Bilirubin Production and Hemeoxygenase-1 Expression in Ischemia-Reperfused Rat Liver in vivo

Takashi Kobayashi, Yoshinobu Sato, Satoshi Yamamoto, Toshiyuki Takeishi, Ken Ichiro Hirano, Takaoki Watanabe, Isao Kurosaki, Yoshio Shirai, Makoto Naito, Makoto Suematsu, Katsuyoshi Hatakeyama

Research output: Contribution to journalArticle

Abstract

Kupffer cells constitute a major source of heme oxygenase (HO)-1, a heme-degrading enzyme. This study aimed to examine roles of Kupffer cells in the modulation of accelerated heme catabolism in ischemia-reperfused rat livers. Livers treated with or without liposome-encapsulated clodronate, a Kupffer cell-depleting reagent, underwent a 20-min ligation of the portal vein followed by reperfusion (I/R), and 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 at 3-12hrs after I/R in both control and Kupffer cell-depleted rats. Immunohistochemistry in the controls revealed that Kupffer cells constitute a major cellular component expressing HO-1, while hepatocytes exhibited little expression. On the other hand, in Kupffer cell-depleted livers, periportal hepatocytes displayed a 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 10hrs after I/R. On the other hand, the Kupffer cell-depleting treatment significantly accelerated the initial rise in bilirubin which peaked at 4hrs, and the total amount of bilirubin excreted within the initial 10hrs after reperfusion was reduced by 50% as compared with the controls. These results suggest that Kupffer cells serve as an I/R sensor that upregulates heme-degrading capacity and ameliorates excessive excretion of bilirubin into bile, functioning as a sink-buffer of bilirubin metabolism.

Original languageEnglish
JournalJapanese Pharmacology and Therapeutics
Volume31
Issue numberSUPPL. 1
Publication statusPublished - 2003

Fingerprint

Heme Oxygenase-1
Kupffer Cells
Bilirubin
Ischemia
Liver
Heme
Reperfusion
Hepatocytes
Clodronic Acid
Messenger RNA
Portal Vein
Bile
Liposomes
Ligation
Buffers
Up-Regulation
Immunohistochemistry
Enzymes

Keywords

  • Heme oxygenase-1 (HO-1)
  • Ischemia/reperfusion
  • Kupffer cells
  • Liver
  • Oxidative stress

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology

Cite this

Kobayashi, T., Sato, Y., Yamamoto, S., Takeishi, T., Hirano, K. I., Watanabe, T., ... Hatakeyama, K. (2003). Bilirubin Production and Hemeoxygenase-1 Expression in Ischemia-Reperfused Rat Liver in vivo. Japanese Pharmacology and Therapeutics, 31(SUPPL. 1).

Bilirubin Production and Hemeoxygenase-1 Expression in Ischemia-Reperfused Rat Liver in vivo. / Kobayashi, Takashi; Sato, Yoshinobu; Yamamoto, Satoshi; Takeishi, Toshiyuki; Hirano, Ken Ichiro; Watanabe, Takaoki; Kurosaki, Isao; Shirai, Yoshio; Naito, Makoto; Suematsu, Makoto; Hatakeyama, Katsuyoshi.

In: Japanese Pharmacology and Therapeutics, Vol. 31, No. SUPPL. 1, 2003.

Research output: Contribution to journalArticle

Kobayashi, T, Sato, Y, Yamamoto, S, Takeishi, T, Hirano, KI, Watanabe, T, Kurosaki, I, Shirai, Y, Naito, M, Suematsu, M & Hatakeyama, K 2003, 'Bilirubin Production and Hemeoxygenase-1 Expression in Ischemia-Reperfused Rat Liver in vivo', Japanese Pharmacology and Therapeutics, vol. 31, no. SUPPL. 1.
Kobayashi T, Sato Y, Yamamoto S, Takeishi T, Hirano KI, Watanabe T et al. Bilirubin Production and Hemeoxygenase-1 Expression in Ischemia-Reperfused Rat Liver in vivo. Japanese Pharmacology and Therapeutics. 2003;31(SUPPL. 1).
Kobayashi, Takashi ; Sato, Yoshinobu ; Yamamoto, Satoshi ; Takeishi, Toshiyuki ; Hirano, Ken Ichiro ; Watanabe, Takaoki ; Kurosaki, Isao ; Shirai, Yoshio ; Naito, Makoto ; Suematsu, Makoto ; Hatakeyama, Katsuyoshi. / Bilirubin Production and Hemeoxygenase-1 Expression in Ischemia-Reperfused Rat Liver in vivo. In: Japanese Pharmacology and Therapeutics. 2003 ; Vol. 31, No. SUPPL. 1.
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abstract = "Kupffer cells constitute a major source of heme oxygenase (HO)-1, a heme-degrading enzyme. This study aimed to examine roles of Kupffer cells in the modulation of accelerated heme catabolism in ischemia-reperfused rat livers. Livers treated with or without liposome-encapsulated clodronate, a Kupffer cell-depleting reagent, underwent a 20-min ligation of the portal vein followed by reperfusion (I/R), and 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 at 3-12hrs after I/R in both control and Kupffer cell-depleted rats. Immunohistochemistry in the controls revealed that Kupffer cells constitute a major cellular component expressing HO-1, while hepatocytes exhibited little expression. On the other hand, in Kupffer cell-depleted livers, periportal hepatocytes displayed a 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 10hrs after I/R. On the other hand, the Kupffer cell-depleting treatment significantly accelerated the initial rise in bilirubin which peaked at 4hrs, and the total amount of bilirubin excreted within the initial 10hrs after reperfusion was reduced by 50{\%} as compared with the controls. These results suggest that Kupffer cells serve as an I/R sensor that upregulates heme-degrading capacity and ameliorates excessive excretion of bilirubin into bile, functioning as a sink-buffer of bilirubin metabolism.",
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