title: The protective role of Kupffer cells in the ischemia-reperfused rat liver.
abstract: Kupffer cells constitute a major source of the heme-degrading enzyme, heme oxygenase (HO). This study examined the roles of Kupffer cells in the modulation of accelerated heme catabolism in ischemia-reperfused rat livers. Livers from rats treated with or without liposome-encapsulated dichloromethylene diphosphonate, a Kupffer cell-depleting reagent, underwent a 20-min ligation of the portal vein followed by reperfusion, The time course of the biliary output of bilirubin, the terminal heme-degrading product, and the expression of HO-1 mRNA and protein were monitored. HO-1 mRNA levels were elevated 3 to 12 h after ischemia/reperfusion in both control and Kupffer cell-depleted rats. Immunohistochemical analyses of control livers revealed that Kupffer cells expressed high levels of HO-1 while its expression in hepatocytes was low. In Kupffer cell-depleted livers, however, periportal hepatocytes displayed marked HO-1 expression. Under these conditions the two groups exhibited distinct profiles of biliary bilirubin excretion. In the controls, total bilirubin excretion increased 8-fold and peaked at 10 h after ischemia/reperfusion. In contrast, the Kupffer cell-depleting treatment resulted in a significant acceleration of the initial rise in bilirubin production, which peaked at 4 h. However, the total amount of bilirubin excreted within the initial 10 h after reperfusion was reduced by 50% as compared with that of the controls. In Kupffer cell-depleted rats, the levels of GOT and GPT as well as serum endotoxin concentrations were elevated after ischemia/reperfusion. These results suggest that Kupffer cells serve as an ischemia/reperfusion sensor that upregulates heme degradation and bilirubin excretion, and that Kupffer cells protect hepatocytes from gut-derived stressers--including endotoxin--following ischemia/reperfusion.
authors.affiliation: Division of Cellular and Molecular Pathology, Niigata University Graduate School of Medical and Dental Sciences, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Ken-ichiro
authors.initials: K
authors.lastname: Hirano
authors.forename: Takashi
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Go
authors.initials: G
authors.lastname: Hasegawa
authors.forename: Katsuyoshi
authors.initials: K
authors.lastname: Hatakeyama
authors.forename: Makoto
authors.initials: M
authors.lastname: Suematsu
authors.forename: Makoto
authors.initials: M
authors.lastname: Naito
mesh_terms: D000410:Alanine Transaminase / Q000032:analysis; D000818:Animals; D001219:Aspartate Aminotransferases / Q000032:analysis; D001646:Bile / Q000502:physiology; D001663:Bilirubin / Q000032:analysis; D004731:Endotoxins / Q000032:analysis / Q000097:blood; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis; D007728:Kupffer Cells / Q000201:enzymology / Q000502:physiology* / Q000648:ultrastructure; D008099:Liver / Q000098:blood supply* / Q000201:enzymology; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000378:metabolism* / Q000473:pathology
chemical_list: D004731:Endotoxins; D012333:RNA, Messenger; D006419:Heme Oxygenase (Decyclizing); D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D001663:Bilirubin