Biliverdin protects the functional integrity of a transplanted syngeneic small bowel.
OBJECTIVE
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.
Nakao
Atsunori
A
Thomas E. Starzl Transplant Institute, University of Pittsburgh, Pennsylvania, USA.
Otterbein
Leo E
LE
Overhaus
Marcus
M
Sarady
Judit K
JK
Tsung
Allan
A
Kimizuka
Kei
K
Nalesnik
Michael A
MA
Kaizu
Takashi
T
Uchiyama
Takashi
T
Liu
Fang
F
Murase
Noriko
N
Bauer
Anthony J
AJ
Bach
Fritz H
FH
D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology; D001663:Bilirubin / Q000378:metabolism; D001664:Biliverdine / Q000493:pharmacokinetics*; D002248:Carbon Monoxide / Q000378:metabolism; D004751:Enteritis / Q000378:metabolism / Q000517:prevention & control; D006085:Graft Survival / Q000187:drug effects*; D007413:Intestinal Mucosa / Q000378:metabolism; D007583:Jejunum / Q000098:blood supply / Q000473:pathology / Q000637:transplantation*; D008297:Male; D017538:Mesenteric Artery, Superior / Q000502:physiology; D009119:Muscle Contraction; D009130:Muscle, Smooth / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000378:metabolism; D010539:Permeability; D051381:Rats; D011917:Rats, Inbred Lew; D015996:Survival Rate
D000890:Anti-Infective Agents; D016328:NF-kappa B; D002248:Carbon Monoxide; D044925:Oxidoreductases Acting on CH-CH Group Donors; C019789:biliverdin reductase; D001664:Biliverdine; D001663:Bilirubin