Journal
GASTROENTEROLOGY
Volume 127, Issue 2, Pages 595-606Publisher
W B SAUNDERS CO-ELSEVIER INC
DOI: 10.1053/j.gastro.2004.05.059
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Funding
- NHLBI NIH HHS [HL 58688, HL-071797] Funding Source: Medline
- NIDDK NIH HHS [DK54232] Funding Source: Medline
- NIGMS NIH HHS [GM-58241, GM-53789] Funding Source: Medline
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Background & Aims: Herne oxygenase-1 (HO-1) protects against inflammation in many disease models. By degrading heme, HO-1 generates carbon monoxide (CO), iron and biliverdin. We investigated whether biliverdin would protect rat syngeneic small intestinal transplants (SITx) against damage and, if so, by what mechanism. Methods: Motility was assessed by organ bath techniques. Inflammatory cytokines and mediators were assessed by RT-PCR and spectrophotometric assays. Myeloperoxidase histochemistry for neutrophils was performed in jejunal segments. Western blots were performed for biliverdin reductase and HO-1 expression. Permeability was expressed as the mucosal to serosal clearance of fluorescent dextran in everted gut sacs. NF-kappaB activation was assessed via EMSA. Results: Bilk verdin significantly improved survival of recipients following SITx after prolonged intestinal ischemia (6 hours). Biliverdin treatment (1) led to a significant decrease in mRNA expression of NOS, Cox-2, and ICAM-1 as well as the inflammatory cytokines IL-6 and IL-1beta; (2) decreased neutrophil infiltration into the jejunal muscularis; and (3) prevented SITx-induced suppression of intestinal circular muscle contractility. Conclusions: Biliverdin administration attenuates transplantation-induced injuries to the small bowel by its anti-inflammatory action. Importantly, biliverdin enhanced recipient survival. A comparison of the mechanisms by which biliverdin exerted these salutary effects compared with inhalation of CO, which we previously showed had salutary effects, suggests that the 2 compounds (biliverdin and CO) exert their effects in part by different mechanisms. This implies that the different products of HO-1 action on heme may exert protective effects that are additive or synergistic.
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