Roles of extra cellular proteases in the pathogenesis and novel treatment of the cytokine storm syndrome

Abstract

 The death toll caused by COVID-19 reached 7 million in the whole world. With a better understanding of the mechanism and pathophysiology underlying COVID-19 and including late COVID, it will be possible to identify novel treatment targets that ultimately reduce or prevent disease aggravation. In previous studies, the authors have identified so-called “cytokine storm syndrome,” constituting the secretion of inflammatory cytokines driven by the coagulation/fibrinolytic system as an inflammatory cytodynamic control mechanism contributing to the aggravated pathology of COVID-19 and the cytokine storm syndrome.

 Vasculature-lining endothelial cells are bioreactors that produce or contribute to the modulation status of cytokines, coagulation, and fibrinolytic system factors using serine proteases and metalloproteases. Critical steps in the organ damage pathophysiology are the angiocrine system’s destabilization triggered by vascular endothelial damage during severe COVID-19. In addition, overproduction or imbalance of angiocrine factors and inflammatory cytokines contribute to cytokine storm syndrome. This paper outlines the significance of two protease systems in the pathophysiology of inflammatory diseases, focusing on the results of our research. Finally, we discuss the possibility of molecular targeting these proteases for inflammatory disease as novel treatment approaches for systemic inflammatory diseases.