Protective effects of anti-C5a in sepsis

抗 C5a 对脓毒症的保护作用

• 批准号: 7677833
• 负责人: Peter A Ward
• 金额: $ 30.17万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-15 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7677833
• 关键词: Affect; Affinity; Appearance; Biological Markers; Blood; Bulla; C5a anaphylatoxin receptor; Cardiac Myocytes; Coagulation Process; Complement 5a; Complement Activation; Equilibrium; Event; Failure; Functional disorder; Generations; Heart; Heart failure; Immune response; In Vitro; Inflammation Mediators; Inflammatory; Interleukin-17; Ligation; Link; Mediator of activation protein; Modeling; Molecular; Mus; Organ; Outcome; Paralysed; Phagocytes; Production; Puncture procedure; Rattus; Regulation; Rodent; Role; Sepsis; Signal Transduction; System; immune function; in vivo; interleukin-23; neutrophil; protective effect; receptor

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.

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).这些结果与补体系统的不受控制激活有关，C5a的产生以及与受体的相互作用（C5AR和C5L2）。受体参与的平衡决定了不利和致命的结果。在AIM 1中。我们建议使用C5A受体KO小鼠来确定CLP后的存活方式以及如何影响全身性炎症介体水平。在AIM 2中，我们将进行最近的研究，该研究表明，在败血症心脏和心肌细胞（CM）功能障碍中，可以将C5A与CMS上的C5A的相互作用联系起来，涉及的信号机制以及CMS在脓毒症期间可以产生有害的介体的程度。在AIM 3中，我们将寻求证据表明C5A会在体外和体内引起C5AR富集的微粒（MPS）在脓毒症期间的体内和体内脱落，以及CLP后C5A后的MP出现是否与C5A相关的MP外观，是否涉及的信号机制，以及MPS是否代表SEPIS的有用生物标志物。最后，在AIM 4中，我们将寻求证据表明IL-17的产量是由IL-23驱动的，并且在败血症期间起着“主开关”的作用，以促进有害炎症介质的系统性生产。这些研究中的统一主题是败血症引起的C5A产生，与其受体相互作用，导致了高度破坏性的结果。