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-select in may critically contribute to injury, priming adhesion for later action o f intercellular adhesion molecule-1 (ICAM-1). Paired experiments were perfo rmed using mutant mice (L-selectin -/-, ICAM-1 -/-, and L-selectin/ICAM-1 - /-) and wild-type mice (C57BL/6) to investigate leukocyte adhesion in the i schemic Liver. Leukocyte adhesion and infiltration were assessed histologic ally. Aspartate aminotransferase levels were significantly reduced (2- to 3 -fold) in mutant vs. wild-type mice in most groups but most significantly a fter 90 min of partial hepatic ischemia. Leukocyte adhesion was significant ly reduced in all mutant mice. Areas of microcirculatory failure, visualize d by intravital microscopy, were prevalent in wild-type but virtually absen t in L-selectin-deficient mice. After total hepatic ischemia for 75 or 90 m in, 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 i n the pathogenesis of hepatic ischemia-reperfusion injury. Poor sinusoidal perfusion due to leukocyte adhesion and clot formation is a factor of injur y and appears to involve L-selectin and ICAM-1 receptors.