Gastroenterology

Gastroenterology

Volume 120, Issue 5, April 2001, Pages 1227-1240
Gastroenterology

Liver, Pancreas, and Biliary Tract
Carbon monoxide from heme catabolism protects against hepatobiliary dysfunction in endotoxin-treated rat liver,☆☆

https://doi.org/10.1053/gast.2001.23249Get rights and content

Abstract

Background & Aims: Liver is a major organ for heme detoxification under disease conditions, but its self-protective mechanisms against the toxicity are unknown. This study aimed to examine roles of carbon monoxide (CO), the gaseous product of heme oxygenase (HO), in ameliorating hepatobiliary dysfunction during catabolism of heme molecules in endotoxemic livers. Methods: Vascular resistance and biliary flux of bilirubin-IXα, an index of HO-derived CO generation, were monitored in perfused livers of endotoxemic rats. Livers were perfused with HbO2, which captures nitric oxide (NO) and CO, or metHb, a reagent trapping NO but not CO. Results: In endotoxin-pretreated livers where inducible NO synthase and HO-1 overproduced NO and CO, HbO2 caused marked vasoconstriction and cholestasis. These changes were not reproduced by the NO synthase inhibitor aminoguanidine alone, but by coadministration of zinc protoporphyrin-IX, an HO inhibitor. CO supplementation attenuated the events caused by aminoguanidine plus zinc protoporphyrin-IX, suggesting that simultaneous elimination of these vasorelaxing gases accounts for a mechanism for HbO2-induced changes. This concept was supported by observation that metHb did not cause any cholestasis; the reagent captures NO but triggers CO overproduction through rapid degradation of the heme by HO-1. Conclusions: These results suggest protective roles of CO against hepatobiliary dysfunction caused by heme overloading under stress conditions.

GASTROENTEROLOGY 2001;120:1227-1240

Section snippets

Preparation of perfused rat livers

Male Wistar rats (260–280 g) were obtained from Nippon Biosupp. Center, Inc. (Tokyo, Japan). All animals were allowed free access to laboratory chow and tap water. Protocols for the current experiments were approved by the Institutional Guidelines for Animal Care and Experiments in Keio University School of Medicine. Rats were anesthetized intraperitoneally with pentobarbital sodium (50 mg/kg). When necessary, rats were pretreated with intraperitoneal injection of lipopolysaccharide (LPS;

LPS induces overproduction of NO and CO in the liver

Figure 1 illustrates an induction of iNOS and HO-1 and overproduction of their products NO and CO in LPS-pretreated livers.

. Overproduction of NO and CO through iNOS and HO-1 in livers undergoing LPS exposure. (A) Western blotting analyses showing effects of LPS on expression of iNOS and HO-1. m, molecular markers; LDD(+), Kupffer cell–depleting procedure by LDD. (B) Measurements of NO2 and CO in the venous perfusate and bilirubin (BR)-IXα in bile collected from LPS-treated livers. ▨, Data

Discussion

Liver is a major organ that helps detoxification of free heme molecules and biliary excretion of their metabolites such as bilirubin and requires self-protective mechanisms for tolerance against the heme toxicity. Impairment of such mechanisms could jeopardize liver homeostasis, and thus lead to a risk of the organ dysfunction. The present study provided evidence that endotoxemic liver could greatly expand its ability to decompose Hb-derived heme through an induction of HO-1 in hepatocytes and

Acknowledgements

The authors thank Dr Ken-ichiro Hirano and Hitomi Irisawa for technical supports.

References (38)

  • KD Poss et al.

    Heme oxygenase-1 is required for mammarian iron reutilization

    Proc Natl Acad Sci U S A

    (1997)
  • PC Hebert et al.

    A multicenter, randomized, controlled clinical trial of transfusion requirements in clinical care

    N Engl J Med

    (1999)
  • M. Tamaki

    Catabolism of heme moiety of hemoglobin; haptoglobin in rat liver cells in vivo

    J Biol Chem

    (1993)
  • LP Stratton et al.

    The reduction of methemoglobin levels by antioxidants

    Hemoglobin

    (1988)
  • A Yachie et al.

    Oxidative stress causes enhanced vascular endothelial cell injury in human heme oxygenase-1 deficiency

    J Clin Invest

    (1999)
  • M Suematsu et al.

    Carbon monoxide: an endogenous modulator of sinusoidal tone in the perfused rat liver

    J Clin Invest

    (1995)
  • T Sano et al.

    Endogenous carbon monoxide suppression stimulates bile acid–dependent biliary transport in perfused rat liver

    Am J Physiol Gastrointest Liver Physiol

    (1997)
  • Y Shinoda et al.

    Carbon monoxide as a regulator of bile canalicular contractility in cultured rat hepatocytes

    Hepatology

    (1998)
  • D Looker et al.

    A human recombinant haemoglobin designed for use as a blood substitute

    Nature

    (1992)
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    Supported by grants from Tokyo Biochemical Research Foundation and from Advanced Medical Technology in Health Sciences Research Grants from Ministry of Health and Welfare in Japan.

    ☆☆

    Address requests for reprints to: Makoto Suematsu, M.D., Ph.D., Associate Professor, Department of Biochemistry, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. e-mail: [email protected]; fax: (81) 3-3358-8138.

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