ADAM17/MMP inhibition prevents neutrophilia and lung injury in a mouse model of COVID-19
Por:
Lartey N.L., Valle-Reyes S., Vargas-Robles H., Jiménez-Camacho K.E., Guerrero-Fonseca I.M., Castellanos-Martínez R., Montoya-García A., García-Cordero J., Cedillo-Barrón L., Nava P., Filisola-Villaseñor J.G., Roa-Velázquez D., Zavala-Vargas D.I., Morales-Ríos E., Salinas-Lara C., Vadillo E., Schnoor M.
Publicada:
1 ene 2022
Resumen:
Severe coronavirus disease 2019 (COVID-19) is characterized by lung injury, cytokine storm, and increased neutrophil-to-lymphocyte ratio (NLR). Current therapies focus on reducing viral replication and inflammatory responses, but no specific treatment exists to prevent the development of severe COVID-19 in infected individuals. Angiotensin-converting enzyme-2 (ACE2) is the receptor for SARS-CoV-2, the virus causing COVID-19, but it is also critical for maintaining the correct functionality of lung epithelium and endothelium. Coronaviruses induce activation of a disintegrin and metalloprotease 17 (ADAM17) and shedding of ACE2 from the cell surface resulting in exacerbated inflammatory responses. Thus, we hypothesized that ADAM17 inhibition ameliorates COVID-19-related lung inflammation. We employed a preclinical mouse model using intratracheal instillation of a combination of polyinosinic:polycytidylic acid (poly(I:C)) and the receptor-binding domain of the SARS-CoV-2 spike protein (RBD-S) to mimic lung damage associated with COVID-19. Histologic analysis of inflamed mice confirmed the expected signs of lung injury including edema, fibrosis, vascular congestion, and leukocyte infiltration. Moreover, inflamed mice also showed an increased NLR as observed in critically ill COVID-19 patients. Administration of the ADAM17/MMP inhibitors apratastat and TMI-1 significantly improved lung histology and prevented leukocyte infiltration. Reduced leukocyte recruitment could be explained by reduced production of proinflammatory cytokines and lower levels of the endothelial adhesion molecules ICAM-1 and VCAM-1. Additionally, the NLR was significantly reduced by ADAM17/MMP inhibition. Thus, we propose inhibition of ADAM17/MMP as a novel promising treatment strategy in SARS-CoV-2-infected individuals to prevent the progression toward severe COVID-19. ©2021 Society for Leukocyte Biology.
Filiaciones:
Lartey N.L.:
Department of Molecular Biomedicine, CINVESTAV-IPN, México City, Mexico
Valle-Reyes S.:
Department of Molecular Biomedicine, CINVESTAV-IPN, México City, Mexico
Vargas-Robles H.:
Department of Molecular Biomedicine, CINVESTAV-IPN, México City, Mexico
Jiménez-Camacho K.E.:
Department of Molecular Biomedicine, CINVESTAV-IPN, México City, Mexico
Guerrero-Fonseca I.M.:
Department of Molecular Biomedicine, CINVESTAV-IPN, México City, Mexico
Castellanos-Martínez R.:
Department of Molecular Biomedicine, CINVESTAV-IPN, México City, Mexico
Montoya-García A.:
Department of Molecular Biomedicine, CINVESTAV-IPN, México City, Mexico
García-Cordero J.:
Department of Molecular Biomedicine, CINVESTAV-IPN, México City, Mexico
Cedillo-Barrón L.:
Department of Molecular Biomedicine, CINVESTAV-IPN, México City, Mexico
Nava P.:
Department of Physiology, Biophysics and Neurosciences, CINVESTAV-IPN, Mexico City, Mexico
Filisola-Villaseñor J.G.:
Department of Biochemistry, CINVESTAV-IPN, Mexico City, Mexico
Roa-Velázquez D.:
Department of Biochemistry, CINVESTAV-IPN, Mexico City, Mexico
Zavala-Vargas D.I.:
Department of Biochemistry, CINVESTAV-IPN, Mexico City, Mexico
Morales-Ríos E.:
Department of Biochemistry, CINVESTAV-IPN, Mexico City, Mexico
Salinas-Lara C.:
Instituto Nacional de Neurología, Mexico City, Mexico
Vadillo E.:
Oncology Research Unit, Hospital de Oncología, Centro Médico Nacional Siglo XXI, Mexico City, Mexico
Schnoor M.:
Department of Molecular Biomedicine, CINVESTAV-IPN, México City, Mexico
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