Complement and ethanol-induced liver injury.

补体和乙醇引起的肝损伤。

基本信息

批准号：
7918880
负责人：
LAURA E. NAGY
金额：
$ 33.42万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-09-11 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7918880
关键词：
Ablation Acetaldehyde Alcohol-Induced Disorders Alcoholic Liver Diseases Alcoholic liver damage Animals Anti-Inflammatory Agents Anti-inflammatory Antibodies Apoptotic Blood C-terminal C5a anaphylatoxin receptor CD14 Antigen CD55 Antigens Cell Adhesion Molecules Cell Wall Cells Chemotaxis Chronic Complement Complement 3 Convertase Complement 3a Complement 3b Complement 5a Complement Activation Complement Membrane Attack Complex Complement Receptor Complex Coupled Data Development Disease model Endotoxins Ethanol Ethanol Metabolism Exhibits Family Fatty Liver Future G-Protein-Coupled Receptors Generations Hepatic Hepatocyte Heterotrimeric GTP-Binding Proteins Immune response Individual Infection Inflammation Inflammation Mediators Inflammatory Inflammatory Response Injury Injury to Liver Intestinal Mucosa Kupffer Cells Lectin Lipid Peroxides Lipopolysaccharides Liver Lytic Malondialdehyde Mediating Membrane Molecular Mus Organism Pathway interactions Plasma Play Primary Cell Cultures Principal Investigator Production Prostaglandins Proteins Rattus Reactive Oxygen Species Research Personnel Respiratory Burst Role Series Serum Signal Transduction Staging Surface System T-Cell Activation TLR4 gene Testing Tissues Triglycerides Wild Type Mouse Wound Healing activation product alcohol effect alcohol exposure base cell injury cell type chemokine complement C5b complement pathway complement system cytokine feeding genetic regulatory protein injury and repair macrophage member mouse model prevent problem drinker programs receptor repaired research study response response to injury toll-like receptor 4 ward

项目摘要

DESCRIPTION (provided by applicant): While our current understanding of the pathophysiological mechanisms involved in the development of ethanol (EtOH)-induced liver injury is incomplete, both innate and adaptive immune responses are implicated in initiation and progression of liver injury. The complement (C) system is a network of more than 30 proteins, involved in both innate and adaptive immune responses. Activation of the C pathway can occur via the classical, lectin or alternative pathways, all three pathways culminate in the activation of C3, which in turn activates the terminal pathway leading to the formation of the C5b-9 membrane attack complex (MAC). C is critical to an organism's ability to ward off infection and also plays a role in the repair response to injury, but uncontrolled C activation may itself cause cellular injury. Further, the C pathway contributes to activation of a number of pro-inflammatory responses. We have recently investigated whether C activation is required for chronic EtOH-induced liver injury in wild-type mice and mice lacking the 3rd (C3) or 5th (C5) components of the C activation pathway, as well as mice lacking decay accelerating factor (CD55/DAF) or CD59, intrinsic regulatory proteins in the C pathway. Chronic EtOH feeding to mice increased activation of C3, increasing the concentration of C3a in the plasma. Importantly, C3 -/- and C5 -/- mice were protected from EtOH-induced fatty liver injury. Injury was exacerbated in CD55/DAF -/- mice, while CD59 -/- were protected from EtOH-induced fatty liver injury. Here we propose to test the hypothesis that C activation is critically involved in the development of chronic EtOH-induced fatty liver and that the intrinsic C regulator CD55/DAF acts as a primary brake against the deleterious effects of EtOH in the liver. Further, we hypothesize that activation of the terminal C pathway and formation of the MAC serves to dampen EtOH- induced injury in the liver. We propose four specific aims to investigate the mechanisms by which the C system modulates EtOH-induced liver injury in a mouse model of chronic EtOH exposure, as well as in primary cell cultures. 1) Elucidate the specific C activation pathway(s) involved in activation of C3- dependent damage by EtOH, 2) Determine the specific contributions of C3 versus C5 in mediating chronic EtOH-induced fatty liver injury, 3) Understand the protective function of the terminal C pathway/MAC during chronic EtOH exposure and 4) Determine the effects of chronic EtOH feeding on the response of Kupffer cells and hepatocytes to activation by C3a and C5a. Understanding the mechanisms by which chronic EtOH feeding activates the C system and the role of C in mediating liver injury will facilitate the development of pharmacotherapeutic strategies to prevent and/or reverse EtOH-induced liver injury.

描述（由申请人提供）：虽然我们目前对乙醇（ETOH）诱导的肝损伤发展的病理生理机制的理解不完整，但先天和适应性免疫反应都与肝损伤的开始和进展有关。补体（C）系统是由30多个蛋白质组成的网络，涉及先天和适应性免疫反应。 C途径的激活可以通过经典，凝集素或替代途径进行，这三个途径在C3的激活中最终导致，这又激活了终端途径，导致C5B-9膜攻击复合物（MAC）形成。 C对于生物体抵御感染的能力至关重要，并且在修复损伤反应中也起作用，但不受控制的C激活本身可能会导致细胞损伤。此外，C途径有助于激活许多促炎反应。我们最近研究了慢性EtOH诱导的野生型小鼠肝损伤是否需要C激活，而缺乏C激活途径的第3（C3）或第5（C5）成分以及缺乏衰减加速因子（CD55/DAF）或CD59或CD59或CD59的小鼠，本质上是condine pathroway pathroway pathroway pathroway。慢性EtOH喂养给小鼠增加了C3的激活，从而增加了血浆中C3A的浓度。重要的是，C3 - / - 和C5 - / - 小鼠受到ETOH诱导的脂肪肝损伤的保护。在CD55/DAF - / - 小鼠中损伤加剧，而CD59 - / - 免受ETOH诱导的脂肪肝损伤的保护。在这里，我们建议检验以下假设：C激活与慢性ETOH诱导的脂肪肝的发展至关重要，并且内在的C调节剂CD55/DAF起着对ETOH在肝脏中有害作用的主要制动。此外，我们假设末端C途径的激活和MAC的形成可抑制肝脏中的eTOH诱导的损伤。我们提出了四个特定的目的，以研究C系统在慢性ETOH暴露的小鼠模型以及原代细胞培养物中调节ETOH诱导的肝损伤的机制。 1）阐明参与ETOH激活C3依赖性损害的特定C活化途径，2）确定C3与C5在介导慢性EtOH诱导的脂肪肝损伤中的特定贡献C3A和C5A。了解慢性ETOH喂养激活C系统的机制以及C在介导肝损伤中的作用将有助于制定药物治疗策略，以预防和/或反向ETOH诱导的肝损伤。