Biliverdin protects the functional integrity of a transplanted syngeneic small bowel

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

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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-κB 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-1β; (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.

Original languageEnglish
Pages (from-to)595-606
Number of pages12
JournalGastroenterology
Volume127
Issue number2
DOIs
Publication statusPublished - Aug 2004
Externally publishedYes

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Keywords

  • COX-2
  • cyclooxygenase-2
  • heme oxygenase-1
  • HO-1
  • ICAM
  • inducible nitric oxide synthase
  • iNOS
  • intercellular adhesion molecule
  • KRB
  • Krebs-Ringer-bicarbonate buffer
  • manganese superoxide dismutase
  • MDA
  • MnSOD
  • MPO
  • myeloperoxidase
  • PMN
  • polymorphonuclear neutrophils

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Nakao, A., Otterbein, L. E., Overhaus, M., Sarady, J. K., Tsung, A., Kimizuka, K., Nalesnik, M. A., Kaizu, T., Uchiyama, T., Liu, F., Murase, N., Bauer, A. J., & Bach, F. H. (2004). Biliverdin protects the functional integrity of a transplanted syngeneic small bowel. Gastroenterology, 127(2), 595-606. https://doi.org/10.1053/j.gastro.2004.05.059