REGULATION OF HEPATIC ISCHEMIA/REPERFUSION INJURY

肝脏缺血/再灌注损伤的调节

• 批准号: 6661229
• 负责人: Alex B. Lentsch
• 金额: $ 19.34万
• 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 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6661229
• 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.

手术切除期间的缺血和再灌注，或 肝脏移植可能导致炎症反应， 局部和远端器官损伤。这种病理性的特征 过程是促炎细胞因子和趋化因子的产生增强， 和血管粘附分子的上调。这些中介促进 中性粒细胞积聚和组织损伤。然而，引发 体内促炎介质的产生是不确定的。同样，内在 用于防止炎性组织损伤的机制是未知的。的 本申请的总体目标是描述调节机制 参与与肝缺血相关的局部和远端器官（肺）损伤 再灌注。该项目的具体目标是：1）确定是否 使用体内IkB-腺病毒转染或 反义寡核苷酸将抑制局部和远端器官（肺）损伤。 初步研究表明，NFkB是体内诱导细胞凋亡所必需的。 炎症反应。由于已知NFkB调节以下基因的表达： 细胞因子，趋化因子和粘附分子，这些研究将定义 目前未知的作用NFkB在诱导和繁殖过程中， 炎性组织损伤。2)确定监管角色 抗炎介质IL-10、IL-13和SLP 1在肝缺血/ 再灌注损伤初步研究表明，这些介质可能 在炎症损伤的调节和消退中发挥重要作用。 研究人员将确定这些介质是否是内源性的， 表达。然后将使用分块来评估功能角色 抗体的3)确定外源性施用IL-10、IL-13或 SLP 1改善肝脏缺血/再灌注损伤。进一步的研究将 使用转基因小鼠和腺病毒转染系统进行体内 这些介质的过度表达。该提案将描述监管 肝缺血/再灌注损伤期间的事件，并可能提供新的 了解各种病理性常见的炎性损伤 states.