REGULATION OF HEPATIC ISCHEMIA/REPERFUSION INJURY

肝脏缺血/再灌注损伤的调节

• 批准号: 6517625
• 负责人: Alex B. Lentsch
• 金额: $ 25.09万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-30 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6517625
• 关键词: Adenoviridae; antiinflammatory agents; antisense nucleic acid; blocking antibody; gel mobility shift assay; gene expression; genetic regulation; genetically modified animals; histopathology; inflammation; interleukin 10; interleukin 13; laboratory mouse; liver ischemia /hypoxia; lung injury; northern blottings; nuclear factor kappa beta; oligonucleotides; polymerase chain reaction; protease inhibitor; reperfusion; tissue /cell culture; transfection /expression vector; vascular cell adhesion molecule; western blottings

Ischemia and reperfusion during surgical resection or transplantation of the liver may result in an inflammatory response causing local and remote organ injury. Characteristic features of this pathological process are enhanced production of proinflammatory cytokines and chemokines, and upregulation of vascular adhesion molecules. These mediators promote neutrophil accumulation and tissue injury. However, the events initiating proinflammatory mediators production in vivo are undefined. Likewise, intrinsic mechanisms that serve to prevent inflammatory tissue injury are unknown. The overall objective of this application is to delineate the regulatory mechanisms involved in local and remote organ (lung) injury related to hepatic ischemia and reperfusion. The Specific Aims of this project will: 1) Determine if specific inhibition of NFkB, using in vivo IkB-adenovirus transfection or antisense oligonucleotides, will suppress local and remote organ (lung) injury. The preliminary studies suggest that NFkB is required for in vivo induction of inflammatory responses. Since NFkB is known to regulate the gene expression of cytokines, chemokines, and adhesion molecules, these studies would define the currently unknown role of NFkB during the induction and propagation of inflammatory tissue injury. 2) Determine the regulatory roles of the anti-inflammatory mediators IL-10, IL-13 and SLP1 in hepatic ischemia/ reperfusion injury. The preliminary studies suggest that these mediators may play important roles in the regulation and resolution of inflammatory injury. The investigators will determine whether these mediators are endogenously expressed. Functional roles will be then be evaluated using blocking antibodies. 3) Determine whether exogenous administration of IL-10, IL-13, or SLP1 ameliorates hepatic ischemia/reperfusion injury. Further studies will employ transgenic mice and adenoviral transfection systems for in vivo overexpression of these mediators. This proposal will delineate the regulatory events during liver ischemia/ reperfusion injury and may provide a new understanding of the inflammatory injury common to a variety of pathological states.

手术切除或手术中的缺血再灌流 肝移植可能会导致炎症反应，引起 局部和远程器官损伤。本病的特点是 过程是促进促炎细胞因子和趋化因子的产生， 和上调血管黏附分子。这些调解人促进 中性粒细胞堆积和组织损伤。然而，发起的事件 促炎症介质在体内的产生尚不确定。同样，内在的 用于预防炎症组织损伤的机制尚不清楚。这个 本申请的总体目标是描述监管机制 与肝脏缺血相关的局部和远端器官(肺)损伤 和再灌流。该项目的具体目标将：1)确定是否 用IKB-腺病毒体内转染法特异性抑制NFkB 反义寡核苷酸，将抑制局部和远程器官(肺)损伤。 初步研究表明，NFkB在体内诱导 炎症反应。由于已知NFkB调节血管紧张素转换酶基因的表达 细胞因子、趋化因子和黏附分子，这些研究将定义 目前尚不清楚NFkB在黄瓜诱导和繁殖中的作用 炎性组织损伤。2)确定监管机构的角色 抗炎介质IL-10、IL-13和SLP1与肝缺血/再灌注损伤 再灌注损伤。初步研究表明，这些介体可能 在炎性损伤的调节和消退中发挥重要作用。 调查人员将确定这些调解人是否是内源性的 表达。然后将使用阻塞来评估功能角色 抗体。3)确定外源性给予IL-10、IL-13或 SLP1可减轻肝脏缺血再灌注损伤。进一步的研究将 利用转基因小鼠和腺病毒转导系统进行体内实验 这些调解人的过度表达。这项提案将划定监管机构 在肝脏缺血/再灌注损伤中的变化，并可能提供新的 对炎性损伤常见的各种病理机制的认识 各州。