title: Reduced inflammatory response and increased microcirculatory disturbances during hepatic ischemia-reperfusion injury in steatotic livers of ob/ob mice.
abstract: Steatosis is a major risk factor for complications after liver surgery. Since neutrophil cytotoxicity is critical for ischemia-reperfusion injury in normal livers, the aim of the present study was to evaluate whether an exaggerated inflammatory response could cause the increased injury in steatotic livers. In C57Bl/6 mice, 60 min of warm hepatic ischemia triggered a gradual increase in hepatic neutrophil accumulation during reperfusion with peak levels of 100-fold over baseline at 12 h of reperfusion. Neutrophil extravasation and a specific neutrophil-induced oxidant stress (immunostaining for hypochlorous acid-modified epitopes) started at 6 h of reperfusion and peaked at 12-24 h. Ob/ob mice, which had a severe macrovesicular steatosis, suffered significantly higher injury (alanine transaminase activity: 18,000 +/- 2,100 U/l; 65% necrosis) compared with lean littermates (alanine transaminase activity: 4,900 +/- 720 U/l; 24% necrosis) at 6 h of reperfusion. However, 62% fewer neutrophils accumulated in steatotic livers. This correlated with an attenuated increase in mRNA levels of several proinflammatory genes in ob/ob mice during reperfusion. In contrast, sham-operated ob/ob mice had a 50% reduction in liver blood flow and 35% fewer functional sinusoids compared with lean littermates. These deficiencies in liver blood flow and the microcirculation were further aggravated only in ob/ob mice during reperfusion. The attenuated inflammatory response and reduced neutrophil-induced oxidant stress observed in steatotic livers during reperfusion cannot be responsible for the dramatically increased injury in ob/ob mice. In contrast, the aggravated injury appears to be mediated by ischemic necrosis due to massive impairment of blood and oxygen supply in the steatotic livers.
authors.affiliation: Liver Research Institute, College of Medicine, University of Arizona, Tucson, Arizona, USA.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Hasegawa
authors.forename: Yoshiya
authors.initials: Y
authors.lastname: Ito
authors.forename: Jayanthika
authors.initials: J
authors.lastname: Wijeweera
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.forename: Ernst
authors.initials: E
authors.lastname: Malle
authors.forename: Anwar
authors.initials: A
authors.lastname: Farhood
authors.forename: Robert S
authors.initials: RS
authors.lastname: McCuskey
authors.forename: Hartmut
authors.initials: H
authors.lastname: Jaeschke
mesh_terms: D000818:Animals; D015815:Cell Adhesion Molecules / Q000096:biosynthesis; D018925:Chemokines / Q000096:biosynthesis; D016207:Cytokines / Q000096:biosynthesis; D005234:Fatty Liver / Q000276:immunology / Q000503:physiopathology*; D007249:Inflammation / Q000503:physiopathology; D008099:Liver / Q000098:blood supply*; D008102:Liver Circulation / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008833:Microcirculation / Q000502:physiology; D009504:Neutrophils / Q000502:physiology*; D015427:Reperfusion Injury / Q000276:immunology / Q000503:physiopathology*
chemical_list: D015815:Cell Adhesion Molecules; D018925:Chemokines; D016207:Cytokines