Recipient hyperbilirubinaemia protects cardiac graft in rat heterotopic heart transplantation.
OBJECTIVE
Since bilirubin is a known powerful antioxidant, this study examined whether recipient hyperbilirubinaemia protected heart grafts from ischaemia/reperfusion (I/R) injury and chronic rejection associated with rat cardiac transplantation.


METHODS
Heterotopic heart transplantation (HTx) was performed using congenitally hyperbilirubinaemic GUNN (j/j) and normobilirubinaemic GUNN (+/+) rats. Syngenic grafts from +/+ rats were transplanted into +/+ or j/j rats with 6 or 18 h cold storage in University of Wisconsin solution to study I/R injury. To evaluate the effect on chronic rejection, Brown Norway rat heart grafts were transplanted into +/+ or j/j rats under short-course tacrolimus immunosuppression.


RESULTS
The +/+ grafts in j/j rats demonstrated significantly lower serum creatine phosphokinase and higher left ventricular developed pressures and had smaller infarct areas than +/+ rats at 3 h after reperfusion. Graft survival with 18 h cold storage increased from 0% in +/+ rats to 41.7% in j/j rats. Malondialdehyde (a marker of lipid peroxidation), mRNA of the inflammatory mediators and phosphorylation of ERK1/2 were significantly decreased in the grafts transplanted into j/j rats compared with those transplanted into +/+ rats 1-3 h after reperfusion. The mean allograft survival in j/j recipients was prolonged to a median survival of 150 days from 84 days in +/+ recipients and was associated with less macrophage infiltrates and less intragraft inflammatory cytokine mRNA at d60. In vitro T-cell proliferation was significantly inhibited in the presence of bilirubin.


CONCLUSIONS
Recipient hyperbilirubinaemia ameliorated cardiac I/R injury, as well as chronic allograft rejection following HTx via regulation of inflammatory responses or T-cell proliferation.
Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
Sungsoo
S
Lee
Taihei
T
Yamada
Takaaki
T
Osako
Donna B
DB
Stolz
Masanori
M
Abe
Kenneth R
KR
McCurry
Noriko
N
Murase
Joji
J
Kotani
Atsunori
A
Nakao
D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D006085:Graft Survival / Q000502:physiology*; D016027:Heart Transplantation; D006932:Hyperbilirubinemia / Q000378:metabolism*; D015227:Lipid Peroxidation; D008297:Male; D051381:Rats; D055647:Rats, Transgenic; D015427:Reperfusion Injury / Q000378:metabolism*; D016042:Transplantation, Heterotopic; D014184:Transplantation, Homologous
D016207:Cytokines
Heart transplantation; Hyperbilirubinaemia; Ischaemia reperfusion