Carbon monoxide inhibition of apoptosis during ischemia-reperfusion lung injury is dependent on the p38 mitogen-activated protein kinase pathway and involves caspase 3.
Carbon monoxide (CO), a reaction product of the cytoprotective gene heme oxygenase, has been shown to be protective against organ injury in a variety of models. One potential mechanism whereby CO affords cytoprotection is through its anti-apoptotic properties. Our studies show that low level, exogenous CO attenuates anoxia-reoxygenation (A-R)-induced lung endothelial cell apoptosis. Exposure of primary rat pulmonary artery endothelial cells to minimal levels of CO inhibits apoptosis and enhances phospho-p38 mitogen-activated protein kinase (MAPK) activation in A-R. Transfection of p38alpha dominant negative mutant or inhibition of p38 MAPK activity with SB203580 ablates the anti-apoptotic effects of CO in A-R. CO, through p38 MAPK, indirectly modulates caspase 3. Furthermore, we correlate our in vitro apoptosis model with an in vivo model of A-R by showing that CO can attenuate I-R injury of the lung. Taken together, our data are the first to demonstrate in models of A-R that the anti-apoptotic effects of CO are via modulation of p38 MAPK and caspase 3.
Zhang
Xuchen
X
Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Shan
Peiying
P
Otterbein
Leo E
LE
Alam
Jawed
J
Flavell
Richard A
RA
Davis
Roger J
RJ
Choi
Augustine M K
AM
Lee
Patty J
PJ
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002248:Carbon Monoxide / Q000494:pharmacology*; D053148:Caspase 3; D020169:Caspases / Q000502:physiology*; D002478:Cells, Cultured; D006162:Guanylate Cyclase / Q000502:physiology; D006419:Heme Oxygenase (Decyclizing) / Q000502:physiology; D020287:In Situ Nick-End Labeling; D008168:Lung / Q000098:blood supply* / Q000473:pathology; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D009569:Nitric Oxide / Q000502:physiology; D051381:Rats; D015427:Reperfusion Injury / Q000473:pathology*; D048051:p38 Mitogen-Activated Protein Kinases
D009569:Nitric Oxide; D002248:Carbon Monoxide; D006419:Heme Oxygenase (Decyclizing); D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D006162:Guanylate Cyclase