Anti-P selectin monoclonal antibody protects against reticuloendothelial system dysfunction following hepatic ischemia/reperfusion

Abstract

Background: A functional hepatic reticuloendothelial system (RES) is important for host defense against circulating microorganisms. Although the relationship between hepatic ischemia/reperft~sion (I/R) and hepatic injury via neutrophil accumulation is reported, alterations of RES function after hepatic I/R are less well characterized. This study was designed to: A) quantify the alterations in RES function after I/R and B) determine the mechanism and effect of neutrophil accumulation on RES function after I/R. Methods: In control mice, the blood supply to the left lateral hepatic lobe was occluded for 45m, after which the liver was reperfused. Experimental mice were pre-treated with either vinblastin (1.5mg/kg) to induce neutropenia or anti-P selectin (50lag/mice) to block initial neutrophil adhesion, 4 days and 5 min before ischemia, respectively. RES function was measured 1, 4 and 24h after reperfusion using the quantitatively validated, double-labeled (51Cr and 125I-UdR) E.coli method (J Leukoc Biol 55:248, 1994). In each case the nonischemic lobe served as a control for I/R. Results: 1) Hepatic phagocytic clearance and hepatic killing efficiency were reduced by I/R and restored by either neutropenia ( < 2 x 102/ram -~) or anti-P selectin in both the ischemic and the adjacent non-ischemic lobes. 2) This hepatic RES function reached a nadir 4h after hepatic I/R. This time point correlated with the peak of MPO activity in liver, which was blocked by anti-P selectin. 3) RES dysfunction after I/R was attenuated by either neutropenia or anti-P selectin.