title: Kupffer cell-initiated remote hepatic injury following bilateral hindlimb ischemia is complement dependent.
abstract: Intravital fluorescence microscopy was applied to the livers of male Wistar rats to test the hypothesis that complement mobilization stimulates Kupffer cells and subsequently initiates hepatic injury after hindlimb ischemia/reperfusion (I/R). Following 3 h of limb reperfusion, hepatocellular viability (serum levels of alanine transaminase and cell death via propidium iodide labeling) decreased significantly from levels in sham-operated animals. Inhibition of complement mobilization with soluble complement receptor type 1 (20 mg/kg body wt) and interruption of Kupffer cell function with GdCl(3) (1 mg/100g body wt) resulted in significant hepatocellular protection. Although the effects of hindlimb I/R on hepatic microvascular perfusion were manifest as increased heterogeneity, both complement inhibition and suppression of Kupffer cell function resulted in marked improvements. No additional hepatocellular protection and microvascular improvements were provided by combining the interventions. Furthermore, inhibition of complement mobilization significantly depressed Kupffer cell phagocytosis by 42% following limb reperfusion. These results suggest that the stimulation of Kupffer cells via complement mobilization is necessary but is not the only factor contributing to the early pathogenesis of hepatic injury following hindlimb I/R.
authors.affiliation: London Health Sciences Centre Research Incorporated, NGA 465, London, Ontario, Canada, N6A 5C1.
authors.forename: R W
authors.initials: RW
authors.lastname: Brock
authors.forename: R G
authors.initials: RG
authors.lastname: Nie
authors.forename: K A
authors.initials: KA
authors.lastname: Harris
authors.forename: R F
authors.initials: RF
authors.lastname: Potter
mesh_terms: D000818:Animals; D016923:Cell Death; D003165:Complement System Proteins / Q000502:physiology*; D006614:Hindlimb / Q000098:blood supply*; D007511:Ischemia / Q000473:pathology*; D007728:Kupffer Cells / Q000502:physiology*; D008099:Liver / Q000473:pathology* / Q000503:physiopathology; D008102:Liver Circulation; D008297:Male; D010587:Phagocytosis / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar
chemical_list: D003165:Complement System Proteins