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

点击翻译按钮获取中文摘要

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