Heart allograft protection with low-dose carbon monoxide inhalation: effects on inflammatory mediators and alloreactive T-cell responses.
BACKGROUND
Carbon monoxide (CO), a byproduct of heme catalysis, has lately received considerable attention as a regulatory molecule in cellular and biological processes. CO has been shown to provide potent protection against a variety of tissue injuries. We hypothesized in this study that low concentration CO would be beneficial for organ allografts, which frequently undergo several types of injury such as ischemia/reperfusion, alloimmune reaction, and inflammation


METHODS
The efficacy of low-dose CO was examined in a fully allogeneic LEW to BN rat heterotopic heart transplantation (HHTx) model. Recipients were kept in air or exposed to low-dose CO (20 ppm) for 14, 28, or 100 days after HHTx under short-course tacrolimus


RESULTS
CO treatment (d0-28, 0-100) was remarkably effective in prolonging heart allograft survival to a median of >100 from 45 days in the air-control group, with significant reductions of arteritis, fibrosis, and cellular infiltration, including macrophages and T cells. CO inhibited intragraft upregulation of Th1 type cytokines (IL-2, IFNgamma), proinflammatory mediators (IL-1beta, TNFalpha, IL-6, COX-2), and adhesion molecule. Shorter CO exposure in early (0-13d) and late (14-28d) posttransplant periods also prolonged graft survival, with a significant inhibition of inflammatory mediators


CONCLUSIONS
These results show that low dose CO inhalation protects heart allografts and can considerably prolong their survival. CO appears to function via multiple mechanisms, including direct inhibition of Th1 type cytokine production and regulation of inflammatory responses.
Nakao
Atsunori
A
Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA.
Toyokawa
Hideyoshi
H
Abe
Masanori
M
Kiyomoto
Tetsuma
T
Nakahira
Kiichi
K
Choi
Augustine M K
AM
Nalesnik
Michael A
MA
Thomson
Angus W
AW
Murase
Noriko
N
D000280:Administration, Inhalation; D000818:Animals; D001483:Base Sequence; D002248:Carbon Monoxide / Q000008:administration & dosage*; D016207:Cytokines / Q000235:genetics; D004247:DNA / Q000235:genetics; D006085:Graft Survival / Q000187:drug effects* / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology* / Q000379:methods* / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism*; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D013601:T-Lymphocytes / Q000276:immunology*; D013997:Time Factors; D014184:Transplantation, Homologous
D016207:Cytokines; D018836:Inflammation Mediators; D012333:RNA, Messenger; D002248:Carbon Monoxide; D004247:DNA