Platelet-activating factor is involved in the regulation of pathological leukocyte adhesion after liver...

An increased leukocyte adhesion and loss of integrity of endothelial cells is known to be a critical step in the reperfusion period after cold ischemia of transplanted livers. Platelet-activating factor (PAF) is discussed as one of the inflammatory mediators involved in mediating reperfusion injury, e.g., by regulation of leukocyte adhesion. In this study we investigated the effect of a synthetic PAF receptor antagonist, WEB 2086 (Boehringer Ingelheim, FRG), on microcirculation and adhesion of leukocytes to sinusoidal endothelium after liver transplantation in the rat. Livers from SPRD rats (n = 6 per group) were stored for 5 hr in ice-cold UW solution and orthotopically transplanted using the cuff technique. In a randomized and blinded fashion WEB 2086 (1 mg/kg body wt) or placebo was given twice intravenously, at the beginning of the recipient operation and 1 min prior to reperfusion of the liver graft. After in vivo staining of leukocytes with acridine orange, microcirculation and leukocyte-endothelium interaction of transplanted livers and livers from sham-operated animals were investigated 90 min and 5 hr after surgery by means of intravital microscopy. After 90 min of reperfusion, temporary leukocyte adhesion in periportal regions was increased after liver transplantation (22.0 +/- 2.5%; mean +/- SEM) in contrast to the sham group (14.2 +/- 1.8%). Administration of WEB 2086 reduced temporary leukocyte adhesion significantly (11.5 +/- 2.5%; P < 0.05), whereas no significant differences were observed with respect to permanent leukocyte adhesion. Five hours after recipient operation, a significant increase of permanent leukocyte adhesion was observed after transplantation (21.0 +/- 2.6%; P < 0.05) compared to sham-operated animals (12.1 +/- 1.7%). Application of WEB 2086 diminished permanent leukocyte adhesion significantly (12.2 +/- 1.3%; P < 0.05), whereas no differences were noticed between the different groups with respect to temporary leukocyte adhesion at this time. The results indicate that reduction of temporary leukocyte adhesion in the early reperfusion period by administration of PAF receptor antagonist WEB 2086 was followed by a reduction of permanent leukocyte adhesion in the late reperfusion period, e.g., at 5 hr. Thus, it is concluded that PAF is one of the mediators which is involved in the regulation of leukocyte adhesion after liver transplantation.