Protective Effects of Anti-C5a in Sepsis

抗 C5a 对脓毒症的保护作用

• 批准号: 6897951
• 负责人: Peter A Ward
• 金额: $ 28.68万
• 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/6897951
• 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 由盲肠连接/穿刺（CLP）引起的败血症的实验模型 大鼠，对先天免疫力的严重损害会发展出来。这导致什么 似乎是NADPH氧化酶和缺陷的C5A依赖性缺陷 中性粒细胞的吞噬功能。这些缺陷可以通过体外复制 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在C5A中的体外暴露如何导致 侦探信号通路：佛波尔12-饱和13-乙酸酯（PMA）诱导的 磷酸激酶C（PKC）的激活，导致NADPH氧化酶的组装； 和通过FCYR的参与而激活细胞，从而导致吞噬反应。 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动物的嗜中性粒细胞，并确定用抗C5A治疗是否阻止 信号不良。在第三个目标中，我们将确定是否治疗正常 抗C5a的大鼠，小鼠和CLP大鼠和小鼠损害了先天免疫力， 通过细菌清除率（假单胞菌sp。和klebsiella sp。）评估 肺并评估对生存的影响。在第四个目标中，我们将雇用 CLP大鼠中的微阵列分析以定义时间的变化 在器官中的全球基因表达中，在易受损伤的器官中 败血症（肝，肺，肾脏，胸腺），并确定用抗C5a治疗 防止这种基因表达模式。微生物可能 分析将预测器官在败血症期间对损伤的敏感性。 总的来说，这些研究应提供与 败血症期间补体激活会损害先天的机制 免疫。