Targeting Urokinase-Type Plasminogen Activator (uPA) and the uPA Receptor, Reduces Vascular Inflammation and Lung Hemorrhage in Systemic Lupus and SARS CoV2 Infection in Mouse Models of Respiratory Distress Syndromes

Introduction: Acute respiratory distress syndromes with vascular inflammation and alveolar hemorrhage have high mortality and limited treatment. Autoimmune disease and severe viral infection cause vascular inflammation and hemorrhage. Serine protease coagulation pathways increase inflammatory cell activation and damage. Viruses have evolved highly effective immune modulating ser ine p roteinase in hibitors, serpins . Myxomavirus Serp-1 improves survival and reduces inflammation, vasculitis and lung hemorrhage in MHV68 gamma herpes infections (P < 0.01). Serp-1 also reduces Lupus alveolar hemorrhage (DAH) and proved safe and effective in a randomized, blinded, dose escalating trial in patients with coronary stent implant. Hypothesis: We hypothesize that treatment with PEGylated Serp-1 (PEGSerp-1) will reduce hemorrhage and inflammatory vasculitis in autoimmune and infectious lung disease. Methods: Pristane induced DAH and SARS-CoV-2 virus infections were treated with PEGSerp-1 in mouse models. Results: Serp-1 and PEGSerp-1 given daily IP for 14 days significantly reduced pristane induced DAH (N = 30 C57Bl/6 mice; P < 0.05) at 14 days follow up. PEGSerp-1 also reduced lung hemorrhage given for 7days treatment (N = 6 mice; P <0.01) or when given 7 days after pristane induction of DAH (N = 6 mice; P < 0.01). Macrophage invasion (P < 0.01), Prussian blue staining for hemosiderosis, C5b-9 complex deposition and soluble uPAR (suPAR) were significantly reduced with PEGSerp-1 treatment. PEGSerp-1 given daily after SARS-CoV-2 infection (48hrs, BALB/c mice, N = 16) also significantly reduced lung inflammation; decreased F4/80+ and iNOS+ macrophage staining (P < 0.02). Virus titer was also reduced in TMPRS2+ Vero cells (10μg/mL), and in SARS infected lungs. PEG Serp-1 homes to areas of pristane lung damage, but not normal lungs, indicating targeting of protease activation. No adverse effects were detected. Conclusion: Treatment for vascular inflammation and hemorrhage in severe autoimmune and virus induced respiratory distress syndromes is very limited. Targeting thrombolytic and inflammatory serine protease uPA/ uPAR complex activation provides a new therapeutic approach to severe respiratory distress in autoimmune disease and viral infection.