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

Research output: Contribution to journalArticle

117 Citations (Scopus)

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

Fingerprint

Biliverdine
Heme Oxygenase-1
Carbon Monoxide
biliverdin reductase
Heme
Cytokines
Neutrophil Infiltration
Intercellular Adhesion Molecule-1
Dextrans
Interleukin-1
Baths
Inhalation
Peroxidase
Interleukin-2
Permeability
Interleukin-6
Neutrophils
Anti-Inflammatory Agents
Ischemia
Iron

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., ... 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

Biliverdin protects the functional integrity of a transplanted syngeneic small bowel. / Nakao, Atsunori; Otterbein, Leo E.; Overhaus, Marcus; Sarady, Judit K.; Tsung, Allan; Kimizuka, Kei; Nalesnik, Michael A.; Kaizu, Takashi; Uchiyama, Takashi; Liu, Fang; Murase, Noriko; Bauer, Anthony J.; Bach, Fritz H.

In: Gastroenterology, Vol. 127, No. 2, 08.2004, p. 595-606.

Research output: Contribution to journalArticle

Nakao, A, Otterbein, LE, Overhaus, M, Sarady, JK, Tsung, A, Kimizuka, K, Nalesnik, MA, Kaizu, T, Uchiyama, T, Liu, F, Murase, N, Bauer, AJ & Bach, FH 2004, 'Biliverdin protects the functional integrity of a transplanted syngeneic small bowel', Gastroenterology, vol. 127, no. 2, pp. 595-606. https://doi.org/10.1053/j.gastro.2004.05.059
Nakao, Atsunori ; Otterbein, Leo E. ; Overhaus, Marcus ; Sarady, Judit K. ; Tsung, Allan ; Kimizuka, Kei ; Nalesnik, Michael A. ; Kaizu, Takashi ; Uchiyama, Takashi ; Liu, Fang ; Murase, Noriko ; Bauer, Anthony J. ; Bach, Fritz H. / Biliverdin protects the functional integrity of a transplanted syngeneic small bowel. In: Gastroenterology. 2004 ; Vol. 127, No. 2. pp. 595-606.
@article{d681e2682cc544b1afdccfa8084d35b1,
title = "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-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.",
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",
author = "Atsunori Nakao and Otterbein, {Leo E.} and Marcus Overhaus and Sarady, {Judit K.} and Allan Tsung and Kei Kimizuka and Nalesnik, {Michael A.} and Takashi Kaizu and Takashi Uchiyama and Fang Liu and Noriko Murase and Bauer, {Anthony J.} and Bach, {Fritz H.}",
year = "2004",
month = "8",
doi = "10.1053/j.gastro.2004.05.059",
language = "English",
volume = "127",
pages = "595--606",
journal = "Gastroenterology",
issn = "0016-5085",
publisher = "W.B. Saunders Ltd",
number = "2",

}

TY - JOUR

T1 - Biliverdin protects the functional integrity of a transplanted syngeneic small bowel

AU - Nakao, Atsunori

AU - Otterbein, Leo E.

AU - Overhaus, Marcus

AU - Sarady, Judit K.

AU - Tsung, Allan

AU - Kimizuka, Kei

AU - Nalesnik, Michael A.

AU - Kaizu, Takashi

AU - Uchiyama, Takashi

AU - Liu, Fang

AU - Murase, Noriko

AU - Bauer, Anthony J.

AU - Bach, Fritz H.

PY - 2004/8

Y1 - 2004/8

N2 - 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.

AB - 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.

KW - COX-2

KW - cyclooxygenase-2

KW - heme oxygenase-1

KW - HO-1

KW - ICAM

KW - inducible nitric oxide synthase

KW - iNOS

KW - intercellular adhesion molecule

KW - KRB

KW - Krebs-Ringer-bicarbonate buffer

KW - manganese superoxide dismutase

KW - MDA

KW - MnSOD

KW - MPO

KW - myeloperoxidase

KW - PMN

KW - polymorphonuclear neutrophils

UR - http://www.scopus.com/inward/record.url?scp=4143089260&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=4143089260&partnerID=8YFLogxK

U2 - 10.1053/j.gastro.2004.05.059

DO - 10.1053/j.gastro.2004.05.059

M3 - Article

VL - 127

SP - 595

EP - 606

JO - Gastroenterology

JF - Gastroenterology

SN - 0016-5085

IS - 2

ER -