Mast Cell Carboxypeptidase A3 Is Associated with Pulmonary Fibrosis Secondary to COVID-19

COVID-19 is an infectious disease caused by SARS-CoV-2; over the course of the disease, a dysregulated immune response leads to excessive inflammation that damages lung parenchyma and compromises its function. One of the cell lineages classically associated with pathological inflammatory processes is mast cells (MCs). MCs and their mediators have been associated with COVID-19; we previously reported the role of carboxypeptidase A3 (CPA3) in severe COVID-19. However, sequelae of SARS-CoV-2 infection have been poorly studied. In patients who successfully resolve the infection, one of the reported sequelae is pulmonary fibrosis (PF). The etiology and exact mechanisms are unknown, and few studies exist. Therefore, the aim of this study was to evaluate whether MCs are associated with PF development after SARS-CoV-2 infection. Our findings demonstrate that during severe cases of SARS-CoV-2 infection, there is an increased amount of CPA3 MCs in areas with pneumonia, around thrombotic blood vessels, and in fibrotic tissue. Moreover, higher numbers of CPA3-expressing MCs correlate with fibrotic tissue development (r = 0.8323; = 0.001170). These results suggest that during COVID-19, exacerbated inflammation favors the recruitment or expansion of MCs and CPA3 expression in the lungs, which favors tissue damage and a failure of repair mechanisms, leading to fibrosis.

References

Soria-Castro R, Meneses-Preza Y, Rodriguez-Lopez G, Romero-Ramirez S, Sosa-Hernandez V, Cervantes-Diaz R . Severe COVID-19 is marked by dysregulated serum levels of carboxypeptidase A3 and serotonin. J Leukoc Biol. 2021; 110(3):425-431. PMC: 8242632. DOI: 10.1002/JLB.4HI0221-087R. View

Atiakshin D, Kostin A, Trotsenko I, Samoilova V, Buchwalow I, Tiemann M . Carboxypeptidase A3-A Key Component of the Protease Phenotype of Mast Cells. Cells. 2022; 11(3). PMC: 8834431. DOI: 10.3390/cells11030570. View

Rathore A, Mantri C, Aman S, Syenina A, Ooi J, Jagaraj C . Dengue virus-elicited tryptase induces endothelial permeability and shock. J Clin Invest. 2019; 129(10):4180-4193. PMC: 6763290. DOI: 10.1172/JCI128426. View

Hu Y, Jin Y, Han D, Zhang G, Cao S, Xie J . Mast cell-induced lung injury in mice infected with H5N1 influenza virus. J Virol. 2012; 86(6):3347-56. PMC: 3302317. DOI: 10.1128/JVI.06053-11. View

Marshall R, McAnulty R, Laurent G . Angiotensin II is mitogenic for human lung fibroblasts via activation of the type 1 receptor. Am J Respir Crit Care Med. 2000; 161(6):1999-2004. DOI: 10.1164/ajrccm.161.6.9907004. View

da Silva Motta Junior J, Dos Santos Miggiolaro A, Nagashima S, De Paula C, Baena C, Scharfstein J . Mast Cells in Alveolar Septa of COVID-19 Patients: A Pathogenic Pathway That May Link Interstitial Edema to Immunothrombosis. Front Immunol. 2020; 11:574862. PMC: 7530169. DOI: 10.3389/fimmu.2020.574862. View

Baratella E, Bussani R, Zanconati F, Marrocchio C, Fabiola G, Braga L . Radiological-pathological signatures of patients with COVID-19-related pneumomediastinum: is there a role for the Sonic hedgehog and Wnt5a pathways?. ERJ Open Res. 2021; 7(3). PMC: 8381265. DOI: 10.1183/23120541.00346-2021. View

Tchougounova E, Lundequist A, Fajardo I, Winberg J, Abrink M, Pejler G . A key role for mast cell chymase in the activation of pro-matrix metalloprotease-9 and pro-matrix metalloprotease-2. J Biol Chem. 2004; 280(10):9291-6. DOI: 10.1074/jbc.M410396200. View

Jimenez M, Cervantes-Garcia D, Cordova-Davalos L, Perez-Rodriguez M, Gonzalez-Espinosa C, Salinas E . Responses of Mast Cells to Pathogens: Beneficial and Detrimental Roles. Front Immunol. 2021; 12:685865. PMC: 8240065. DOI: 10.3389/fimmu.2021.685865. View

10.

Iwashita H, Kawabata Y, Hayashi H, Matsushita S, Yamashiro T, Matsumura M . Frequency of subclinical interstitial lung disease in COVID-19 autopsy cases: potential risk factors of severe pneumonia. BMC Pulm Med. 2023; 23(1):408. PMC: 10612296. DOI: 10.1186/s12890-023-02692-1. View

11.

Bhardwaj A, Sapra L, Saini C, Azam Z, Mishra P, Verma B . COVID-19: Immunology, Immunopathogenesis and Potential Therapies. Int Rev Immunol. 2021; 41(2):171-206. PMC: 7919479. DOI: 10.1080/08830185.2021.1883600. View

12.

Li X, Zhuang J, Rayford H, Zhang H, Shu R, Uhal B . Attenuation of bleomycin-induced pulmonary fibrosis by intratracheal administration of antisense oligonucleotides against angiotensinogen mRNA. Curr Pharm Des. 2007; 13(12):1257-68. DOI: 10.2174/138161207780618867. View

13.

Li L, Li Y, Reddel S, Cherrian M, Friend D, Stevens R . Identification of basophilic cells that express mast cell granule proteases in the peripheral blood of asthma, allergy, and drug-reactive patients. J Immunol. 1998; 161(9):5079-86. View

14.

Goldstein S, Leong J, Bunnett N . Human mast cell proteases hydrolyze neurotensin, kinetensin and Leu5-enkephalin. Peptides. 1991; 12(5):995-1000. DOI: 10.1016/0196-9781(91)90049-u. View

15.

Hellman L, Akula S, Fu Z, Wernersson S . Mast Cell and Basophil Granule Proteases - Targets and Function. Front Immunol. 2022; 13:918305. PMC: 9294451. DOI: 10.3389/fimmu.2022.918305. View

16.

Lundequist A, Tchougounova E, Abrink M, Pejler G . Cooperation between mast cell carboxypeptidase A and the chymase mouse mast cell protease 4 in the formation and degradation of angiotensin II. J Biol Chem. 2004; 279(31):32339-44. DOI: 10.1074/jbc.M405576200. View

17.

Ahmad Alhiyari M, Ata F, Islam Alghizzawi M, Bilal A, Salih Abdulhadi A, Yousaf Z . Post COVID-19 fibrosis, an emerging complicationof SARS-CoV-2 infection. IDCases. 2021; 23:e01041. PMC: 7785952. DOI: 10.1016/j.idcr.2020.e01041. View

18.

Wygrecka M, Kwapiszewska G, Jablonska E, von Gerlach S, Henneke I, Zakrzewicz D . Role of protease-activated receptor-2 in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2011; 183(12):1703-14. DOI: 10.1164/rccm.201009-1479OC. View

19.

Zhou Y, Pan P, Yao L, Su M, He P, Niu N . CD117-positive cells of the heart: progenitor cells or mast cells?. J Histochem Cytochem. 2009; 58(4):309-16. PMC: 2842594. DOI: 10.1369/jhc.2009.955146. View

20.

Ross B, DOrleans-Juste P, Giaid A . Potential role of endothelin-1 in pulmonary fibrosis: from the bench to the clinic. Am J Respir Cell Mol Biol. 2009; 42(1):16-20. DOI: 10.1165/rcmb.2009-0175TR. View