Possible Role of Matrix Metalloproteinases and TGF-β in COVID-19 Severity and Sequelae

Abstract

The costs of coronavirus disease 2019 (COVID-19) are devastating. With millions of deaths worldwide, specific serological biomarkers, antiviral agents, and novel therapies are urgently required to reduce the disease burden. For these purposes, a profound understanding of the pathobiology of COVID-19 is mandatory. Notably, the study of immunity against other respiratory infections has generated reference knowledge to comprehend the paradox of the COVID-19 pathogenesis. Past studies point to a complex interplay between cytokines and other factors mediating wound healing and extracellular matrix (ECM) remodeling that results in exacerbated inflammation, tissue injury, severe manifestations, and a sequela of respiratory infections. This review provides an overview of the immunological process elicited after severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. Also, we analyzed available data about the participation of matrix metalloproteinases (MMPs) and transforming growth factor-beta (TGF-β) in immune responses of the lungs. Furthermore, we discuss their possible implications in severe COVID-19 and sequela, including pulmonary fibrosis, and remark on the potential of these molecules as biomarkers for diagnosis, prognosis, and treatment of convalescent COVID-19 patients. Our review provides a theoretical framework for future research aimed to discover molecular hallmarks that, combined with clinical features, could serve as therapeutic targets and reliable biomarkers of the different clinical forms of COVID-19, including convalescence.

Keywords: ARDS; COVID-19; MMPs; SARS-CoV-2; TGF-β; pulmonary fibrosis.

Color images are available online.

FIG. 1.

COVID-19 characteristic cytokine storm, highlighting the interplay between hyperinflammatory and tissue injury mediators, leading to pulmonary fibrosis. Schematic figure illustrating proposed mechanisms by which SARS-CoV-2 infection triggers a sustained dysregulated immune response in the lung resulting in a cytokine storm syndrome. ARDS may ensue by the upregulation of cytokines, chemokines, growth factors, and proteases such as metalloproteinases (MMPs) as well as their inhibitors (TIMPs), accompanied by a variety of complications according to disease severity. Growth factors, especially TGF-β, can be activated by cytokines and MMPs, promoting fibroblast proliferation and myofibroblast differentiation. These processes lead to altered ECM turnover, thus setting a profibrotic environment. ARDS, acute respiratory distress syndrome; COVID-19, coronavirus disease 2019; ECM, extracellular matrix; MMPs, matrix metalloproteinases; SARS-CoV-2, severe acute respiratory syndrome coronavirus-2; TGF-β, transforming growth factor beta; TIMPs, tissue inhibitors of metalloproteinases. The art pieces used in this figure were modified from Servier Medical Art by Servier and Biorender, licensed under a Creative Commons Attribution 3.0 Unported License.

FIG. 2.

Mechanisms of action of MMPs and TGF-β that link hyperinflammation and pulmonary fibrosis in severe COVID-19. The replication rate of SARS-CoV-2 and associated lung epithelial cell death may trigger a cytokine storm, hyperinflammation, and epithelial dysfunction. During severe COVID-19, the initial acute inflammatory response might be followed by epithelial cell hyperplasia, where key mediators such as MMPs drive epithelial and endothelial injury and uncontrolled fibroblast proliferation. Moreover, some MMPs can activate other profibrotic mediators such as TGF-β, which also contributes to fibroblast accumulation, differentiation to myofibroblasts, ECM disorganization, dysregulated collagen I and III turnover, excessive ECM deposition, and thick alveolar walls. MMPs can also be involved in the regulation of other pathways, such as MMP-1, implicated in the reduction of mitochondrial function, the reduction of reactive oxygen species, and the overexpression of HIF-1α, and MMP3 in latent TGF-β activation, β-catenin signaling activation, and lung epithelial cell apoptosis, among others. The art pieces used in this figure were modified from Servier Medical Art by Servier and Biorender, licensed under a Creative Commons Attribution 3.0 Unported License.