Complement C5 inhibition as sepsis therapy

项目总结 脓毒症是一种因宿主对感染的反应失调而导致的危及生命的器官功能障碍。败血症是一种 重症监护病房的主要死因。病原体与血管内隔膜的接触 宿主导致全身炎症，其中补体和凝血系统的激活起作用 关键角色。 这项建议的目的是研究补体激活的作用及其与 炎症和凝血对脓毒症进展和多器官功能衰竭(MOF)的影响 补体在C5水平的激活可以预防多器官功能衰竭，改善脓毒症的结局。 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：(I)确定补体和凝血在发病中的作用 微血栓形成、血管功能障碍、器官衰竭和死亡；(2)针对 补体和凝血级联在脓毒症中提供器官保护和生存益处 进步的财政部。 这些目标的成功完成将决定：(I)C5水平的定时补体抑制 可作为脓毒症诱导的多器官功能衰竭的有效治疗方法；(Ii)如果抑制C5a受体-1信号转导可以 延缓疾病进展并提供器官保护；(3)如果早期采用综合疗法 使用抗凝剂治疗和延迟使用C5抑制剂治疗将提供协同保护 在高度败血症/休克的情况下。 总之，我们的项目将结合基础和临床前研究来验证关于 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，其中 从长远来看，这种致命的疾病可能会在没有特效药的情况下拯救生命。

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.