title: Participation of hepatic macrophages and plasma factors in endotoxin-induced liver injury.
abstract: The present study was designed to investigate the mechanism responsible for endotoxin-induced liver injury, based on the working hypothesis that hepatic macrophages activated by endotoxin play a key role in the development of this injury. At both the protein and the transcription levels, the intravenous administration of endotoxin was shown to have increased the capacity of hepatic macrophages to produce chemical mediators. To inhibit the function of hepatic macrophages, gadolinium chloride (GdCl3), a specific inhibitor of resident hepatic macrophages, was preadministered to rats before endotoxin injection. GdCl3 reduced the elevated glutamic oxaloacetic transamiase and lactate dehydrogenase serum levels produced by endotoxin treatment, suppressed the increased mRNA expression of tumor necrosis factor (TNF-alpha) produced in liver nonparenchymal cells by endotoxin, and then improved the survival rate of lipopolysaccharide-injected rats. These results indicated that hepatic macrophages played a crucial role in liver injury and that TNF-alpha was the most likely factor implicated in the development of endotoxin-induced liver injury. Furthermore, we found that liver injury did not progress during perfusion of endotoxin-pretreated extirpated liver with lactate Ringer's solution, whereas liver perfused with plasma developed remarkable hepatic impairment, which was inhibited almost completely by GdCl3-pretreatment; moreover, addition of heparin to the perfusate also prevented this deterioration. Thus, the present study showed that the activation of hepatic macrophages and factors in the plasma were two essential elements in the occurrence and development of endotoxin-induced liver injury.
authors.affiliation: First Department of Surgery, Faculty of Medicine, Kyoto University, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Fujita
authors.forename: S
authors.initials: S
authors.lastname: Arii
authors.forename: K
authors.initials: K
authors.lastname: Monden
authors.forename: Y
authors.initials: Y
authors.lastname: Adachi
authors.forename: N
authors.initials: N
authors.lastname: Funaki
authors.forename: H
authors.initials: H
authors.lastname: Higashitsuji
authors.forename: M
authors.initials: M
authors.lastname: Furutani
authors.forename: M
authors.initials: M
authors.lastname: Mise
authors.forename: S
authors.initials: S
authors.lastname: Ishiguro
authors.forename: T
authors.initials: T
authors.lastname: Kitao
mesh_terms: D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury; D004731:Endotoxins / Q000633:toxicity*; D005682:Gadolinium / Q000494:pharmacology; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D008107:Liver Diseases / Q000378:metabolism / Q000503:physiopathology; D008264:Macrophages / Q000473:pathology / Q000502:physiology*; D008297:Male; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000235:genetics / Q000378:metabolism
chemical_list: D004731:Endotoxins; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D005682:Gadolinium; D007770:L-Lactate Dehydrogenase; D001219:Aspartate Aminotransferases; C038958:gadolinium chloride