Autophagy is essential for ultrafine particle-induced inflammation and mucus hyperproduction in airway epithelium
Autophagy is essential for ultrafine particle-induced inflammation and mucus hyperproduction in airway epithelium
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自噬对于超细颗粒诱导的气道上皮炎症和粘液过度产生至关重要
DOI：
10.1080/15548627.2015.1124224
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发表时间：
2016-01-01
期刊：
影响因子：
13.3
通讯作者：
Shen, Hua-Hao
中科院分区：
文献类型：
--
作者：
Chen, Zhi-Hua;Wu, Yin-Fang;Shen, Hua-Hao
摘要环境中的超细颗粒物（PM）可引起气道损伤，但其具体的分子机制尚不清楚。在这里，我们证明了自噬在调节炎症和粘液分泌过多引起的PM含有环境持久性自由基在人支气管上皮细胞（HBE）和小鼠气道中的关键作用。PM被HBE细胞内吞并同时触发自噬体，自噬体然后吞噬入侵颗粒以形成两性体和随后的自溶酶体。自噬的遗传阻断显著降低了PM诱导的炎性细胞因子（例如HBE细胞中的IL 8和IL 6以及MUC 5AC）的表达。由于自噬相关基因Becn 1或Lc 3b的敲低而导致自噬受损的小鼠在体内暴露于PM时表现出显著降低的气道炎症和粘液过度产生。通过溶酶体抑制对自噬通量的干扰导致累积的自噬体/两性体，并且有趣的是，该过程通过NFKB 1显著加剧了IL 8的产生，并且通过激活蛋白1显著减弱了MUC 5AC的表达。这些数据表明，自噬是PM诱导的气道上皮损伤所必需的，并且自噬的抑制对PM诱导的气道炎症和粘液过度产生治疗益处，尽管它们由自噬通量差异地编排。
ABSTRACT Environmental ultrafine particulate matter (PM) is capable of inducing airway injury, while the detailed molecular mechanisms remain largely unclear. Here, we demonstrate pivotal roles of autophagy in regulation of inflammation and mucus hyperproduction induced by PM containing environmentally persistent free radicals in human bronchial epithelial (HBE) cells and in mouse airways. PM was endocytosed by HBE cells and simultaneously triggered autophagosomes, which then engulfed the invading particles to form amphisomes and subsequent autolysosomes. Genetic blockage of autophagy markedly reduced PM-induced expression of inflammatory cytokines, e.g. IL8 and IL6, and MUC5AC in HBE cells. Mice with impaired autophagy due to knockdown of autophagy-related gene Becn1 or Lc3b displayed significantly reduced airway inflammation and mucus hyperproduction in response to PM exposure in vivo. Interference of the autophagic flux by lysosomal inhibition resulted in accumulated autophagosomes/amphisomes, and intriguingly, this process significantly aggravated the IL8 production through NFKB1, and markedly attenuated MUC5AC expression via activator protein 1. These data indicate that autophagy is required for PM-induced airway epithelial injury, and that inhibition of autophagy exerts therapeutic benefits for PM-induced airway inflammation and mucus hyperproduction, although they are differentially orchestrated by the autophagic flux.