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

本研究的目的是观察预处理对肝脏缺血/再灌注（I/R）的影响。首先，为了建立肝脏I/R实验模型，进行了高胆固醇血症小鼠肝脏I/R实验。本系列研究的目的是确定高胆固醇血症是否影响小鼠肝脏I/R后白细胞粘附和组织损伤。在常温缺血30分钟后1小时内，在正常（WT）和低密度脂蛋白受体缺陷（LDLr^<-/->）小鼠的肝脏中监测（通过活体显微镜）罗丹明-6G-标记的白细胞的积累和非灌注血窦的数量。测量血浆丙氨酸转氨酶（ALT）水平作为肝组织损伤的指标。在肝I/R后60分钟，在WT和LDLr <-/->小鼠中均观察到微血管白细胞停滞以及ALT和血浆ALT水平的增加;然而，这些反应在LDLr <-/->小鼠中被大大夸大。L的预处理 ...更多信息 用氯化钆降低枯否细胞功能的DLr^<-/->小鼠减轻了I/R引起的肝白细胞停滞、坏死和肝组织损伤。在用针对肿瘤坏死因子-α、细胞间粘附分子-1（ICAM-1）或P-选择素的抗体预处理的LDLr^<-/->小鼠中观察到类似的对I/R的保护作用。这些发现表明，慢性高胆固醇血症使肝脏微血管易于受到I/R的有害影响。枯否细胞活化和白细胞粘附受体ICAM-1和P-选择素似乎有助于在LDLr^<-/->小鼠的缺血后肝脏中观察到的过度炎症反应。使用这种建立的小鼠肝脏实验模型，在野生型小鼠肝脏缺血1小时之前24小时腹膜内施用少量内毒素。内毒素预处理可减轻小鼠肝缺血再灌注后60 min的微血管白细胞淤滞，并证实了内毒素预处理对小鼠肝缺血再灌注后微血管白细胞淤滞的影响。在此基础上，我们将通过短时间的缺血来研究预处理的效果，并阐明其机制。少

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