Upregulationof autophagy decreases chlorine-induced mitochondrial injury and lunginflammation

Upregulation of autophagy decreases chlorine-induced mitochondrial injury and lu.pdf

ppt.pdf

http://www.sciencedirect.com/science/article/pii/S0891584915001732

Highlights

•Chlorineis often released into the atmosphere by industrial accidents.

1.在工业事故中氯气经常被释放到大气中。

•Accidentalexposure of humans to Cl2 results in severe injury to lungs and heart.

2.人类偶然地接触到Cl₂导致对肺和心脏的严重损伤。

•Exposureof lung epithelial cells to Cl2 damages complexes I and II, but not complex IV,and mitochondrial bioenergetics as measured by the Seahorse analyzer.

3.通过Seahorse分析仪检测，暴露于Cl₂肺上皮细胞内线粒体复合物I和II发生损伤，但是复合物IV没有发生损伤，同时还发现氯气暴露导致了线粒体生物能量障碍。

•Upregulationof autophagy by trehalose decreases mitochondrial injury.

4.通过海藻糖干预可以通过上调自噬减少线粒体损伤。

•Exposureof mice to Cl2 results in lung inflammation and alveolar injury.

5.小鼠暴露于Cl₂导致肺部炎症和肺泡损伤。

•Intratrachealtrehalose increases lung autophagy and decreases injury.

6.气管内给予海藻糖增加肺自噬，并减少损伤。

Abstract

The mechanisms oftoxicity during exposure of the airways to chlorinated biomolecules generatedduring the course of inflammation and to chlorine (Cl2) gas are poorlyunderstood. We hypothesized that lung epithelial cell mitochondria are damagedby Cl2 exposure and activation of autophagy mitigates this injury. To addressthis, NCI-H441 (human lung adenocarcinoma epithelial) cells were exposed to Cl2(100 ppm/15 min) and bioenergetics were assessed. One hour after Cl2, cellularbioenergetic function and mitochondrial membrane potential were decreased.These changes were associated with increased MitoSOX signal, and treatment withthe mitochondrial redox modulator MitoQ attenuated these bioenergetic defects.At 6 h postexposure, there was significant increase in autophagy, which was associatedwith an improvement of mitochondrial function. Pretreatment of H441 cells withtrehalose (an autophagy activator) improved bioenergetic function, whereas3-methyladenine (an autophagy inhibitor) resulted in increased bioenergeticdysfunction 1 h after Cl2 exposure. These data indicate that Cl2 inducesbioenergetic dysfunction, and autophagy plays a protective role in vitro.Addition of trehalose (2 vol%) to the drinking water of C57BL/6 mice for 6weeks, but not 1 week, before Cl2 (400 ppm/30 min) decreased white blood cellsin the bronchoalveolar lavage fluid at 6 h after Cl2 by 70%. Acuteadministration of trehalose delivered through inhalation 24 and 1 h before theexposure decreased alveolar permeability but not cell infiltration. These data indicatethat Cl2 induces bioenergetic dysfunction associated with lung inflammation andsuggests that autophagy plays a protective role.

气道暴露于炎症过程中产生的氯化生物分子和氯（Cl₂）气体时的毒性机制了解甚少。我们假设肺上皮细胞线粒体受到Cl₂暴露的损伤，自噬的激活可以减轻这种损伤。为了解决这个问题，将NCI-H441（人肺腺癌上皮）细胞暴露于Cl₂（100ppm / 15分钟），并评估生物能量变化。Cl₂暴露后1小时，细胞生物能量功能和线粒体膜电位降低。这些变化与增加的MitoSOX信号相关，线粒体氧化还原调节剂MitoQ的治疗减弱了这些生物能量缺陷。暴露后6h，自噬显着增加，与线粒体功能改善有关。用海藻糖（自噬激活剂）预处理H441细胞可以改善生物能量功能，而3-甲基腺嘌呤（自噬抑制剂）导致Cl₂暴露后1小时生物能量功能障碍增加。这些数据表明，Cl₂诱导生物能量功能障碍，自噬在体外起保护作用。在Cl₂（400ppm / 30分钟）之前，向C57BL / 6小鼠的饮用水中加入海藻糖（2％）6周，检测Cl₂暴露后6小时的支气管肺泡灌洗液，发现白细胞减少70％。在接触前24和1小时通过吸入输送的海藻糖的急性给药降低了肺泡通透性，但没有细胞浸润。这些数据表明Cl₂诱导与肺部炎症相关的生物能量功能障碍相关，并表明自噬能够发挥保护作用。

总之，这些研究强调了维持线粒体功能在从暴露于有毒物质如Cl₂的肺中恢复的潜在重要性，以及自噬途径作为急性肺损伤治疗策略的潜在作用。