Carbon Monoxide Protects Rat Lung Transplants From Ischemia‐Reperfusion Injury via a Mechanism Involving p38 MAPK Pathway

https://doi.org/10.1111/j.1600-6143.2007.01940.xGet rights and content
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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.

Key words:

Carbon monoxide
heme oxygenase‐1
ischemia‐reperfusion
lung transplantation
p38 MAPK

Abbreviations:

CO
carbon monoxide
COHb
carboxyhemoglobin
COX‐2
cycloxygenase‐2
Egr‐1
early growth response‐1
ERK1/2
extracellular signal‐regulated protein kinase 1/2
HO‐1
heme oxygenase‐1
iNOS
inducible nitric oxide synthase
IRI
ischemia‐reperfusion injury
JNK
c‐Jun N‐terminal kinase
MAPK
mitogen‐activated protein kinase
MEK
MAPK/ERK kinase
PAI‐1
plasminogen activator inhibitor‐1
pCO2
carbon dioxide partial pressure
PEEP
positive end expiratory pressure
PMN
polymorphonuclear
pO2
oxygen partial pressure
ROS
reactive oxygen species
sGC
soluble guanylyl cyclase
UW
University of Wisconsin
VECs
vascular endothelial cells

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