Downregulation of DUOX1 function contributes to aging-related impairment of innate airway injury responses and accelerated senile emphysema.
Downregulation of DUOX1 function contributes to aging-related impairment of innate airway injury responses and accelerated senile emphysema.
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DOI：
10.1152/ajplung.00021.2021
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发表时间：
2021-05
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通讯作者：
C. Schiffers;L. Lundblad;Milena Hristova;A. Habibovic;Christopher M. Dustin;N. Daphtary;M. Aliyeva;D. Seward;Y. Janssen-Heininger;E. Wouters;N. Reynaert;A. Vliet
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作者：
C. Schiffers;L. Lundblad;Milena Hristova;A. Habibovic;Christopher M. Dustin;N. Daphtary;M. Aliyeva;D. Seward;Y. Janssen-Heininger;E. Wouters;N. Reynaert;A. Vliet
由于细胞衰老增加、再生能力下降和先天宿主防御受损，衰老与肺功能的逐渐丧失有关。先天气道上皮宿主防御非微生物触发因素的一个重要方面是IL-33等警报器的分泌和2型炎症的激活，之前发现这依赖于NADPH氧化酶（NOX）同源物DUOX1的激活，以及促进警报器分泌的氧化还原依赖信号通路。在这里，我们证明了C57BL/6J小鼠的正常衰老导致肺部先天上皮2型对外源性刺激物（如空气中的过敏原，翼龙鼻窦）的反应显著降低，这与DUOX1的显著下调以及DUOX1介导的氧化还原依赖性信号传导有关。研究还发现，duox1缺乏会加速与年龄相关的空域扩大和肺功能下降，但不会持续影响肺部衰老的其他特征，如衰老相关的炎症。有趣的是，在缺乏功能性线粒体烟酰胺核苷酸转氢酶（NNT）的C57BL/6J小鼠中，由于DUOX1缺乏而导致的年龄相关的DUOX1下调和空域扩大的观察结果，在NNT功能正常的C57BL/6NJ小鼠中则不那么明显，尽管后者小鼠随着年龄的增长也表现出先天上皮损伤反应受损。总体而言，我们的研究结果表明，对外部非微生物触发的先天气道损伤反应（DUOX1依赖性）存在明显的衰老依赖性下降，但衰老对DUOX1下调的影响及其在年龄相关的老年性肺气肿发展中的意义在不同的C57BL6亚株之间是不同的，可能与NNT功能差异导致的代谢改变有关。
Aging is associated with a gradual loss of lung function due to increased cellular senescence, decreased regenerative capacity and impaired innate host defense. One important aspect of innate airway epithelial host defense to non-microbial triggers is the secretion of alarmins such as IL-33 and activation of type 2 inflammation, which were previously found to depend on activation of the NADPH oxidase (NOX) homolog DUOX1, and redox-dependent signaling pathways that promote alarmin secretion. Here, we demonstrate that normal aging of C57BL/6J mice resulted in markedly decreased lung innate epithelial type 2 responses to exogenous triggers such as the airborne allergen, D. pteronyssinus, which was associated with marked downregulation of DUOX1, as well as DUOX1-mediated redox-dependent signaling. DUOX1-deficiency was also found to accelerate age-related airspace enlargement and decline in lung function, but did not consistently affect other features of lung aging such as senescence-associated inflammation. Intriguingly, observations of age-related DUOX1 downregulation and enhanced airspace enlargement due to DUOX1 deficiency in C57BL/6J mice, which lack a functional mitochondrial nicotinamide nucleotide transhydrogenase (NNT), were much less dramatic in C57BL/6NJ mice with normal NNT function, although the latter mice also displayed impaired innate epithelial injury responses with advancing age. Overall, our findings indicate a marked aging-dependent decline in (DUOX1-dependent) innate airway injury responses to external non-microbial triggers, but the impact of aging on DUOX1 downregulation and its significance for age-related senile emphysema development was variable between different C57BL6 substrains, possibly related to metabolic alterations due to differences in NNT function.