Protective Effects of Anti-C5a in Sepsis

抗 C5a 对脓毒症的保护作用

• 批准号: 6647193
• 负责人: Peter A Ward
• 金额: $ 29.56万
• 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 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6647193
• 关键词: Klebsiella; NAD(P)H dehydrogenase; Pseudomonas; antibody receptor; bacterial disease; biological signal transduction; blood toxicology; clinical research; complement inhibitors; complement pathway; disease /disorder model; enzyme activity; gene expression; human tissue; ileocolonic region; immunity; immunoglobulin structure; laboratory mouse; laboratory rat; messenger RNA; microarray technology; neutrophil; phagocytosis; phorbols; protein kinase C

DESCRIPTION (provided by applicant): On the basis of our studies to date using the experimental model of sepsis induced by cecal ligation/puncture (CLP) in rats, serious impairment of innate immunity develops. This results in what appears to be a C5a-dependent defect in assembly of NADPH oxidase and defective phagocytic function of neutrophils. These defects can be reproduced by in vitro exposure of neutrophils to concentrations of C5a found in sepsis. In the first aim, we will evaluate how in vitro exposure of neutrophils to C5a results in detective signaling pathways: phorbol 12-myristate 13-acetate (PMA)-induced activation of phosphokinase C (PKC) which results in assembly of NADPH oxidase; and cell activation by engagement of FcyRs resulting in phagocytic responses. In the second aim, we will evaluate the same signaling pathways in blood neutrophils from CLP animals and determine if treatment with anti-C5a prevents defective signaling. In the third aim, we will determine if treatment of normal rats and mice and CLP rats and mice with anti-C5a compromises innate immunity, as assessed by bacterial clearance (Pseudomonas sp. and Klebsiella sp.) from lungs and evaluate the effects on survival. In the fourth aim, we will employ microarray analysis in CLP rats to define, as a function of time, alterations in global gene expression in organs that are predisposed to injury during sepsis (liver, lungs, kidneys, thymus) and determine if treatment with anti-C5a prevents this pattern of gene expression. It is possible that microarrary analysis will be predictive of organ susceptibility to damage during sepsis. Collectively, these studies should provide important evidence related to the mechanisms by which complement activation during sepsis impairs innate immunity.

描述（由申请人提供）：根据我们迄今为止的研究，使用 盲肠结扎/穿刺（CLP）诱发败血症的实验模型 大鼠的先天免疫会严重受损。这导致什么 似乎是 NADPH 氧化酶组装过程中的 C5a 依赖性缺陷和缺陷 中性粒细胞的吞噬功能。这些缺陷可以通过体外重现 中性粒细胞暴露于败血症中发现的 C5a 浓度。在第一个 目的，我们将评估中性粒细胞体外暴露于 C5a 的结果如何 检测信号通路：佛波醇 12-肉豆蔻酸酯 13-乙酸酯 (PMA) 诱导 磷酸激酶 C (PKC) 的激活导致 NADPH 氧化酶的组装； 以及通过 FcyR 参与导致吞噬反应的细胞激活。 在第二个目标中，我们将评估血液中相同的信号通路 来自 CLP 动物的中性粒细胞，并确定抗 C5a 治疗是否可以预防 有缺陷的信号。在第三个目标中，我们将确定治疗是否正常 具有抗 C5a 的大鼠和小鼠以及 CLP 大鼠和小鼠会损害先天免疫， 通过细菌清除率（假单胞菌属和克雷伯氏菌属）进行评估 肺并评估对生存的影响。在第四个目标中，我们将采用 对 CLP 大鼠进行微阵列分析，以定义随时间变化的变化 在易受损伤的器官中的整体基因表达 败血症（肝、肺、肾、胸腺）并确定是否使用抗 C5a 治疗 阻止这种基因表达模式。微阵列有可能 分析将预测败血症期间器官对损伤的易感性。 总的来说，这些研究应该提供与以下方面相关的重要证据： 脓毒症期间补体激活损害先天的机制 免疫。