SARS-CoV-2 acute respiratory distress syndrome (ARDS) induces uncontrolled lung inflammation and coagulopathy with high mortality. Anti-viral drugs and monoclonal antibodies reduce early COVID-19 severity, but treatments for late-stage immuno-thrombotic syndromes and long COVID are limited. Serine protease inhibitors (SERPINS) regulate activated proteases. The myxoma virus-derived Serp-1 protein is a secreted immunomodulatory serpin that targets activated thrombotic, thrombolytic, and complement proteases as a self-defense strategy to combat clearance. Serp-1 is effective in multiple animal models of inflammatory lung disease and vasculitis. Here, we describe systemic treatment with purified PEGylated Serp-1 as a therapy for immuno-coagulopathic complications during ARDS. Treatment with PEGSerp-1 in two mouse-adapted SARS-CoV-2 models in C57Bl/6 and BALB/c mice reduced lung and heart inflammation, with improved outcomes. PEGSerp-1 significantly reduced M1 macrophages in the lung and heart by modifying urokinase-type plasminogen activator receptor (uPAR), thrombotic proteases, and complement membrane attack complex (MAC). Sequential changes in gene expression for uPAR and serpins (complement and plasminogen inhibitors) were observed. PEGSerp-1 is a highly effective immune-modulator with therapeutic potential for severe viral ARDS, immuno-coagulopathic responses, and Long COVID.

中文翻译：

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病毒抗炎丝氨酸蛋白酶抑制剂可减少 SARS-CoV-2 感染小鼠模型的免疫凝血病理学

SARS-CoV-2 急性呼吸窘迫综合征 (ARDS) 会引起不受控制的肺部炎症和凝血病，死亡率很高。抗病毒药物和单克隆抗体可减轻早期 COVID-19 的严重程度，但对晚期免疫血栓综合征和长期 COVID 的治疗有限。丝氨酸蛋白酶抑制剂 (SERPINS) 调节激活的蛋白酶。粘液瘤病毒衍生的 Serp-1 蛋白是一种分泌的免疫调节性丝氨酸蛋白酶抑制剂，其目标是激活的血栓形成、溶栓和补体蛋白酶，作为对抗清除的自卫策略。Serp-1 对多种炎症性肺病和血管炎动物模型有效。在这里，我们描述了用纯化的聚乙二醇化 Serp-1 进行全身治疗，作为 ARDS 期间免疫凝血并发症的治疗方法。在 C57Bl/6 和 BALB/c 小鼠的两种小鼠适应 SARS-CoV-2 模型中使用 PEGSerp-1 治疗可减少肺部和心脏炎症，并改善预后。PEGSerp-1 通过修饰尿激酶型纤溶酶原激活剂受体 (uPAR)、血栓蛋白酶和补体膜攻击复合物 (MAC) 显着减少肺和心脏中的 M1 巨噬细胞。观察到 uPAR 和丝氨酸蛋白酶抑制剂（补体和纤溶酶原抑制剂）基因表达的连续变化。PEGSerp-1 是一种高效的免疫调节剂，具有治疗严重病毒性 ARDS、免疫凝血反应和长新冠肺炎的潜力。