DUOX1 Silencing in Age-Related COPD

项目总结 慢性阻塞性肺疾病(COPD)等慢性肺部疾病的发病率增加 随着年龄的增长而增强，这表明与年龄相关的肺部改变有助于发育和加速 慢性阻塞性肺疾病患者肺功能下降。事实上，衰老已被证明会导致宿主天然防御能力减弱。 机制以及降低的再生能力，两者都导致感染增加和进展 慢性阻塞性肺疾病的肺损害。NADPH氧化酶DUOX1在呼吸道和肺泡上皮细胞中显著表达 最近被确定为天然宿主防御和维持上皮完整性的关键组成部分。 有趣的是，我们的初步研究表明，小鼠肺组织DUOX1的表达显著减少 随着年龄的增长。此外，发现遗传DUOX1缺乏的小鼠表现出与年龄相关的特征 空域扩大和肺顺应性增加，以及肺泡巨噬细胞对 LPs，提示DUOX1缺乏导致上皮再生受损和巨噬细胞依赖 宿主对与COPD加重相关的机会性病原体的防御。除了老化的影响外， 环境因素，如吸烟，是慢性阻塞性肺疾病的主要危险因素，因为它导致加速或 肺衰老异常现象是慢性阻塞性肺疾病发展的关键因素。有趣的是，最近的研究表明 健康吸烟者和COPD患者肺上皮细胞DUOX1表达降低及实验研究 表明小鼠长期暴露在香烟烟雾或丙烯醛(其主要有害成分之一)中会导致 在气道DUOX1表达缺失。此外，DUOX1表达的缺失也被发现与 以上皮向间充质转化(EMT)和 上皮下纤维化是COPD的重要病理特征。这些不同的发现表明，进行性的 DUOX1的丢失，作为长期吸烟暴露和衰老的综合结果，有助于重要的 COD的病理特征，通过最小化上皮修复能力和固有的宿主防御机制和 通过促进气道重塑和小气道纤维化。本提案将探讨机械性 DUOX1沉默与生物衰老的关系以及DUOX1抑制与年龄的相关性 弹性酶诱导肺气肿实验模型中的相关肺气肿(目标1)。其次，我们将 DUOX1缺乏症对慢性肾小管上皮细胞重塑和上皮下纤维化的影响 暴露于丙烯醛。总体而言，这些研究将解决吸烟和年龄对DUOX1作为一种 慢性阻塞性肺疾病发病机制中的基因-环境交互作用实例。

PROJECT SUMMARY The incidence of chronic lung diseases such as chronic obstructive pulmonary disease (COPD) increases strongly with age, indicating that age-related alterations in the lung contribute to development and accelerated lung function decline in COPD. Indeed, aging has been demonstrated to lead to attenuated innate host defense mechanisms as well as reduced regenerative capacity, both contributing to increased infections and progressive lung destruction in COPD. The NADPH oxidase DUOX1 is prominently expressed in airway and alveolar epithelia and was recently identified as a critical component of innate host defense and maintenance of epithelial integrity. Interestingly, our preliminary studies indicate that lung tissue DUOX1 expression in mice markedly decreases with age. Furthermore, mice with genetic DUOX1-deficiency were found to display age-related features of airspace enlargement and increased lung compliance, as well as reduced alveolar macrophage responses to LPS, suggesting that DUOX1 deficiency leads to impaired epithelial regeneration and macrophage-dependent host defense against opportunistic pathogens relevant to COPD exacerbations. In addition to effects of aging, environmental factors such as tobacco smoking are major risk factor for COPD by inducing accelerated or abnormal lung aging phenomena as a critical factor in COPD development. Intriguingly, recent studies indicate reduced lung epithelial DUOX1 expression in healthy smokers and COPD patients, and experimental studies show that chronic exposure of mice to cigarette smoke or acrolein (one of its major harmful components) results in loss of airway DUOX1 expression. Moreover, loss of DUOX1 expression was also found to be associated with enhanced features of airway remodeling, characterized by epithelial-to-mesenchymal transition (EMT) and subepithelial fibrosis, important pathological features COPD. These various findings indicate that progressive loss of DUOX1, as a combined result of chronic tobacco smoke exposure and aging, contributes to important features of COD pathology, by minimizing epithelial repair capacity and innate host defense mechanisms and by enhancing airway remodeling and small airway fibrosis. The present proposal will explore mechanistic relationships between DUOX1 silencing and biological aging, and the relevance of DUOX1 suppression for age- related emphysema in an experimental model of elastase-induce emphysema (Aim 1). Secondly, we will determine the impact of DUOX1-deficiency on epithelial remodeling and subepithelial fibrosis induced by chronic acrolein exposure. Overall, these studies will address combined effects of smoking and age on DUOX1 as an example of gene-environment interactions in the disease pathology of COPD.