Kupffer cell-initiated remote hepatic injury following bilateral hindlimb ischemia is complement dependent

Intravital fluorescence microscopy was applied to the livers of male Wistar rats to test the hypothesis that complement mobilization stimulates Kupffe r cells and subsequently initiates hepatic injury after hindlimb ischemia/r eperfusion (I/R). Following 3 h of limb reperfusion, hepatocellular viabili ty (serum levels of alanine transaminase and cell death via propidium iodid e labeling) decreased significantly from levels in sham-operated animals. I nhibition of complement mobilization with soluble complement receptor type 1 (20 mg/kg body wt) and interruption of Kupffer cell function with GdCl3 ( 1 mg/100g body wt) resulted in significant hepatocellular protection. Altho ugh the effects of hindlimb I/R on hepatic microvascular perfusion were man ifest as increased heterogeneity, both complement inhibition and suppressio n of Kupffer cell function resulted in marked improvements. No additional h epatocellular protection and microvascular improvements were provided by co mbining the interventions. Furthermore, inhibition of complement mobilizati on significantly depressed Kupffer cell phagocytosis by 42% following limb reperfusion. These results suggest that the stimulation of Kupffer cells vi a complement mobilization is necessary but is not the only factor contribut ing to the early pathogenesis of hepatic injury following hindlimb I/R.