Hepatic microvascular responses to ischemia-reperfusion in low-density lipoprotein receptor knockout mice.
The overall objective of this study was to determine whether genetically induced hypercholesterolemia alters the inflammatory and microvascular responses of mouse liver to ischemia-reperfusion (I/R). The accumulation of rhodamine 6G-labeled leukocytes and the number of nonperfused sinusoids (NPS) were monitored (by intravital microscopy) in the liver of wild-type (WT) and low-density lipoprotein receptor-deficient (LDLr(-/-)) mice for 1 h after a 30-min period of normothermic ischemia. Plasma alanine transaminase (ALT) levels were used to monitor hepatocellular injury. Microvascular leukostasis as well as increases in NPS and plasma ALT 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 LDLr(-/-) mice with gadolinium chloride, which reduces Kupffer cell function, attenuated the hepatic leukostasis, NPS, and hepatocellular injury elicited by I/R. Similar protection against I/R was observed in LDLr(-/-) mice pretreated with antibodies directed against tumor necrosis factor-alpha, 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 postischemic liver of LDLr(-/-) mice.
Mori
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N
Departments of Molecular and Cellular Physiology and Medicine, Center of Excellence in Arthritis and Rheumatology, Lousiana State University Health Sciences Center, Shreveport, Louisiana 71130, USA.
Horie
Y
Y
Nimura
Y
Y
Wolf
R
R
Granger
D N
DN
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000911:Antibodies, Monoclonal; D002784:Cholesterol / Q000097:blood; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007511:Ischemia / Q000503:physiopathology; D007728:Kupffer Cells / Q000378:metabolism; D008099:Liver / Q000098:blood supply*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008833:Microcirculation; D019007:P-Selectin / Q000378:metabolism; D011973:Receptors, LDL / Q000502:physiology*; D015424:Reperfusion
D000911:Antibodies, Monoclonal; D019007:P-Selectin; D011973:Receptors, LDL; D018799:Intercellular Adhesion Molecule-1; D002784:Cholesterol; D000410:Alanine Transaminase