Complement C5 inhibition as sepsis therapy

项目摘要 脓毒症是由宿主对感染的反应失调引起的危及生命的器官功能障碍。败血症是一 重症监护室的主要死因病原体与血管内隔室的接触 宿主导致全身性炎症，其中补体和凝血系统的激活起作用， 关键角色。 该提议的目的是研究补体激活的作用及其与 炎症和凝血到脓毒症进展和多器官衰竭（MOF），以及是否阻断 C5水平的补体激活可预防MOF并改善脓毒症的预后。 我们将使用两种最常见的病原体大肠杆菌引起的败血症的临床相关模型 和金黄色葡萄球菌，以：（i）确定补体和凝血对发病机制的贡献 微血栓形成、血管功能障碍、器官衰竭和死亡的风险;（ii）测试针对微血栓形成、血管功能障碍、器官衰竭和死亡的阶段特异性疗法。 补体和凝血级联提供器官保护和败血症诱导的存活益处 渐进式MOF。 这些目标的成功完成将决定：（i）在C5水平的定时补体抑制是否 可用作脓毒症诱导的MOF的有效疗法;（ii）如果抑制C5 a受体-1信号传导可 减缓疾病进展并提供器官保护;（iii）如果联合治疗采用早期 抗凝血剂治疗和C5抑制剂延迟治疗将提供协同保护 在高脓毒性菌血症/休克的情况下。 总之，我们的项目将结合联合收割机的基础和临床前研究，以验证新的假设， 革兰氏阴性和革兰氏阳性脓毒症的病理生理学，并测试创新的方法， 长期治疗可能会挽救这种没有特效药的致命疾病的生命。

PROJECT SUMMARY Sepsis is a life-threatening organ dysfunction caused by dysregulated host response to infection. Sepsis is a leading cause of death in intensive care units. The contact of pathogens with the intravascular compartment of the host leads to systemic inflammation, wherein activation of the complement and coagulation systems plays critical roles. The objectives of this proposal are to investigate the role of complement activation and its crosstalk with inflammation and coagulation to sepsis progression and multiple organ failure (MOF) and, whether blocking complement activation at the C5 level could prevent MOF and improve the outcome of sepsis. We will use clinically relevant models of sepsis caused by two of the most common pathogens, Escherichia coli and Staphylococcus aureus to: (i) determine the contribution of complement and coagulation to pathogenesis of microthrombosis, vascular dysfunction, organ failure and death; (ii) test stage-specific therapies targeting the complement and coagulation cascades to provide organ protection and survival benefit in sepsis-induced progressive MOF. Successful completion of these aims will determine: (i) whether timed complement inhibition at the C5 level could be used as an effective therapy for sepsis-induced MOF; (ii) if inhibition of C5a receptor-1 signaling could attenuate disease progression and provide organ protection; (iii) if combination therapies employing early treatment with an anticoagulant and a delayed treatment with a C5 inhibitor will provide synergistic protection in cases of high septic bacteremia/shock. Altogether, our project will combine basic and preclinical research to verify novel hypotheses on the pathophysiology of both Gram-negative and Gram-positive sepsis, and test innovative approaches, which in the long-term may save lives from this deadly disease with no specific cure.