DUOX1 Silencing in Age-Related COPD

年龄相关性 COPD 中的 DUOX1 沉默

• 批准号: 9262578
• 负责人: ALBERT VAN DER VLIET
• 金额: $ 23.4万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9262578
• 关键词: Acrolein; Address; Age; Age-Months; Aging; Aging-Related Process; Air; Alveolar; Alveolar Macrophages; Animals; Attenuated; Biological Aging; Cell Aging; Chronic; Chronic Obstructive Airway Disease; Chronic lung disease; DNA; Development; Disease; Elastases; Elderly; Environmental Risk Factor; Enzymes; Epigenetic Process; Epithelial; Epithelial Cells; Experimental Models; Fibrosis; Genetic; Goals; Haemophilus influenzae; Host Defense; Host Defense Mechanism; Impairment; In Vitro; Incidence; Infection; Influenza; Influenza A virus; Lead; Link; Lung; Lung Compliance; Maintenance; Mediating; Mus; NADPH Oxidase; Natural regeneration; Oxidases; Oxidation-Reduction; Pathologic; Pathology; Pathway interactions; Patients; Peripheral; Predisposition; Protein Tyrosine Kinase; Pulmonary Emphysema; Reporting; Respiratory physiology; Risk Factors; Smoker; Smoking; Stress; Structure of parenchyma of lung; Telomere Shortening; Tobacco smoke; Tobacco smoking; Tracheobronchial; Viral; age effect; age related; airway epithelium; airway remodeling; alveolar destruction; alveolar epithelium; cigarette smoke-induced; cigarette smoking; environmental tobacco smoke exposure; epithelial to mesenchymal transition; experimental study; functional decline; functional disability; gene environment interaction; immune function; insight; macrophage; pathogen; regenerative; repaired; response

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.

项目摘要 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，这表明与年龄相关的肺部变化有助于发育， COPD患者肺功能下降。事实上，衰老已被证明会导致先天宿主防御能力减弱 机制以及再生能力降低，两者都有助于增加感染和进行性 慢性阻塞性肺病的肺部破坏。NADPH氧化酶DUOX 1在气道和肺泡上皮细胞中显著表达 并且最近被鉴定为先天宿主防御和维持上皮完整性的关键组分。 有趣的是，我们的初步研究表明，小鼠肺组织DUOX 1表达显著降低， 随年龄此外，发现遗传性DUOX 1缺陷的小鼠显示出与年龄相关的特征， 空气空间扩大和增加肺顺应性，以及减少肺泡巨噬细胞对 LPS，表明DUOX 1缺陷导致上皮再生受损和巨噬细胞依赖性 宿主对COPD急性加重相关机会性病原体的防御。除了衰老的影响， 吸烟等环境因素是COPD的主要危险因素， 异常肺老化现象是COPD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DUOX 1表达减少，以及实验研究 表明小鼠长期暴露于香烟烟雾或丙烯醛（其主要有害成分之一）导致 气道DUOX 1表达的缺失。此外，还发现DUOX 1表达的缺失与 气道重塑的增强特征，其特征在于上皮向间质转化（EMT）， 上皮下纤维化是COPD的重要病理特征。这些不同的发现表明， DUOX 1的丢失，作为慢性烟草烟雾暴露和衰老的综合结果，有助于重要的 COD病理学的特征，通过最小化上皮修复能力和先天宿主防御机制， 通过增强气道重塑和小气道纤维化。目前的建议将探讨机制 DUOX 1沉默与生物衰老之间的关系，以及DUOX 1抑制与年龄的相关性。 在弹性蛋白酶诱导的肺气肿的实验模型中的相关肺气肿（目的1）。其次，我们将 确定DUOX 1缺陷对慢性炎症诱导的上皮重塑和上皮下纤维化的影响。 丙烯醛暴露。总体而言，这些研究将探讨吸烟和年龄对DUOX 1的综合影响， COPD疾病病理学中基因-环境相互作用的例子。