FXI and Sepsis

 描述（由申请人提供）：我们的研究项目旨在检验我们的中心假设，即接触因子途径的激活有助于导致特定感染性病原体诱导的脓毒症期间血管功能障碍、凝血酶生成和炎症反应的病理机制。脓毒症是分子和细胞事件的后果，这些事件在这种危及生命的疾病状况的过程中不断变化。血管调节失败、组织灌注不良、水肿和全身性低血压是严重脓毒症的标志，并且通过触发心肺和血管塌陷，在不治疗时导致死亡。严重脓毒症可伴有弥散性血管内凝血（DIC），其加重血管舒张和水肿相关的组织灌注不足。DIC可导致止血失败，随后由于凝血因子和血小板的消耗而出血。我们专注于接触活化途径，因为1）凝血因子XII的病理活化与某些形式脓毒症的不良预后之间似乎存在因果关系，2）靶向接触活化途径作为治疗方法不太可能对宿主产生有害后果。我们将明确凝血接触途径中的分子步骤在严重脓毒症的发展和结局中的作用。我们将定义FXII（目的1）及其促凝血底物FXI（目的2）的作用，并将我们的体外和离体研究机制转化为定义2种不同的严重脓毒症灵长类动物模型中接触途径激活的病理作用。我们的项目的潜在翻译相关性将是确定安全和 接触激活途径中的药物分子靶点和机制。我们的研究可能最终为开发选择性接触激活途径抑制剂提供理论基础，这些抑制剂可能使感染利用接触激活途径致病的病原体的脓毒症患者受益。重要的是，这种方法不会对感染由内源性外源性途径依赖性纤维蛋白形成作为先天免疫应答的一部分控制的患者造成伤害。

 DESCRIPTION (provided by applicant): Our research project is designed to test our central hypothesis that activation of the contact factor pathway contributes to pathologic mechanisms that lead to vascular dysfunction, thrombin generation, and inflammatory responses during sepsis induced by specific infectious pathogens. Sepsis is a sequel of molecular and cellular events that perpetually change over the course of this life threatening disease condition. Failure of vasoregulation, poor tissue perfusion, edema, and systemic hypotension are hallmarks of severe sepsis, and, by triggering a cardiopulmonary and vascular collapse, leads to death when left untreated. Severe sepsis may be accompanied by disseminated intravascular coagulation (DIC) that aggravates the vasodilation and edema-associated tissue perfusion insufficiency. DIC can lead to the failure of hemostasis, and subsequent bleeding due to the consumption of coagulation factors and platelets. We focus on the contact activation pathway, because 1) there appears to be a causal relationship between pathological activation of the coagulation factor XII and the poor prognosis of some forms of sepsis, and 2) targeting the contact activation pathway as a therapeutic approach is unlikely to have detrimental consequences for the host. We will define the role of the molecular steps in the contact pathway of coagulation in the development and outcomes of severe sepsis. We will define the roles of FXII (Aim 1) and its procoagulant substrate FXI (Aim 2), and will translate our mechanistic in vitro and ex vivo studies to define th pathological role of activation of the contact pathway in 2 distinct primate models of severe sepsis. The potential translational relevance of our project will be the identification of safe and druggable molecular targets and mechanisms within the contact activation pathway. Our research may ultimately provide rationale for the development of selective contact activation pathway inhibitors that could benefit sepsis patients infected with pathogens that exploit the contact activation pathway for virulence. Importantly, this approach would not do harm to patients whose infection is controlled by endogenous extrinsic pathway-dependent fibrin formation as part of the innate immune response.