Hepatic microvascular responses to ischemia-reperfusion in low-density lipoprotein receptor knockout mice

The overall objective of this study was to determine whether genetically in duced hypercholesterolemia alters the inflammatory and microvascular respon ses of mouse liver to ischemia-reperfusion (I/R). The accumulation of rhoda mine 6G-labeled leukocytes and the number of nonperfused sinusoids (NPS) we re monitored (by intravital microscopy) in the liver of wild-type (WT) and low-density lipoprotein receptor-deficient (LDLr-/-) mice for 1 h after a 3 0-min period of normothermic ischemia. Plasma alanine transaminase (ALT) le vels were used to monitor hepatocellular injury. Microvascular leukostasis as well as increases in NPS and plasma ALT were observed at 60 min after he patic I/R in both WT and in LDLr-/- mice; however, these responses were gre atly exaggerated in LDLr-/- mice. Pretreatment of LDLr-/- mice with gadolin ium chloride, which reduces Kupffer cell function, attenuated the hepatic l eukostasis, NPS, and hepatocellular injury elicited by I/R. Similar protect ion against I/R was observed in LDLr-/- mice pretreated with antibodies dir ected against tumor necrosis factor-alpha, intercellular adhesion molecule- 1 (ICAM-1), or P-selectin. These findings indicate that chronic hypercholes terolemia predisposes the hepatic microvasculature to the deleterious effec ts of I/R. Kupffer cell activation and the leukocyte adhesion receptors ICA M-1 and P-selectin appear to contribute to the exaggerated inflammatory res ponses observed in the postischemic liver of LDLr-/- mice.