Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai, Japan.
Biochem Biophys Res Commun. 2011 Feb 4;405(1):13-8. doi: 10.1016/j.bbrc.2010.12.092. Epub 2010 Dec 23.
Autophagy is a highly conserved process primarily known for its role in cellular adaptation to nutritional stress. This bulk protein degradation pathway relocates nutrients during starvation. Recent studies, however, have revealed essential roles of autophagy in various organs under normal conditions. Especially, autophagy is now recognized as the pathway responsible for the elimination of damaged proteins resulting from environmental stress. Lungs are constantly exposed to high oxygen tension and environmental chemicals. To investigate the importance of autophagy in lung physiology, we used an inducible system to ablate Atg7 expression, which is a protein essential for autophagy, in the respiratory epithelial cells of adult mice. We found that Atg7 deficiency caused swelling of bronchiolar epithelial cells and accumulation of p62, which links substrate proteins to the autophagy machinery. Bronchiolar epithelial cells, isolated by micro-dissection of lung tissues, had elevated expression of cytoprotective genes that are typically activated by Nrf2. Interestingly, Atg7-deficient lungs displayed hyper-responsiveness to cholinergic stimuli without apparent inflammatory signs. Swollen bronchiolar epithelial cells may have lead to mechanical airway constriction and lowered the threshold for the increase of airway resistance. This study demonstrates the critical role of autophagy in the lungs for the maintenance of pulmonary homeostasis.
自噬是一种高度保守的过程，主要因其在细胞适应营养压力中的作用而闻名。这条大规模的蛋白质降解途径在饥饿时重新分配营养物质。然而，最近的研究揭示了自噬在正常情况下各种器官中的重要作用。特别是，自噬现在被认为是负责消除环境应激引起的受损蛋白质的途径。肺经常暴露在高氧张力和环境化学物质中。为了研究自噬在肺生理学中的重要性，我们使用一种诱导系统在成年小鼠的呼吸上皮细胞中敲除自噬所必需的 Atg7 表达。我们发现 Atg7 缺乏导致细支气管上皮细胞肿胀和 p62 的积累，p62 将底物蛋白与自噬机制联系起来。通过肺组织的微解剖分离的细支气管上皮细胞中，细胞保护基因的表达升高，这些基因通常被 Nrf2 激活。有趣的是，Atg7 缺陷的肺对胆碱能刺激表现出超敏反应，而没有明显的炎症迹象。肿胀的细支气管上皮细胞可能导致机械性气道收缩，并降低气道阻力增加的阈值。这项研究表明自噬在维持肺内平衡方面对肺具有关键作用。
