New strategies for treating septic vasculopathy, inflammation and thrombosis

描述（由申请人提供）：严重脓毒症的预后不良与微循环受损、多器官损伤和弥散性血管内凝血（DIC）有关，这是全身性血管内炎症、血管渗漏、微血管血栓形成和血小板减少相互依赖的机制。目前，没有药物可以同时治疗败血症中的这些事件。我们最近发现了VWF/GPIb-IX和整合素依赖性血小板粘附和血栓形成在败血症中的重要作用（Yin ATVB 2013），并且G /13异三聚体G蛋白家族在血小板中整合素外向内信号传导中起关键作用（Gong et al ., Science 2010, Shen et al . Nature 2013）和内皮细胞分泌VWF （Rusu et al Blood 2014）。G /13也负调控钙粘蛋白功能（Meigs JBC 2002）并增加内皮通透性。此外，我们已经发现单核细胞/巨噬细胞中nos1依赖性的细胞因子信号抑制因子（SOCS1）表达调控（Baig等，Science Signaling, In revision）是脓毒症诱导的血管炎症和高通透性的关键决定因素。在这里，我们将验证这样的假设，即脓毒症可以通过同时使用不引起出血和血管渗漏的新型药物进行抗血栓、抗炎和抗超渗治疗。我们已经生成了抑制内皮细胞VWF分泌的G / AP相互作用的新型抑制肽，以及G -整合素和VWF - gpib - ix相互作用的抑制剂，这些抑制剂可以有效抑制血栓形成，而不会对出血产生不利影响（Shen等人，Nature 2013； Yin等人，ATVB 2013； Rusu等人，Blood 2013）。我们建议(1)确定抑制GPIb和G /13/整合素信号通路对脓毒症的治疗效果；(2)确定G依赖性内皮细胞VWF分泌在脓毒症诱导的微血栓形成中的作用；(3)干预伴随抗血栓治疗的脓毒症诱导内皮细胞高通透性的炎症反应。本研究不仅将为脓毒症提供新的治疗理念，而且将这些理念转化为新的抗脓毒症药物和治疗方法。

DESCRIPTION (provided by applicant): Poor prognosis of severe sepsis is associated with impaired microcirculation, multiple organ injury and disseminated intravascular coagulation (DIC) as a result of interdependent mechanisms of systemic intravascular inflammation, vascular leakage, microvascular thrombosis, and thrombocytopenia. Currently, no drug is available to concomitantly treat these events in sepsis. We recently discovered an important role for VWF/GPIb-IX- and integrin-dependent platelet adhesion and thrombus formation in sepsis (Yin ATVB 2013), and that G�/13 family of heterotrimeric G proteins play critical roles in integrin outside-in signaling in platelets (Gong et al, Science 2010, Shen et al Nature 2013) and in vWF secretion by endothelial cells (Rusu et al Blood 2014). G�/13 also negatively regulates cadherin function (Meigs JBC 2002) and increases endothelial permeability. In addition, we have identified NOS1-dependent regulation of Suppressor of Cytokine Signaling (SOCS1) expression in monocytes/macrophages (Baig et al, Science Signaling, in revision) as a critical determinant of sepsis-induced vascular inflammation and hyperpermeability. Here, we will test the hypotheses that sepsis can be effectively treated by concomitant anti-thrombotic, anti-inflammatory and anti- hyperpermeability therapy with novel agents that do not cause hemorrhage and vascular leakage. We have generated novel inhibitory peptides of G�/�AP interaction that inhibit endothelial VWF secretion as well as inhibitors of G�-integrin and vWF-GPIb-IX interactions that potently inhibit thrombosis without adversely inducing hemorrhage (Shen et al, Nature 2013; Yin et al, ATVB 2013; Rusu et al., Blood 2013). We propose to (1) determine the therapeutic effect of inhibiting GPIb and G�/13/integrin signaling in sepsis; (2) determine the role of G�-dependent endothelial cell VWF secretion in sepsis-induced microthrombosis; and (3) interfere with the inflammatory response that induces endothelial hyperpermeability in sepsis concomitantly with anti-thrombotic therapy. This study will not only provide novel therapeutic concepts in sepsis, but also translate these concepts into new anti-sepsis drugs and treatments.