Carbon monoxide protects rat lung transplants from ischemia-reperfusion injury via a mechanism involving p38 MAPK pathway.
Carbon monoxide (CO) provides protection against oxidative stress via anti-inflammatory and cytoprotective actions. In this study, we tested the hypothesis that a low concentration of exogenous (inhaled) CO would protect transplanted lung grafts from cold ischemia-reperfusion injury via a mechanism involving the mitogen-activated protein kinase (MAPK) signaling pathway. Lewis rats underwent orthotopic syngeneic or allogeneic left lung transplantation with 6 h of cold static preservation. Exposure of donors and recipients (1 h before and then continuously post-transplant) to 250 ppm CO resulted in significant improvement in gas exchange, reduced leukocyte sequestration, preservation of parenchymal and endothelial cell ultrastructure and reduced inflammation compared to animals exposed to air. The beneficial effects of CO were associated with p38 MAPK phosphorylation and were significantly prevented by treatment with a p38 MAPK inhibitor, suggesting that CO's efficacy is at least partially mediated by activation of p38 MAPK. Furthermore, CO markedly suppressed inflammatory events in the contralateral naïve lung. This study demonstrates that perioperative exposure of donors and recipients to CO at a low concentration can impart potent anti-inflammatory and cytoprotective effects in a clinically relevant model of lung transplantation and support further evaluation for potential clinical use.
Kohmoto
J
J
Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
Nakao
A
A
Stolz
D B
DB
Kaizu
T
T
Tsung
A
A
Ikeda
A
A
Shimizu
H
H
Takahashi
T
T
Tomiyama
K
K
Sugimoto
R
R
Choi
A M K
AM
Billiar
T R
TR
Murase
N
N
McCurry
K R
KR
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D002248:Carbon Monoxide / Q000627:therapeutic use*; D051546:Cyclooxygenase 2 / Q000235:genetics; D007378:Interleukins / Q000235:genetics; D008168:Lung / Q000648:ultrastructure; D016040:Lung Transplantation / Q000502:physiology*; D008297:Male; D048308:Mitogen-Activated Protein Kinase 14 / Q000378:metabolism*; D009504:Neutrophils / Q000502:physiology; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D011917:Rats, Inbred Lew; D015427:Reperfusion Injury / Q000517:prevention & control*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014184:Transplantation, Homologous; D014185:Transplantation, Isogeneic
D000893:Anti-Inflammatory Agents; D007378:Interleukins; D012333:RNA, Messenger; D002248:Carbon Monoxide; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; D048308:Mitogen-Activated Protein Kinase 14