Yap/Taz regulate alveolar regeneration and resolution of lung inflammation
Yap/Taz regulate alveolar regeneration and resolution of lung inflammation
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YAP/TAZ调节肺泡再生和肺部炎症消退
DOI：
10.1172/jci125014
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发表时间：
2019-05-01
影响因子：
15.9
通讯作者：
Tian, Ying
中科院分区：
文献类型：
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作者：
LaCanna, Ryan;Liccardo, Daniela;Tian, Ying
肺泡上皮细胞在保护肺部免受吸入性感染方面起着关键作用。因此，肺泡上皮的再生能力对于从这些损伤中恢复以重建上皮屏障和恢复肺功能是至关重要的。在这里，我们表明，亚致死性感染的小鼠与肺炎链球菌，最常见的病原体的社区获得性肺炎，导致专门的损害肺泡，其次是肺泡上皮细胞再生和肺部炎症的决议。我们发现，表面活性蛋白C表达（SPC表达）肺泡上皮II型细胞（AECIIs）感染后进行增殖和分化，这有助于新形成的肺泡上皮。AECII活性的增加与Hippo通路的介体雅普和Taz的核表达增加相关。AECII中缺乏雅普/Taz的小鼠在细菌性肺炎期间表现出肺中延长的炎症反应和肺泡上皮再生延迟。这种受损的肺泡上皮细胞再生是由于未能上调I κ Ba，终止NF-κ B介导的炎症反应的分子。这些结果表明，控制肺部炎症消退的信号在雅普/Taz突变小鼠中发生了改变，这阻止了适当再生生态位的发展，延迟了细菌性肺炎期间肺泡上皮的修复和再生。
Alveolar epithelium plays a pivotal role in protecting the lungs from inhaled infectious agents. Therefore, the regenerative capacity of the alveolar epithelium is critical for recovery from these insults in order to rebuild the epithelial barrier and restore pulmonary functions. Here, we show that sublethal infection of mice with Streptococcus pneumoniae, the most common pathogen of community-acquired pneumonia, led to exclusive damage in lung alveoli, followed by alveolar epithelial regeneration and resolution of lung inflammation. We show that surfactant protein C-expressing (SPC-expressing) alveolar epithelial type II cells (AECIIs) underwent proliferation and differentiation after infection, which contributed to the newly formed alveolar epithelium. This increase in AECII activities was correlated with increased nuclear expression of Yap and Taz, the mediators of the Hippo pathway. Mice that lacked Yap/Taz in AECIIs exhibited prolonged inflammatory responses in the lung and were delayed in alveolar epithelial regeneration during bacterial pneumonia. This impaired alveolar epithelial regeneration was paralleled by a failure to upregulate I kappa Ba, the molecule that terminates NF-kappa B-mediated inflammatory responses. These results demonstrate that signals governing resolution of lung inflammation were altered in Yap/Taz mutant mice, which prevented the development of a proper regenerative niche, delaying repair and regeneration of alveolar epithelium during bacterial pneumonia.