The Role of the Plasminogen/Plasmin System in Inflammation of the Oral Cavity.

The oral cavity is a unique environment that consists of teeth surrounded by periodontal tissues, oral mucosae with minor salivary glands, and terminal parts of major salivary glands that open into the oral cavity. The cavity is constantly exposed to viral and microbial pathogens. Recent studies indicate that components of the plasminogen (Plg)/plasmin (Pm) system are expressed in tissues of the oral cavity, such as the salivary gland, and contribute to microbial infection and inflammation, such as periodontitis. The Plg/Pm system fulfills two major functions: (a) the destruction of fibrin deposits in the bloodstream or damaged tissues, a process called fibrinolysis, and (b) non-fibrinolytic actions that include the proteolytic modulation of proteins. One can observe both functions during inflammation. The virus that causes the coronavirus disease 2019 (COVID-19) exploits the fibrinolytic and non-fibrinolytic functions of the Plg/Pm system in the oral cavity. During COVID-19, well-established coagulopathy with the development of microthrombi requires constant activation of the fibrinolytic function. Furthermore, viral entry is modulated by receptors such as TMPRSS2, which is necessary in the oral cavity, leading to a derailed immune response that peaks in cytokine storm syndrome. This paper outlines the significance of the Plg/Pm system for infectious and inflammatory diseases that start in the oral cavity.

COVID-19 Severity and Thrombo-Inflammatory Response Linked to Ethnicity.

Although there is strong evidence that SARS-CoV-2 infection is associated with adverse outcomes in certain ethnic groups, the association of disease severity and risk factors such as comorbidities and biomarkers with racial disparities remains undefined. This retrospective study between March 2020 and February 2021 explores COVID-19 risk factors as predictors for patients' disease progression through country comparison. Disease severity predictors in Germany and Japan were cardiovascular-associated comorbidities, dementia, and age. We adjusted age, sex, body mass index, and history of cardiovascular disease comorbidity in the country cohorts using a propensity score matching (PSM) technique to reduce the influence of differences in sample size and the surprisingly young, lean Japanese cohort. Analysis of the 170 PSM pairs confirmed that 65.29% of German and 85.29% of Japanese patients were in the uncomplicated phase. More German than Japanese patients were admitted in the complicated and critical phase. Ethnic differences were identified in patients without cardiovascular comorbidities. Japanese patients in the uncomplicated phase presented a suppressed inflammatory response and coagulopathy with hypocoagulation. In contrast, German patients exhibited a hyperactive inflammatory response and coagulopathy with hypercoagulation. These differences were less pronounced in patients in the complicated phase or with cardiovascular diseases. Coagulation/fibrinolysis-associated biomarkers rather than inflammatory-related biomarkers predicted disease severity in patients with cardiovascular comorbidities: platelet counts were associated with severe illness in German patients. In contrast, high D-dimer and fibrinogen levels predicted disease severity in Japanese patients. Our comparative study indicates that ethnicity influences COVID-19-associated biomarker expression linked to the inflammatory and coagulation (thrombo-inflammatory) response. Future studies will be necessary to determine whether these differences contributed to the less severe disease progression observed in Japanese COVID-19 patients compared with those in Germany.

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

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.Figure

The multifaceted role of plasminogen in inflammation.

A fine-tuned activation and deactivation of proteases and their inhibitors are involved in the execution of the inflammatory response. The zymogen/proenzyme plasminogen is converted to the serine protease plasmin, a key fibrinolytic factor by plasminogen activators including tissue-type plasminogen activator (tPA). Plasmin is part of an intricate protease network controlling proteins of initial hemostasis/coagulation, fibrinolytic and complement system. Activation of these protease cascades is required to mount a proper inflammatory response. Although best known for its ability to dissolve clots and cleave fibrin, recent studies point to the importance of fibrin-independent functions of plasmin during acute inflammation and inflammation resolution. In this review, we provide an up-to-date overview of the current knowledge of the enzymatic and cytokine-like effects of tPA and describe the role of tPA and plasminogen receptors in the regulation of the inflammatory response with emphasis on the cytokine storm syndrome such as observed during coronavirus disease 2019 or macrophage activation syndrome. We discuss tPA as a modulator of Toll like receptor signaling, plasmin as an activator of NFkB signaling, and summarize recent studies on the role of plasminogen receptors as controllers of the macrophage conversion into the M2 type and as mediators of efferocytosis during inflammation resolution.