New strategies for treating septic vasculopathy, inflammation and thrombosis

描述（由申请方提供）：由于全身性血管内炎症、血管渗漏、微血管血栓形成和血小板减少症的相互依赖机制，严重脓毒症的不良预后与微循环受损、多器官损伤和弥散性血管内凝血（DIC）相关。目前，没有药物可用于伴随治疗脓毒症中的这些事件。我们最近发现VWF/GPIb-IX-和整合素依赖性血小板粘附和血栓形成在脓毒症中的重要作用（Yin ATVB 2013），并且异源三聚体G蛋白的G β/13家族在血小板中的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）和内皮细胞的vWF分泌中起关键作用（Rusu et al Blood 2014）。G β/13还负调节钙粘蛋白功能（Meigs JBC 2002）并增加内皮通透性。此外，我们已经鉴定了单核细胞/巨噬细胞中细胞因子信号传导抑制因子（SOCS 1）表达的NOS 1依赖性调节（Baig等，Science Signaling，修订版）是脓毒症诱导的血管炎症和高通透性的关键决定因素。在此，我们将检验脓毒症可以通过伴随使用不引起出血和血管渗漏的新型药物的抗血栓形成、抗炎和抗高渗透性治疗来有效治疗的假设。我们已经产生了抑制内皮VWF分泌的G β/AP相互作用的新型抑制肽以及G β-整联蛋白和vWF-GPIb-IX相互作用的抑制剂，其有效地抑制血栓形成而不会不利地诱导出血（Shen et al，Nature 2013; Yin et al，ATVB 2013; Rusu et al，Blood 2013）。我们建议（1）确定抑制GPIb和G β/13/整合素信号在脓毒症中的治疗效果;（2）确定G β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）在抗血栓治疗的同时干扰脓毒症中诱导内皮通透性增高的炎症反应。这项研究不仅将为脓毒症提供新的治疗概念，而且还将这些概念转化为新的抗菌药物和治疗方法。

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.