Targeting MMP-Regulation of Inflammation to Increase Metabolic Tolerance to COVID-19 Pathologies: A Hypothesis

Abstract

Many individuals infected with the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) develop no or only mild symptoms, but some can go on onto develop a spectrum of pathologies including pneumonia, acute respiratory distress syndrome, respiratory failure, systemic inflammation, and multiorgan failure. Many pathogens, viral and non-viral, can elicit these pathologies, which justifies reconsidering whether the target of therapeutic approaches to fight pathogen infections should be (a) the pathogen itself, (b) the pathologies elicited by the pathogen interaction with the human host, or (c) a combination of both. While little is known about the immunopathology of SARS-CoV-2, it is well-established that the above-mentioned pathologies are associated with hyper-inflammation, tissue damage, and the perturbation of target organ metabolism. Mounting evidence has shown that these processes are regulated by endoproteinases (particularly, matrix metalloproteinases (MMPs)). Here, we review what is known about the roles played by MMPs in the development of COVID-19 and postulate a mechanism by which MMPs could influence energy metabolism in target organs, such as the lung. Finally, we discuss the suitability of MMPs as therapeutic targets to increase the metabolic tolerance of the host to damage inflicted by the pathogen infection, with a focus on SARS-CoV-2.

Impact of High Serum Levels of MMP-7, MMP-9, TGF-β and PDGF Macrophage Activation Markers on Severity of COVID-19 in Obese-Diabetic Patients

“…For example, MMP-9 contributes to COPD-associated pulmonary damage, while MMP-7 and MMP-9 are associated with asthma, ARDS and idiopathic pulmonary fibrosis. 24 In this study, MMP-7 and MMP-9 levels were significantly higher in the serum of obese-diabetic COVID 19 patient group than in the non-obese, non-diabetic group (p < 0.0001 for both). Both markers also were significantly elevated in obese diabetic patients who developed ARDS than those who did not develop ARDS during the follow-up period (p 0.02 and p 0.01 respectively).…”

“…For example, MMP-9 contributes to COPD-associated pulmonary damage, while MMP-7 and MMP-9 are associated with asthma, ARDS and idiopathic pulmonary fibrosis. 24 …”

Structural characterisation of inhibitory and non-inhibitory MMP-9–TIMP-1 complexes and implications for regulatory mechanisms of MMP-9

“…The role of MMPs in many lung diseases has been unquestioned for years 46 . As MMP-9 secretion promotes inflammation and destruction of lung tissue during lung injuries, it has been proposed that targeting MMP-9 activity could be beneficial in COVID-19, as well—especially because an increase in the MMP-9 level in circulating blood has been observed prior to respiratory failure in COVID-19 patients 47 .…”

Recent Progress in Metabolic Syndrome Research and Therapeutics

“…Matrix metalloproteinases were pinpointed to be responsible for the orchestration of tissue inflammation and metabolism of end organs. The hypothesis was therefore raised to enhance metabolic tolerance under SARS-CoV-2 infection by manipulating this target [29]. Finally, the concept of immunometabolic reprogramming was suggested as a potential novel therapeutic modality.…”