Heme oxygenase-1-generated biliverdin ameliorates experimental murine colitis.
BACKGROUND
Heme oxygenase-1 (HO-1) seems to have an important protective role in acute and chronic inflammation. The products of heme catalysis, biliverdin/bilirubin, carbon monoxide (CO), and iron (that induces apoferritin) mediate the beneficial effects of HO-1. Blockade of HO-1 activity results in exacerbation of experimental colitis. We tested whether HO-1 has protective effects in the development of colitis and determined that specific enzymatic products of HO-1 are responsible for these effects.


METHODS
Colitis was induced by oral administration of dextran sodium sulfate (5%) to C57BL/6 mice for 7 days. HO-1 was up-regulated by cobalt-protoporphyrin (5 mg/kg, intraperitoneally). Biliverdin, exogenous CO, or the iron chelator desferrioxamine was administered to other groups.


RESULTS
Cobalt-protoporphyrin treatment resulted in significant up-regulation of HO-1 protein in mucosal and submucosal cells. Induction of HO-1 was associated with significantly less loss of body weight in mice with induced colitis (-12% versus -22% in the control animals, P < 0.001). Development of diarrhea and gastrointestinal hemorrhage was substantially delayed in animals in which HO-1 was induced, and mucosal injury was significantly attenuated. Administration of CO or desferrioxamine alone had no significant effects, whereas enhanced protection with lesser evidence of bowel inflammation was observed with systemic biliverdin administration (50 micromol/kg, 3 times per day, intraperitoneally).


CONCLUSIONS
We conclude that heightened HO-1 expression or administration of biliverdin ameliorates dextran sodium sulfate-induced experimental colitis. Novel therapeutic strategies based on HO-1 and/or biliverdin administration may have use in inflammatory bowel disease.
Berberat
Pascal O
PO
Immunobiology Research Center, Department of Surgery, Beth Israel Deconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
A-Rahim
Yousif I
YI
Yamashita
Kenichiro
K
Warny
Michel M
MM
Csizmadia
Eva
E
Robson
Simon C
SC
Bach
Fritz H
FH
D000208:Acute Disease; D000818:Animals; D001664:Biliverdine / Q000502:physiology*; D003092:Colitis / Q000201:enzymology* / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000502:physiology*; D051547:Heme Oxygenase-1; D007413:Intestinal Mucosa / Q000201:enzymology / Q000473:pathology; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D011524:Protoporphyrins / Q000494:pharmacology
D008565:Membrane Proteins; D011524:Protoporphyrins; C017803:zinc protoporphyrin; C007095:cobaltiprotoporphyrin; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D001664:Biliverdine