factor Rev. 2020;54:62–75. doi: 10.1016/j.cytogfr.2020.06.001.
    1. Narasaraju T., Tang B.M., Herrmann M., Muller S., Chow V.T.K., Radic M. Neutrophilia and NETopathy as key pathologic drivers of progressive lung impairment in patients with COVID-19. Front. Pharm. 2020;11:870. doi: 10.3389/fphar.2020.00870.
    1. Hanania A.N., Mainwaring W., Ghebre Y.T., Hanania N.A., Ludwig M. Radiation-induced lung injury: Assessment and management. Chest. 2019;156:150–162. doi: 10.1016/j.chest.2019.03.033.
    1. Gong L., Li Y., Nedeljkovic-Kurepa A., Sarkar F.H. Inactivation of NF-KappaB by genistein is mediated via akt signaling pathway in breast cancer cells. Oncogene. 2003;22:4702–4709. doi: 10.1038/sj.onc.1206583.
    1. Liu T., Liu X., Li W. Tetrandrine, a Chinese plant-derived alkaloid, is a potential candidate for cancer chemotherapy. Oncotarget. 2016;7:40800–40815. doi: 10.18632/oncotarget.8315.
    1. Bhagya N., Chandrashekar K.R. Tetrandrine—A molecule of wide bioactivity. Phytochemistry. 2016;125:5–13. doi: 10.1016/j.phytochem.2016.02.005.
    1. Kim D.E., Min J.S., Jang M.S., Lee J.Y., Shin Y.S., Park C.M., Song J.H., Kim H.R., Kim S., Jin Y.-H., et al. Natural bis-benzylisoquinoline alkaloids-tetrandrine, fangchinoline, and cepharanthine, inhibit human coronavirus OC43 infection of MRC-5 human lung cells. Biomolecules. 2019;9:696. doi: 10.3390/biom9110696.
    1. Dong H., Liu Y., Zhang J., Zhong W., Chen W., Cai S. B64. Mechanistic Advances in Lung Fibrosis. American Thoracic Society; New York, NY, USA: 2020. Tetrandrine attenuates pulmonary fibrosis through Rheb/mTOR/p70S6k signaling mediated activation of autophagy; p. 4051.
    1. Su W., Liang Y., Meng Z., Chen X., Lu M., Han X., Deng X., Zhang Q., Zhu H., Fu T. Inhalation of tetrandrine-hydroxypropyl-β-cyclodextrin inclusion complexes for pulmonary fibrosis treatment. Mol. Pharm. 2020;17:1596–1607. doi: 10.1021/acs.molpharmaceut.0c00026.
    1. Borghardt J.M., Kloft C., Sharma A. Inhaled therapy in respiratory disease: The complex interplay of pulmonary kinetic Processes. Can. Respir. J. 2018;2018:2732017. doi: 10.1155/2018/2732017.
    1. Liu W., Li Z., Sun Z., Xu Y., Wang S., Hu Y., Peng J. The components data of Fuzheng Huayu extracts, cordyceps sinensis mycelia polysaccharide, gypenosides and amygdalin. Data Brief. 2019;25:104087. doi: 10.1016/j.dib.2019.104087.
    1. Dong S., Chen Q.-L., Su S.-B. Curative effects of Fuzheng Huayu on liver fibrosis and cirrhosis: A meta-analysis. Evid. Based Complementary Altern. Med. 2015;2015:e125659. doi: 10.1155/2015/125659.
    1. Tomaru A., Gabazza E., Kobayashi T., Kobayashi H., Taguchi O., Takagi T., Oonishi M., Fujiwara K., Gabazza C.D., Takahashi Y., et al. Matrix metalloproteinase-2 is protective in bleomycin-induced pulmonary fibrosis. Eur. Respir. J. 2015;46 doi: 10.1183/13993003.congress-2015.PA1903.
    1. Tan S.-Z., Liu C.-H., Zhang W., Lu X., Ye W.-C., Cai Z.-Z., Liu P. Effects of Fuzheng Huayu recipe on MMP-2 activity and type IV collagen expression at fibrotic lung. Zhongguo Zhong Yao Za Zhi. 2007;32:835–839.
    1. Wu R., Dong S., Cai F.-F., Chen X.-L., Yang M.-D., Liu P., Su S.-B. Active compounds derived from Fuzheng Huayu formula protect hepatic parenchymal cells from apoptosis based on network pharmacology and transcriptomic analysis. Molecules. 2019;24:338. doi: 10.3390/molecules24020338.
    1. Ma W., Huang Q., Xiong G., Deng L., He Y. The protective effect of hederagenin on pulmonary fibrosis by regulating the Ras/JNK/NFAT4 axis in rats. Biosci. Biotechnol. Biochem. 2020;84:1131–1138. doi: 10.1080/09168451.2020.1721263.
    1. Walker N.M., Mazzoni S.M., Vittal R., Fingar D.C., Lama V.N. C-Jun N-terminal kinase (JNK)-mediated induction of MSin1 expression and MTORC2 activation in mesenchymal cells during fibrosis. J. Biol. Chem. 2018;293:17229–17239. doi: 10.1074/jbc.RA118.003926.
    1. Huang J., Huang H., Jiao Y., Ai G., Huang T., Li L., Yu H., Ma K., Xiao F. Effect of Anluohuaxian tablet combined with gamma-IFN on schistosomal liver fibrosis. J. Huazhong Univ. Sci. Technol. Med. Sci. 2009;29:53–58. doi: 10.1007/s11596-009-0111-7.
    1. Makarev E., Izumchenko E., Aihara F., Wysocki P.T., Zhu Q., Buzdin A., Sidransky D., Zhavoronkov A., Atala A. Common pathway signature in lung and liver fibrosis. Cell Cycle. 2016;15:1667–1673. doi: 10.1080/15384101.2016.1152435.
    1. Alexander R.W. Overview of COVID-19 lung damage clinical trial using Cellular Stromal Vascular Fraction (CSVF) and Functional Respiratory Imaging (FRI) analysis of pulmonary injury & post-viral (SARS=Cov-2) adult respiratory distress syndrome (ARDS) Ann. Stem Cell Res. Ther. 2020;4:1–10.
    1. Alexander R.W. Potential use of cellular stromal vascular fraction in Post-COVID-19 pulmonary injury and adult respiratory distress syndrome. J. Curr. Med. Res. Opin. 2020;3:468–474. doi: 10.15520/jcmro.v3i05.296.
    1. Ntolios P., Manoloudi E., Tzouvelekis A., Bouros E., Steiropoulos P., Anevlavis S., Bouros D., Froudarakis M.E. Longitudinal outcomes of patients enrolled in a phase Ib Clinical trial of the adipose-derived stromal cells-stromal vascular fraction in idiopathic pulmonary fibrosis. Clin. Respir. J. 2018;12:2084–2089. doi: 10.1111/crj.12777.
    1. Michalek J., Dudasova Z., Brown C. Stromal vascular fraction cell therapy for idiopathic pulmonary fibrosis—Cure without side effects. Ann. Clin. Case Rep. 2019;4:1698
    1. Tzouvelekis A., Ntolios P., Karameris A., Vilaras G., Boglou P., Koulelidis A., Archontogeorgis K., Kaltsas K., Zacharis G., Sarikloglou E., et al. Increased expression of epidermal growth factor receptor (EGF-R) in patients with different forms of lung fibrosis. Biomed. Res. Int. 2013;2013:654354. doi: 10.1155/2013/654354.
    1. Venkataraman T., Frieman M.B. The role of epidermal growth factor receptor (EGFR) signaling in SARS coronavirus-induced pulmonary fibrosis. Antivir. Res. 2017;143:142–150. doi: 10.1016/j.antiviral.2017.03.022.
    1. Kućma M. Drug Candidate OATD-01 May Find Use in Treatment of Pulmonary Fibrosis in Patients Who Have Survived a New Coronavirus Infection (COVID-19). OncoArendi Ther. [(accessed on 11 August 2021)];2020 Available online:
    1. Lee C.-M., He C.-H., Park J.W., Lee J.H., Kamle S., Ma B., Akosman B., Cotez R., Chen E., Zhou Y., et al. Chitinase 1 regulates pulmonary fibrosis by modulating TGF-β/SMAD7 pathway via TGFBRAP1 and FOXO3. Life Sci Alliance. 2019;2 doi: 10.26508/lsa.201900350.
    1. Dymek B., Sklepkiewicz P., Mlacki M., Zagozdzon A., Koralewski R., Mazur M., Paplinska-Goryca M., Nejman-Gryz P., Proboszcz M., Gorska K., et al. CHIT1 Is a novel therapeutic target in Idiopathic Pulmonary Fibrosis (IPF): Anti-fibrotic efficacy of OATD-01, a potent and selective chitinase inhibitor in the mouse model of pulmonary fibrosis. Eur. Respir. J. 2018;52 doi: 10.1183/13993003.congress-2018.OA5361.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe