替代氧化酶减轻香烟烟雾引起的肺功能障碍和组织损伤

Alternative Oxidase Attenuates Cigarette Smoke–induced Lung Dysfunction and Tissue Damage

Keywords：cigarette smoke, COPD, mitochondria, alternative oxidase

关键词：香烟烟雾，慢性阻塞性肺病，线粒体，替代氧化酶

哺乳动物：小鼠

细胞：成纤维细胞
作者：Luca Giordano, Antoine Farnham, Praveen K. Dhandapani, Laura Salminen, Jahnavi Bhaskaran,Robert Voswincke, Peter Rauschkolb, Susan Scheibe, Natascha Sommer, Christoph Beisswenger,Norbert Weissmann, Thomas Braun, Howard T. Jacobs1, Robert Bals, Christian Herr, and Marten Szibor
出版期刊：《American Journal of Respiratory Cell and Molecular Biology》（2018/10/18）

Abstract：

Cigarette smoke (CS) exposure is the predominant risk factor for the development of chronic obstructive pulmonary disease (COPD) and the third leading cause of death worldwide. We aimed to elucidate whether mitochondrial respiratory inhibition and oxidative stress are triggers in its etiology. In different models of CS exposure, we investigated the effect on lung remodeling and cell signaling of restoring mitochondrial respiratory electron flow using alternative oxidase (AOX), which bypasses the cytochrome segment of the respiratory chain. AOX attenuated CS-induced lung tissue destruction and loss of function in mice exposed chronically to CS for 9 months. It preserved the cell viability of isolated mouse embryonic fibroblasts treated with CS condensate, limited the induction of apoptosis, and decreased the production of reactive oxygen species (ROS). In contrast, the early-phase inflammatory response induced by acute CS exposure of mouse lung, i.e., infiltration by macrophages and neutrophils and adverse signaling, was unaffected. The use of AOX allowed us to obtain novel pathomechanistic insights into CS-induced cell damage, mitochondrial ROS production, and lung remodeling. Our findings implicate mitochondrial respiratory inhibition as a key pathogenic mechanism of CS toxicity in the lung. We propose AOX as a novel tool to study CS-related lung remodeling and potentially to counteract CS-induced ROS production and cell damage.

文章摘要：

香烟烟雾 (CS) 暴露是慢性阻塞性肺病 (COPD) 发展的主要危险因素，也是全球第三大死亡原因。我们旨在阐明线粒体呼吸抑制和氧化应激是否是其病因的触发因素。在不同的 CS 暴露模型中，我们研究了使用绕过呼吸链细胞色素片段的替代氧化酶 (AOX) 恢复线粒体呼吸电子流对肺重塑和细胞信号传导的影响。在长期暴露于 CS 9 个月的小鼠中，AOX 减弱了 CS 诱导的肺组织破坏和功能丧失。它保留了用 CS 凝聚物处理的分离的小鼠胚胎成纤维细胞的细胞活力，限制了细胞凋亡的诱导，并减少了活性氧 (ROS) 的产生。相比之下，小鼠肺急性 CS 暴露诱导的早期炎症反应，即巨噬细胞和中性粒细胞的浸润和不良信号传导，不受影响。 AOX 的使用使我们能够获得对 CS 诱导的细胞损伤、线粒体 ROS 产生和肺重塑的新的病理机制见解。我们的研究结果表明线粒体呼吸抑制是肺中 CS 毒性的关键致病机制。我们建议将 AOX 作为一种新工具来研究与 CS 相关的肺重塑，并可能抵消 CS 诱导的 ROS 产生和细胞损伤。

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文章题目、关键词与摘要译文仅用于参考。