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Protective Effects of Anti-C5a in Sepsis

抗 C5a 对脓毒症的保护作用

基本信息

批准号：
8654004
负责人：
Peter A Ward
金额：
$ 5.29万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-08-15 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8654004
关键词：
Action Potentials Affect Anaphylatoxins Animals Antibodies Appearance C5a anaphylatoxin receptor Calcium Cardiac Cardiac Myocytes Cardiac Output Cardiomyopathies Cardiovascular system Characteristics Clinical Complement 5a Complication Coupling Data Defect Development Dose Echocardiography Exposure to FDA approved Failure Functional disorder Generic Drugs Heart Heart failure Human In Vitro Individual Interleukin-12 Interleukin-17 Interleukin-6 Intervention Knockout Mice Ligation Literature Location Measures Mediator of activation protein Molecular Mus Muscle Cells North America Organ failure Pathogenesis Patients Performance Peripheral Resistance Plasma Puncture procedure Rodent Role Sepsis Septic Shock Signal Pathway Stroke Volume TNF gene Time Ventricular base chemokine cytokine in vivo mortality mouse model neutralizing antibody protective effect public health relevance receptor receptor upregulation response septic statistics

项目摘要

DESCRIPTION (provided by applicant): We will continue our studies to define molecular mechanisms related to development of septic cardiomyopathy in rodents after cecal ligation and puncture (CLP), with an emphasis on the roles of C5a anaphylatoxin and its receptors, C5aR and C5L2. Aim 1 will define the requirements for C3, C5, C5a receptors (C5aR, C5L2) and IL-17 for spontaneous release of cardiosuppressive cytokines (IL-12, TNF1, IL-6) from sham and CLP cardiomyocytes (CMs). These data will be compared to the presence of cytokines in heart homogenates and plasma from CLP mice. Aim 2 will determine the time course after CLP for upregulation of receptors for C5a and the cardiosuppressive cytokines (IL-12, TNF1 and IL-6) on CMs. Aim 3 will assess electrophysiological responses (action potentials, Ca2+ transients, and K+ and Ca2+ currents) as well as functional responses (by measuring intracellular calcium transients and myocyte contraction) in CMs obtained from sham and CLP rodents as a function of time after CLP. In addition, sham and CLP CMs will be studied for changes in electrophysiological and contractile responses after in vitro exposure to C5a in an effort to define molecular mechanisms by which C5a causes contractile dysfunction in CMs. Aim 4 will assess the ability of C5a to induce changes in CMs (as described in Aim 3), using sham and CLP CMs to which varying concentrations of C5a or cardiosuppressive cytokines, or both, have been added. We will determine if there is a synergy in development of electrophysiological dysfunction with combination of C5a and cardiosuppressive cytokines. Aim 5 will employ non-invasive echocardiography approaches to assess systolic and diastolic function and systemic vascular resistance, as well as other parameters, in CLP mice as compared to sham mice. We will attempt to define the roles of C3, C5, C5a and IL-17 receptors in CM dysfunction. These studies will also feature CLP mice that have been treated with neutralizing antibodies to C5a or IL-17. A C5aR knockout mouse model will also be utilized to define the role of the C5a signaling pathways in the pathogenesis of septic cardiomyopathy. Collectively, these studies should define the roles of C5a and its receptors as well as cardiosuppressive cytokines in the development of septic cardiomyopathy and how this complication can be averted or treated.

描述（由申请人提供）：我们将继续研究，以确定与盲肠结扎和穿刺（CLP）后啮齿动物发生脓毒性心肌病相关的分子机制，重点是C5 a过敏毒素及其受体C5 aR和C5 L2的作用。目的1将定义C3，C5，C5 a受体（C5 aR，C5 L2）和IL-17从假手术和CLP心肌细胞（CM）自发释放心脏抑制细胞因子（IL-12，TNF-1，IL-6）的要求。将这些数据与CLP小鼠心脏匀浆和血浆中细胞因子的存在进行比较。目的2将确定CLP后CM上C5 a受体和心脏抑制细胞因子（IL-12、TNF 1和IL-6）上调的时间过程。目的3将评估从假手术和CLP啮齿动物获得的CM中的电生理反应（动作电位、Ca 2+瞬变、K+和Ca 2+电流）以及功能反应（通过测量细胞内钙瞬变和肌细胞收缩），作为CLP后时间的函数。此外，将研究假手术和CLP CM在体外暴露于C5 a后的电生理和收缩反应变化，以确定C5 a导致CM收缩功能障碍的分子机制。目的4将使用添加了不同浓度的C5 a或心脏抑制细胞因子或两者的假手术和CLP CM，评估C5 a诱导CM变化的能力（如目的3所述）。我们将确定C5 a和心脏抑制细胞因子的组合在电生理功能障碍的发展中是否存在协同作用。目的5将采用非侵入性超声心动图方法来评估CLP小鼠与假手术小鼠相比的收缩和舒张功能以及全身血管阻力以及其他参数。我们将尝试确定C3，C5，C5 a和IL-17受体在CM功能障碍中的作用。这些研究还将采用C5 a或IL-17中和抗体治疗的CLP小鼠。C5 aR基因敲除小鼠模型也将用于确定C5 a信号通路在脓毒性心肌病发病机制中的作用。总的来说，这些研究应该确定C5 a及其受体以及心脏抑制细胞因子在脓毒性心肌病发展中的作用，以及如何避免或治疗这种并发症。

项目成果

期刊论文数量（53）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

New approaches to the study of sepsis.

DOI：
10.1002/emmm.201201375
发表时间：
2012-12
期刊：
EMBO MOLECULAR MEDICINE
影响因子：
11.1
作者：
Ward, Peter A.
通讯作者：
Ward, Peter A.

Harmful Roles of TLR3 and TLR9 in Cardiac Dysfunction Developing during Polymicrobial Sepsis.

DOI：
10.1155/2018/4302726
发表时间：
2018
期刊：
BioMed research international
影响因子：
0
作者：
Fattahi F;Russell MW;Malan EA;Parlett M;Abe E;Zetoune FS;Ward PA
通讯作者：
Ward PA

Sepsis, complement and the dysregulated inflammatory response.

DOI：
10.1111/j.1582-4934.2009.00893.x
发表时间：
2009-10
期刊：
Journal of cellular and molecular medicine
影响因子：
5.3
作者：
Ward PA;Gao H
通讯作者：
Gao H

The inflammatory response in sepsis.

DOI：
10.1016/j.it.2012.09.004
发表时间：
2013-03
期刊：
Trends in immunology
影响因子：
16.8
作者：
Bosmann M;Ward PA
通讯作者：
Ward PA

The interaction between C5a and both C5aR and C5L2 receptors is required for production of G-CSF during acute inflammation.

DOI：
10.1002/eji.201243075
发表时间：
2013-07
期刊：
EUROPEAN JOURNAL OF IMMUNOLOGY
影响因子：
5.4
作者：
Bosmann, Markus;Haggadone, Mikel D.;Zetoune, Firas S.;Sarma, J. Vidya;Ward, Peter A.
通讯作者：
Ward, Peter A.