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<p>A virus-derived serpin, Serp-1, has proven efficacy in treating inflammatory and coagulation disorders in preclinical and clinical studies. Serp-1 evolved over millions of years to block host immune responses, targeting serine proteases in immune and coagulation pathways. Treatment with PEGylated Serp-1 (PEGSerp-1) protein reduced lung injury in both lupus lung hemorrhage and SARS-CoV-2 models. Here, PEGSerp-1 effects on immune-coagulopathic responses is examined in a mouse colitis model. Inflammatory bowel disease (IBD) is associated with life-threatening complications with severe inflammation, bleeding, vasculitis, cancer and toxic megacolon. <i>Ser</i>ine <i>p</i>rotease cascades activate coagulation and complement pathways throughout the human body and are regulated by <i>in</i>hibitors, termed <i>serpins</i>, that can reduce gut inflammation. Prophylactic PEGSerp-1 significantly improved survival in severe 5% Dextran sodium sulfate (DSS) colitis, reducing inflammation and crypt damage. Colon damage and inflammation were also reduced after either acute colitis induced by 5% DSS or repeat 2% DSS induced colitis. PEGSerp-1 reduced inflammatory M1 macrophage invasion, urokinase-type plasminogen activator receptor (uPAR), fibrinogen and complement on immunohistochemical analysis. PEGSerp-1 reduced uPAR expression in human macrophage, but not colon cells. Here we report analysis of PEGSerp-1 as a tissue and macrophage targeting therapeutic for colitis, reducing immune and coagulation induced damage in the colon.</p>

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Virus-derived serpin reduces immuno-coagulopathic damage in murine colitis by targeting the urokinase-type plasminogen activator receptor (uPAR) and complement

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月19日

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  • Alexandra R. Lucas,
  • Henna Monder,
  • Junior Enow,
  • Cheyanne Woodrow,
  • Laurel Spaccarelli,
  • Aman Garg,
  • Jessika Schlievert,
  • Nora Elmadbouly,
  • Aashika Dupati,
  • Emily Aliskevich,
  • Rohan Saju,
  • Jacqueline Kilbourne,
  • Kenneth Lowe,
  • Mostafa Hamada,
  • Aubrey Pinteric,
  • Isabela R. Zanetti,
  • Ritvik Srivant Satyanarayanan,
  • Savanah Gisriel,
  • Esther Borges Florsheim,
  • Masmudur Rahman,
  • James Irving,
  • Grant McFadden,
  • Wei Kong,
  • Liqiang Zhang

摘要

A virus-derived serpin, Serp-1, has proven efficacy in treating inflammatory and coagulation disorders in preclinical and clinical studies. Serp-1 evolved over millions of years to block host immune responses, targeting serine proteases in immune and coagulation pathways. Treatment with PEGylated Serp-1 (PEGSerp-1) protein reduced lung injury in both lupus lung hemorrhage and SARS-CoV-2 models. Here, PEGSerp-1 effects on immune-coagulopathic responses is examined in a mouse colitis model. Inflammatory bowel disease (IBD) is associated with life-threatening complications with severe inflammation, bleeding, vasculitis, cancer and toxic megacolon. Serine protease cascades activate coagulation and complement pathways throughout the human body and are regulated by inhibitors, termed serpins, that can reduce gut inflammation. Prophylactic PEGSerp-1 significantly improved survival in severe 5% Dextran sodium sulfate (DSS) colitis, reducing inflammation and crypt damage. Colon damage and inflammation were also reduced after either acute colitis induced by 5% DSS or repeat 2% DSS induced colitis. PEGSerp-1 reduced inflammatory M1 macrophage invasion, urokinase-type plasminogen activator receptor (uPAR), fibrinogen and complement on immunohistochemical analysis. PEGSerp-1 reduced uPAR expression in human macrophage, but not colon cells. Here we report analysis of PEGSerp-1 as a tissue and macrophage targeting therapeutic for colitis, reducing immune and coagulation induced damage in the colon.