Upregulation of autophagy decreases chlorine-induced mitochondrial injury and lung inflammation

作者：Jurkuvenaite Asta; Benavides Gloria A; Komarova Svetlana; Doran Stephen F; Johnson Michelle; Aggarwal Saurabh; Zhang Jianhua; Darley Usmar Victor M; Matalon Sadis^*

来源：Free Radical Biology and Medicine, 2015, 85: 83-94.

DOI：10.1016/j.freeradbiomed.2015.03.039

• Chlorine
• Mitochondrial dysfunction
• Lung injury
• MitoQ
• Trehalose
• Autophagy
• Bioenergetics
• 3-Methyladenine
• Free radicals

The mechanisms of toxicity during exposure of the airways to chlorinated biomolecules generated during the course of inflammation and to chlorine (Cl-2) gas are poorly understood. We hypothesized that lung epithelial cell mitochondria are damaged by Cl-2 exposure and activation of autophagy mitigates this injury. To address this, NCI-H441 (human lung alenocarcinoma epithelial) cells were exposed to Cl2 (100 ppm/15 min) and bioenergetics were assessed. One hour after Cl-2, cellular bioenergetic function and mitochonclrial membrane potential were decreased. These changes were associated with increased MitoSOX signal, and treatment with the mitochonclrial redox modulator MitoQ attenuated these bioenergetic defects. At 6 h postexposure, there was significant increase in autophagy, which was associated with an improvement of mitochondrial function. Pretreatment of H441 cells with trehalose (an autophagy activator) improved bioenergetic function, whereas 3-methyladenine (an autophagy inhibitor) resulted in increased bioenergetic dysfunction 1 h after Cl-2 exposure. These data indicate that Cl-2 induces bioenergetic dysfunction, and autophagy plays a protective role in vitro. Addition of trehalose (2 vol%) to the drinking water of C57BL/6 mice for 6 weeks, but not 1 week, before Cl-2 (400 ppm/30 min) decreased white blood cells in the bronchoalveolar lavage fluid at 6 h after Cl-2 by 70%. Acute administration of trehalose delivered through inhalation 24 and 1 h before the exposure decreased alveolar permeability but not cell infiltration. These data indicate that Cl-2 induces bioenergetic dysfunction associated with lung inflammation and suggests that autophagy plays a protective role. Published by Elsevier Inc.

• 出版日期2015-8