Biliverdin protects the functional integrity of a transplanted syngeneic small bowel.

Abstract

BACKGROUND & AIMS:

Heme 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:

Biliverdin 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 iNOS, 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.

• Authors: Atsunori Nakao, Leo E Otterbein, Marcus Overhaus, Judit K Sarady, Allan Tsung, Kei Kimizuka, Michael A Nalesnik, Takashi Kaizu, Takashi Uchiyama, Fang Liu, Noriko Murase, Anthony J Bauer, Fritz H Bach
• Journal: Gastroenterology (Gastroenterology) Vol. 127 Issue 2 Pg. 595-606 (Aug 2004) ISSN: 0016-5085 [Print] United States
• PMID: 15300591 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Anti-Infective Agents
• NF-kappa B
• Carbon Monoxide
• Oxidoreductases Acting on CH-CH Group Donors
• biliverdin reductase
• Biliverdine
• Bilirubin

Topics

• Animals
• Anti-Infective Agents (pharmacology)
• Bilirubin (metabolism)
• Biliverdine (pharmacokinetics)
• Carbon Monoxide (metabolism)
• Enteritis (metabolism, prevention & control)
• Graft Survival (drug effects)
• Intestinal Mucosa (metabolism)
• Jejunum (blood supply, pathology, transplantation)
• Male
• Mesenteric Artery, Superior (physiology)
• Muscle Contraction
• Muscle, Smooth (physiology)
• NF-kappa B (metabolism)
• Oxidoreductases Acting on CH-CH Group Donors (metabolism)
• Permeability
• Rats
• Rats, Inbred Lew
• Survival Rate