Experimental study on effect of preconditioning to hepatic ischemia/reperfusion injury.

预处理对肝缺血/再灌注损伤影响的实验研究。

基本信息

批准号：
11671228
负责人：
NAGINO Masato
金额：
$ 2.18万
依托单位：
Nagoya University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

项目摘要

Our goal of this study was to examine the effect of preconditioning to hepatic ischemia/reperfusion (I/R). At first, to establish experimental model for hepatic I/R, experiments on hepatic I/R in hypercholesterolemic mice were conducted. The objective of this series was to determine whether hypercholesterolemia affects leukocyte adhesion and tissue injury after I/R in the mouse liver. The accumulation of rhodamine-6G-labelled leukocytes and number of non-perfused sinusoids (NPS) were monitored (by intravital microscopy) in liver of normal (WT) and low-density lipoprotein receptor-deficient (LDLr^<-/->) mice for 1 hr after a 30 min period of normothermic ischemia. Plasma Alanine Transaminase (ALT) level was measured as an index of liver tissue injury Microvascular leukostasis as well as increases in NPS and plasma ALT level were observed at 60 min after hepatic I/R in both WT and in LDLr^<-/-> mice ; however, these responses were greatly exaggerated in LDLr^<-/-> mice. Pretreatment of L … More DLr^<-/-> mice with gadolinium chloride, which reduces Kupffer cell function, attenuated the hepatic leukostasis, NPS and liver tissue injury elicited by I/R.Similar protection against I/R was observed in LDLr^<-/-> mice pretreated with antibodies directed against either tumor necrosis factor-α, intercellular adhesion molecule-1 (ICAM-1), or P-selectin. These findings indicate that chronic hypercholesterolemia predisposes the hepatic microvasculature to the deleterious effects of I/R.Kupffer cell activation and the leukocyte adhesion receptors ICAM-1 and P-selectin appear to contribute to the exaggerated inflammatory responses observed in the postishemic liver of LDLr^<-/-> mice. Using this established experimental model of mice liver, a small amount of endotoxin was intraperitoneally administered 24 hours prior to 1 hour hepatic ischemia in wild-type mice. Pretreatment of endotoxin attenuated microvascular leukostasis at 60 win after hepatic I/R, and preconditioning effect in mice liver was confirmed. Hereafter, we will examine the preconditioning effect by a short duration of ischemia and elucidate its mechanism. Less

这项研究的目标是检查对肝缺血/再灌注（I/R）的预处理的影响。首先，为了建立肝I/R的实验模型，对高胆固醇小鼠的肝I/R进行了实验。该系列的目的是确定高胆固醇血症是否会影响小鼠肝脏I/R后的白细胞粘合剂和组织损伤。在正常（WT）肝脏（WT）和低密度脂蛋白受体缺乏症的肝脏中监测（通过浸润性显微镜），监测了若丹明-6g标记的白细胞和数量的非吞噬正弦（NP）（NPS）的积累（LDLR^<----->）小鼠在30分钟后的正常（LDLR^<--->）小鼠中的积累。血浆丙氨酸跨纳米病（ALT）水平被测量为肝组织损伤微血管白细胞的指数，以及NPS和血浆ALT水平的增加，在WT和LDLR^<--/ - >小鼠中肝I/R后60分钟观察到肝I/R后60分钟；但是，在LDLR^< - / - >小鼠中，这些反应大大夸大了。 L…使用氯化gadolinium降低kupffer细胞功能的L…更多的Dlr^< - / - >小鼠，减轻了I/类似型乳化性肝脏损伤，在ldlr^< - / - > mice tirecties tribie n prunor n pruties np tribie n pribies np i/r.simiar to i/r.s i/r. i/rive tire np i/r.simar损伤中，抗体均与aNTIES抗体有关。细胞间粘合分子-1（ICAM-1）或P-选择素。这些发现表明，慢性高胆固醇血症使肝微举行的肝微血管造成I/r.kupffer细胞活化的有害作用，白细胞粘附受体ICAM-1和P-塞染料显得有助于expserageation的炎症反应在lddlr^<-/------ <-ICICe中观察到夸张的炎症反应。使用这种已建立的小鼠肝脏实验模型，在野生型小鼠1小时前24小时腹膜内腹膜内介入术。内毒素预处理在肝I/R后60次胜利时减弱了微血管白细胞，并确认了小鼠肝脏的预处理作用。此后，我们将通过短暂的缺血持续时间检查预处理效果，并阐明其机制。较少的