Autophagy protects against ischemia/reperfusion-induced lung injury through alleviating blood-air barrier damage.
BACKGROUND
Understanding the role and underlying regulation mechanism of autophagy in ischemia/reperfusion (I/R)-induced lung injury may provide potentially new pharmacologic targets for treatment of acute lung injury. The aim of this study was to adjust autophagy with pharmacologic agents to determine its functional significance in I/R-induced lung injury.


METHODS
Human pulmonary microvascular endothelial cells (HPMVECs) and mice were pre-conditioned with autophagy inhibitor chloroquine or promoter rapamycin before they were challenged with oxygen-glucose deprivation/oxygen-glucose restoration (OGD) and lung I/R, respectively. Extracellular signal-regulated kinase (ERK)1/2 inhibitor U0126 was pre-injected into I/R-induced mice to test the role of ERK1/2 in regulating autophagy.


RESULTS
OGD caused tight conjunction damage and cell death in HPMVECs, which was further aggravated by blocking autophagy, yet ameliorated through promoting autophagy. On a consistent basis, inhibiting autophagy aggravated I/R-induced lung edema and tissue inflammation, which was significantly alleviated by promoting autophagy with rapamycin. In addition, inhibition of ERK1/2 increased expression of active mammalian target-of-rapamycin and thus decreased I/R-induced autophagy.


CONCLUSIONS
It appears that autophagy plays a protective role in I/R-induced lung injury and this effect may be enhanced by moderately improving autophagy level. Meanwhile, the ERK1/2 signal pathway has a positively regulating role in lung I/R-induced autophagy.
Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, China.
Dan
D
Zhang
Department of Plastic Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou city, Zhejiang Province, China.
Chichi
C
Li
Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, China.
Jian
J
Zhou
Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, China.
Yuanlin
Y
Song
Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, China.
Xiaocong
X
Fang
Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, China.
Jiaxian
J
Ou
Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, China.
Jing
J
Li
Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, China. Electronic address: cxbai@fudan.edu.cn.
Chunxue
C
Bai
D000818:Animals; D001343:Autophagy / Q000502:physiology*; D015824:Blood-Air Barrier / Q000502:physiology*; D002470:Cell Survival; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D055370:Lung Injury / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology*
acute lung injury; autophagy; extracellular signal-regulated kinase; ischemia/reperfusion; rapamycin