Contact Activation and Infection

项目摘要 我们的研究项目旨在验证我们的中心假设，即接触激活系统 有助于导致血管功能障碍、凝血酶生成的病理机制， 在特定病原体的全身细菌攻击期间的炎症反应。 尽管有有效的抗生素，脓毒症仍然是一种普遍的临床综合征， 严重的院内发病率和死亡率的原因，所带来的一系列迅速推进 动态分子和细胞事件发生后，暴露于和随后的全身感染， 某些病原体。使问题复杂化的是， 病原体目前，经过半个多世纪的研究、药物开发， 临床试验，仍然没有FDA批准的上市药物专门用于治疗 败血症脓毒症可导致多器官系统衰竭，包括血管调节功能衰竭、组织差 灌注、水肿和全身性低血压，这是严重脓毒症的标志。通过触发 心肺和血管衰竭，即使有支持和抗生素，也往往是致命的 治疗。脓毒症可能伴有弥散性血管内凝血（DIC），这可能导致 血栓形成和消耗性凝血病引起的出血我们专注于接触激活 系统，因为1）凝血因子XII的激活之间似乎存在因果关系 以及某些形式的脓毒症的不良预后，以及2）靶向接触激活系统作为 治疗方法不太可能对宿主产生有害后果，例如出血。我们将 研究接触活化系统中的分子步骤在发展和结果中的作用， 体内实验细菌感染。我们将定义FXII（Aim 1）及其促凝血剂的作用， 底物FXI（目的2），并将我们的体外研究机制转化为表征 在两种不同的狒狒细菌感染模型中的接触激活。 我们的项目的潜在翻译相关性将是确定安全和可药用的 接触活化系统内的分子靶点和机制。我们的研究可能最终 为选择性接触活化抑制剂的开发提供理论依据， 患有或有感染可能导致接触系统激活的病原体的风险的患者。

Project Summary Our research project is designed to test our central hypothesis that the contact activation system contributes to pathologic mechanisms that lead to vascular dysfunction, thrombin generation, and inflammatory responses during systemic bacterial challenge by specific pathogens. Despite the availability of effective antibiotics, sepsis remains a prevalent clinical syndrome and significant cause of severe in-hospital morbidity and mortality, brought about by a sequence of rapidly advancing dynamic molecular and cellular events that occur upon exposure to and subsequent systemic infection by certain pathogens. Complicating the problem is the increasing prevalence of multiresistant bacterial pathogens. At present, after more than half a century of research, drug development, and countless clinical trials, there are still no FDA-approved marketed drugs specifically indicated for the treatment of sepsis. Sepsis can lead to multiple organ system failure, including failure of vasoregulation, poor tissue perfusion, edema, and systemic hypotension, which are hallmarks of severe sepsis. By triggering cardiopulmonary and vascular collapse, it is often lethal even with available supportive and antibiotic treatments. Sepsis may be accompanied by disseminated intravascular coagulation (DIC), which can lead to both thrombosis and bleeding due to the consumptive coagulopathy. We focus on the contact activation system, because 1) there appears to be a causal relationship between activation of coagulation factor XII and the poor prognosis of some forms of sepsis, and 2) targeting the contact activation system as a therapeutic approach is unlikely to have detrimental consequences for the host such as bleeding. We will study the role of the molecular steps in the contact activation system in the development and outcome of experimental bacterial infection, in vivo. We will define the roles of FXII (Aim 1) and its procoagulant substrate FXI (Aim 2), and translate our mechanistic in vitro studies to characterize the pathological role of contact activation in two distinct baboon models of bacterial infection. The potential translational relevance of our project will be the identification of safe and druggable molecular targets and mechanisms within the contact activation system. Our research may ultimately provide rationale for the development of selective contact activation inhibitors that could safely benefit patients that have or are at risk of infections by pathogens that can cause contact system activation.