Protective effects of anti-C5a in sepsis

描述(申请人提供)：在这份完全修订的竞争更新申请中，我们将继续寻找证据，证明在啮齿动物盲肠结扎和穿孔(CLP)后的实验性脓毒症过程中，炎症系统的调节丢失，导致各种有害后果(器官功能障碍、吞噬细胞固有免疫功能丧失和凝血/纤溶系统激活)。这些结果与补体系统的不受控制的激活、C5a的产生及其与其受体(C5aR和C5L2)的相互作用有关。受体参与的平衡决定了不利和致命的结果。在目标1中，我们建议使用C5a受体KO小鼠来确定CLP后的存活率如何受到影响，以及全身炎症介质水平是如何受到影响的。在目标2中，我们将继续我们最近的研究，这些研究表明，在脓毒症中，心脏和心肌细胞(CM)功能障碍可能与C5a和C5aR在CMS上的相互作用、所涉及的信号机制以及CMS在脓毒症过程中产生有害介质的程度有关。在目标3中，我们将寻求证据表明，C5a可以在体外和体内导致脓毒症期间C5aR富集型微粒(MPS)的泡泡形成和脱落，以及CLP后MP的出现是否依赖于C5a，涉及的信号机制，以及MPS是否代表脓毒症的有用生物标志物。最后，在目标4中，我们将寻求证据表明，IL-17的产生是由IL-23驱动的，并在脓毒症期间起到“总开关”的作用，促进全身有害炎症介质的产生。这些研究的统一主题是败血症诱导的C5a的产生，它与其受体相互作用，导致高度破坏性的结果。

DESCRIPTION (provided by applicant): In this completely revised Competiting Renewal Application, we will continue to pursue evidence that, during experimental sepsis after cecal ligation and puncture (CLP) in rodents, regulation of the inflammatory system is lost, resulting in a variety of harmful outcomes (organ dysfunction, loss of innate immune functions of phagocytic cells and activation of the clotting/fibrinolytic system). These outcomes are linked to uncontrolled activation of the complement system, generation of C5a and its interaction with its receptors (C5aR and C5L2). The balance in receptor engagement determines adverse and lethal outcomes. In Aim 1. we propose to use C5a receptor KO mice to determine how survival after CLP is affected and how systemic levels of inflammatory mediators are affected. In Aim 2 we will pursue our recent studies which indicate that in sepsis heart and cardiomyocyte (CM) dysfunction can be linked to interaction of C5a with C5aR on CMs, the signaling mechanisms involved, and the extent to which CMs can produce harmful mediators during sepsis. In Aim 3 we will pursue evidence that C5a can cause bleb formation and shedding of C5aR-enriched microparticles (MPs) in vitro and in vivo during sepsis and whether MP appearance after CLP is C5a dependent, the signaling mechanisms involved, and whether MPs represent a useful biomarker of sepsis. Finally, in Aim 4 we will pursue evidence that IL-17 production is driven by IL-23 and functions as "master switch" during sepsis to promote systemic production of harmful inflammatory mediators. The unifying theme in these studies is sepsis-induced production of C5a which, interacting with its receptors, results in highly destructive outcomes.