The Role of Fibrinolytic Factors, a Subset of Angiocrine Factors in Cytokine Storm-Associated Diseases

Abstract

Cytokine storm syndrome is a general term applied to maladaptive cytokine release in response to infection and other stimuli. It occurs during graft versus host disease after hematopoietic stem cell transplantation.Recent evidence suggested that, during the coronavirus disease 2019 (COVID-19) epidemic, the severe deterioration of some patient's health with Coronavirus Disease 2019 (COVID-19) was compatible with symptoms as they are known for the cytokine storm syndrome. The cytokine storm syndrome in COVID-19 is associated with the development and progression of macrophage activation syndrome (MAS), vascular endotheliitis like Kawasaki disease, and acute respiratory distress syndrome. Abnormalities of coagulation and fibrinolysis are known clinical features of COVID-19 or MAS. We reported previously that plasmin inhibition reduced GVHD associated lethality and prevented increases in inflammatory cytokines in mice. But the role of the fibrinolytic system and its key player, plasmin, in the development of COVID-19 is not well defined. Toll-like receptors (TLRs) might contribute to the pathogenesis of the disease.We established a murine model of fulminant MAS by repeated injections of TLR-9 agonist and D-galactosamine in immunocompetent mice. We found increases in circulating urokinase and the angiocrine factor tissue-type plasminogen activator (tPA) levels during the progression of fulminant MAS in mice, which causes the enhanced conversion of the proenzyme plasminogen into plasmin. Genetic and pharmacological inhibition of plasmin counteracted MAS-associated lethality and other related symptoms. We show that plasmin regulates the influx of inflammatory cells and the production of inflammatory cytokines, chemokines, and proteases like soluble forms or membrane forms of matrix metalloproteases generating an amplification loop. Based on these data, we hypothesize that COVID-19-induced vascular endothelial dysfunction causes the aggravation of COVID-19 leading up to cytokine storm or MAS syndrome, endotheliitis, and hypercoagulability with the induction of disseminated intravascular coagulation syndrome(Fig.1.). In summary, we propose that plasmin and potentially MMPs inhibitors might offer a novel treatment to control the deadly cytokine storm syndrome in patients with MAS or COVID-19, thereby preventing multiple organ failure.FigureDisclosuresNo relevant conflicts of interest to declare.