L-selectin and ICAM-1 mediate reperfusion injury and neutrophil adhesion in the warm ischemic mouse liver.
Leukocytes recruited during ischemia-reperfusion to the liver are important mediators of injury. However, the mechanisms of leukocyte adhesion and the role of adhesion receptors in hepatic vasculature remain elusive. L-selectin may critically contribute to injury, priming adhesion for later action of intercellular adhesion molecule-1 (ICAM-1). Paired experiments were performed using mutant mice (L-selectin -/-, ICAM-1 -/-, and L-selectin/ICAM-1 -/-) and wild-type mice (C57BL/6) to investigate leukocyte adhesion in the ischemic liver. Leukocyte adhesion and infiltration were assessed histologically. Aspartate aminotransferase levels were significantly reduced (2- to 3-fold) in mutant vs. wild-type mice in most groups but most significantly after 90 min of partial hepatic ischemia. Leukocyte adhesion was significantly reduced in all mutant mice. Areas of microcirculatory failure, visualized by intravital microscopy, were prevalent in wild-type but virtually absent in L-selectin-deficient mice. After total hepatic ischemia for 75 or 90 min, survival was better in mutant L-selectin and L-selectin/ICAM-1 mice vs. wild-type mice and ICAM-1 mutants. In conclusion, L-selectin is critical in the pathogenesis of hepatic ischemia-reperfusion injury. Poor sinusoidal perfusion due to leukocyte adhesion and clot formation is a factor of injury and appears to involve L-selectin and ICAM-1 receptors.
Yadav
S S
SS
Hepatobiliary and Liver Transplant Laboratory, Duke University Medical Center, Durham, North Carolina 27710, USA.
Howell
D N
DN
Gao
W
W
Steeber
D A
DA
Harland
R C
RC
Clavien
P A
PA
D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D006358:Hot Temperature; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000502:physiology*; D007511:Ischemia / Q000473:pathology / Q000503:physiopathology*; D019041:L-Selectin / Q000235:genetics / Q000502:physiology*; D008099:Liver / Q000473:pathology / Q000503:physiopathology; D008102:Liver Circulation / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL / Q000235:genetics; D008833:Microcirculation / Q000502:physiology; D009154:Mutation; D009504:Neutrophils / Q000502:physiology*; D015427:Reperfusion Injury / Q000473:pathology / Q000503:physiopathology*; D016019:Survival Analysis
D018799:Intercellular Adhesion Molecule-1; D019041:L-Selectin