L-selectin and ICAM-1 mediate reperfusion injury and neutrophil adhesion in the warm ischemic mouse liver

Abstract

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.

P–Selectin Mediates Reperfusion Injury Through Neutrophil and Platelet Sequestration in the Warm Ischemic Mouse Liver

“…In view of our previous demonstration of diffuse hepatic microvasculature occlusion by increased PMN adhesion, cell swelling and clot formation in wild-type animals, it is possible that at this extreme ischemia time platelets do not accumulate because of the obstruction of hepatic sinusoids. This finding also confirms previous studies by others 9,15,43,44 and us 13 that obstruction of the vasculature after reperfusion of ischemic tissue, often called the no-reflow phenomenon, is mainly related to plugging of vessels by FIG. 5.…”

“…13 Briefly, mice were anesthetized by inhalation of metofane. A midline incision was made and the liver exposed completely.…”

“…13 Histological evaluation was performed on mice subjected to 90 minutes of ischemia because of the striking difference in serum transaminase levels (n ϭ 5 in each group).…”

“…[7][8][9] The leukocyte-endothelial interaction that occurs following ischemia/reperfusion (I/Rp) injury has been shown to be important for microvascular dysfunction and release of cytotoxic mediators such as reactive oxygen intermediates and a variety of proteases. [10][11][12] We 13 and others 5,6,9,14,15 have shown leukocyte accumulation to be a critical determinant of hepatic I/Rp injury. Other blood elements including platelets adhere to the hepatic sinusoids in conditions of ischemia, 16,17 but little is known about their contribution to the injury.…”

“…13 Experimental studies in other organs suggest P-selectin to be of greater importance than other examined adhesion molecules in mediating reperfusion injury. [25][26][27] For instance, in a dog model of myocardial ischemia, a blocking monoclonal antibody (Mab) against P-selectin was found to dramatically attenuate PMN accumulation and tissue necrosis.…”