title: Priming of phagocytes for reactive oxygen production during hepatic ischemia-reperfusion potentiates the susceptibility for endotoxin-induced liver injury.
abstract: Plasma levels of glutathione disulfide (GSSG) as an indicator of a vascular oxidant stress, tumor necrosis factor-alpha (TNF-alpha) formation, and liver injury (alanine aminotransferase activity, histology) were monitored in male Fischer rats after 30 min of hepatic ischemia followed by up to 4 hr of reperfusion. The injection of 1 mg/kg Salmonella enteritidis endotoxin at 30 min of reflow potentiated the postischemic oxidant stress and liver injury. TNF-alpha levels increased from 10 +/- 7 pg/ml (baseline) to 3,553 +/- 738 pg/ml after ischemia-reperfusion followed by endotoxin, or to 3,670 +/- 508 pg/ml after endotoxin alone. Depletion of serum complement before ischemia attenuated the endotoxin-mediated increase of reactive oxygen formation by 70% but did not affect TNF-alpha levels. Complement activation with cobra venom factor (CVF) during reperfusion had an effect similar to that of endotoxin on the oxidant stress and liver injury. CVF did not increase TNF-alpha formation during reperfusion. Kupffer cells and neutrophils isolated from the postischemic liver 2.5 hr after endotoxin injection generated 600% and 400% more superoxide, respectively, than cells isolated from control livers. The results demonstrate a substantial priming of hepatic phagocytes for reactive oxygen production but not TNF-alpha formation, even after short periods of hepatic ischemia, and the vulnerability of the postischemic liver to severe endotoxin-induced injury. Activated complement seems to be mainly responsible for the effects. These results may explain the high risk for hepatic failure after extensive liver resection and hypovolemic shock.
authors.affiliation: Upjohn Company, Kalamazoo, MI 49001.
authors.forename: P
authors.initials: P
authors.lastname: Liu
authors.forename: S L
authors.initials: SL
authors.lastname: Vonderfecht
authors.forename: M A
authors.initials: MA
authors.lastname: Fisher
authors.forename: G M
authors.initials: GM
authors.lastname: McGuire
authors.forename: H
authors.initials: H
authors.lastname: Jaeschke
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D003167:Complement Activation; D004546:Elapid Venoms / Q000494:pharmacology; D004731:Endotoxins / Q000633:toxicity*; D005978:Glutathione / Q000097:blood; D007511:Ischemia; D007728:Kupffer Cells / Q000378:metabolism; D008099:Liver / Q000098:blood supply*; D008107:Liver Diseases / Q000209:etiology*; D008297:Male; D009504:Neutrophils / Q000378:metabolism; D010084:Oxidation-Reduction; D010586:Phagocytes / Q000502:physiology*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015427:Reperfusion Injury; D012477:Salmonella enteritidis; D013481:Superoxides / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D004546:Elapid Venoms; D004731:Endotoxins; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; C016310:cobra venom factor; D013481:Superoxides; D000255:Adenosine Triphosphate; D000410:Alanine Transaminase; D005978:Glutathione