Carbon monoxide inhibition of apoptosis during ischemia-reperfusion lung injury is dependent on the p38 mitogen-activated protein kinase pathway and involves caspase 3

被引:242
作者
Zhang, XC
Shan, PY
Otterbein, LE
Alam, J
Flavell, RA
Davis, RJ
Choi, AMK
Lee, PJ
机构
[1] Yale Univ, Sch Med, Pulm & Crit Care Med Sect, New Haven, CT 06520 USA
[2] Univ Pittsburgh, Div Pulm Allergy & Crit Care, Pittsburgh, PA 15213 USA
[3] Alton Ochsner Med Fdn & Ochsner Clin, Dept Mol Genet, New Orleans, LA 70121 USA
[4] Yale Univ, Sch Med, Dept Immunobiol, New Haven, CT 06520 USA
[5] Univ Massachusetts, Sch Med, Dept Biochem & Mol Biol, Program Mol Med, Worcester, MA 01605 USA
关键词
D O I
10.1074/jbc.M208419200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 anoxiareoxygenation (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.
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收藏
页码:1248 / 1258
页数:11
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