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Protective Effect of Bilirubin in Ischemia-Reperfusion Injury in the Rat Intestine

Hammerman, C.*; Goldschmidt, D.*; Caplan, M. S.; Kaplan, M.‡§; Bromiker, R.; Eidelman, A. I.*; Gartner, L. M.; Hochman, A.**

Journal of Pediatric Gastroenterology and Nutrition: September 2002 - Volume 35 - Issue 3 - p 344-349
Original Articles: Gastroenterology and Hepatology

Background Although bilirubin, which crosses the blood–brain barrier, can cause irreversible brain damage, it also possesses antioxidant properties that may be protective against oxidative stress. Intestinal ischemia–reperfusion (IR) injury results in cell destruction, mediated via the generation of reactive oxygen species. Although increased serum bilirubin is correlated with increased antioxidant potential in the face of hyperoxia, evidence of bilirubin-associated protective effect against IR injury remains nonspecific. We therefore sought to investigate whether hyperbilirubinemia would be protective against IR injury to the intestine.

Methods Young adult rats were randomly assigned to one of three groups: 1) IR/control (n = 12); 2) IR/hyperbilirubinemia (n = 10), in which IR was generated while the rats were treated with a continuous infusion of bilirubin; and 3) hyperbilirubinemia controls (n = 10). Blood and intestinal tissue samples were obtained to determine serial thiobarbituric acid reducing substances (index of lipid peroxidation) and for xanthine oxidase/xanthine dehydrogenase and glutathione/glutathione disulfide ratios. Intestinal histopathology was graded from 1 (normal) to 4 (severe necrotic lesions).

Results Histopathologic scoring and circulating and tissue thiobarbituric acid reducing substances were highest in the IR/control animals compared with either the IR/hyperbilirubinemics or the controls. All of these are consistent with the most severe injury in this group. Xanthine oxidase/xanthine dehydrogenase ratios were not significantly different among the groups.

Conclusion Hyperbilirubinemia ameliorates the extent of intestinal IR injury in our model and appears to act as an antioxidant. This study supports the concept that bilirubin possesses some beneficial properties in vivo, although no direct clinical conclusions can be drawn from these data.

*Department of Neonatology, Shaare Zedek Medical Center and the Ben Gurion University of the Negev, Beersheva, Israel; †Department of Perinatal Pediatrics, Evanston Hospital, Evanston, Illinois, U.S.A.; ‡Shaare Zedek Medical Center; §the Hebrew University, Hadassah Medical School, Jerusalem, Israel; ¶Department of Pediatrics, The University of Chicago, Chicago, Illinois, U.S.A.; **Department of Biochemistry, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel

Received July 3, 2001; accepted April 16, 2002.

Supported by grant no. 3302 from the Chief Scientist Office of Ministry of Health of Israel and a generous donation from Mr. and Mrs. Stephen Hammerman.

Address correspondence and reprint requests to Dr. Cathy Hammerman, Department of Neonatology, Shaare Zedek Medical Center, 12 Bayit Street, Jerusalem 91031, Israel (e-mail:

© 2002 Lippincott Williams & Wilkins, Inc.