TY  - JOUR
PY  - 2011//
TI  - Carbon Monoxide Activates Autophagy via Mitochondrial Reactive Oxygen Species Formation
JO  - American journal of respiratory cell and molecular biology
A1  - Lee, Seon-Jin
A1  - Ryter, Stefan W.
A1  - Xu, Jin-Fu
A1  - Nakahira, Kiichi
A1  - Kim, Hong Pyo
A1  - Choi, Augustine M. K.
A1  - Kim, Young Sam
SP  - 867
EP  - 873
VL  - 45
IS  - 4
N2  - Autophagy, an autodigestive process that degrades cellular organelles and protein, plays an important role in maintaining cellular homeostasis during environmental stress. Carbon monoxide (CO), a toxic gas and candidate therapeutic molecule, confers cytoprotection in animal models of acute lung injury. The mechanisms underlying CO-dependent lung cell protection and the role of autophagy in this process remain unclear. Here, we demonstrate that CO exposure time-dependently increased the expression and activation of the autophagic protein, microtubule-associated protein-1 light chain-3B (LC3B) in mouse lung, and in cultured human alveolar (A549) or human bronchial epithelial cells. Furthermore, CO increased autophagosome formation in epithelial cells by electron microscopy and green fluorescent protein (GFP)-LC3 puncta assays. Recent studies indicate that reactive oxygen species (ROS) play an important role in the activation of autophagy. CO up-regulated mitochondria-dependent generation of ROS in epithelial cells, as assayed by MitoSOX fluorescence. Furthermore, CO-dependent induction of LC3B expression was inhibited by N-acetyl-L-cysteine and the mitochondria-targeting antioxidant, Mito-TEMPO. These data suggest that CO promotes the autophagic process through mitochondrial ROS generation. We investigated the relationships between autophagic proteins and CO-dependent cytoprotection using a model of hyperoxic stress. CO protected against hyperoxia-induced cell death, and inhibited hyperoxia-associated ROS production. The ability of CO to protect against hyperoxia-induced cell death and caspase-3 activation was compromised in epithelial cells infected with LC3B-small interfering (si)RNA, indicating a role for autophagic proteins. These studies uncover a new mechanism for the protective action of CO, in support of potential therapeutic application of this gas.<p />  <p>Language: en</p>
LA  - en
SN  - 1044-1549
UR  - http://dx.doi.org/10.1165/rcmb.2010-0352OC
ID  - ref1
ER  -