Early Origins of Chronic Lung Disease: Outcomes into the Fifth Decade of Life

哮喘、慢性阻塞性肺疾病（COPD）和限制性肺功能测定模式（RSP）是 与发病率和死亡率负担增加有关。最近的发现有力地表明， 许多成年哮喘、慢性阻塞性肺病和呼吸道细颗粒物的病例可在生命早期发现。预防这些 异质条件，目前没有治愈存在，需要彻底了解自然 构成其不同临床表型基础的历史和机制途径。图森儿童 呼吸系统研究（TCRS）已经为我们理解呼吸系统疾病的自然史做出了重大贡献。 哮喘和肺功能轨迹，随着其参与者进入第五个十年，现在准备 前瞻性地研究哮喘、COPD和RSP的早期危险因素以及 它们独特的临床表型。虽然特应性哮喘（T2）的起源已经很好地确定，但特应性哮喘的起源 非T2型哮喘，在严重哮喘患者中比例过高，并且没有有效的治疗方法， 但它是不太知名的。我们最近发现，高血清胰岛素和非过敏性鼻炎， 6岁是儿童期至36岁哮喘的强独立预测因子。这些发现 提供了令人兴奋的新途径，以了解非T2哮喘的发病机制的基础上，其自然史。 在这里，我们建议使用最先进的单细胞表观遗传和基因表达技术来比较 有和没有这两个早期生命危险因素的参与者痰液中的细胞类型分布。关于 COPD，我们最近的研究结果表明，至少有一半的患者诊断患有这种疾病不显示 在成年期加速肺功能下降，表明气流限制起源于低气道 从童年开始的功能轨迹。我们现在建议使用CT成像来确定解剖结构 持续性低气道功能轨迹的特征。此外，我们还发现， 由于呼吸道合胞病毒（RSV）在生命早期确诊的下呼吸道疾病增加， 在生命的第三个十年中有慢性呼吸道症状的风险。我们现在建议将数据用于 第五个十年的生活，以确定是否RSV吸烟的相互作用解释了为什么只有少数吸烟者发展 慢性阻塞性肺病最后，我们会探讨可吸入悬浮粒子的主要风险因素是营养问题的假设， 子宫和童年时期。我们将讨论三个具体目标：1。评估细胞和分子内型 以及早期生命危险因素对哮喘表型从儿童期到中年的持续影响。 2.评估生命早期危险因素的持续影响以及临床、生理和气道 早期COPD在中年期的结构改变。3.评估生命早期危险因素的影响 体积描记法定义的肺限制在中年人的生活。作为唯一一个有数百名非- 选定的参与者从出生到生命的第五个十年，TCRS提供了一个独特的机会， 研究成人哮喘、COPD和RSP早期起源的潜在疾病机制。

Asthma, chronic obstructive pulmonary disease (COPD) and a restrictive spirometry pattern (RSP) are strongly associated with increased morbidity and mortality burden. Recent discoveries strongly suggest that the roots of many cases of asthma, COPD and RSP in adulthood can be found during early life. Prevention of these heterogeneous conditions, for which no cure currently exists, requires a thorough understanding of the natural history and mechanistic pathways that underlie their distinct clinical phenotypes. The Tucson Children's Respiratory Study (TCRS) has already made major contributions to our understanding of the natural history of asthma and of lung function trajectories and, as its participants are entering their fifth decade, is now poised to investigate, prospectively, the early risk factors for asthma, COPD and RSP as well as the molecular basis of their distinct clinical phenotypes. While the origins of atopic asthma (T2) are well established, the origins of non-T2 asthma, which is overrepresented among severe asthmatics and for which no efficacious treatment is available, are less well known. We recently showed that both high serum insulin and non-atopic rhinitis at the age of six years are strong, separate predictors of asthma from childhood up to age 36 years. These findings offer exciting new avenues to understand the pathogenesis of non-T2 asthma based on its natural history. Here, we propose to use state-of-the-art single-cell epigenetic and gene expression technologies to compare the cell type distribution in sputum of participants with and without these two early life risk factors. Regarding COPD, our recent findings suggest that at least half of all patients diagnosed with the disease do not show accelerated lung function decline during adult life, suggesting that airflow limitation had its origins in low airway function trajectories starting in childhood. We now propose to use CT imaging to determine the anatomical features of the persistently low airway function trajectory. In addition, we showed that smokers who had confirmed lower respiratory tract illnesses due to respiratory syncytial virus (RSV) in early life are at increased risk of having chronic respiratory symptoms in the third decade of life. We now propose to use data into the fifth decade of life to ascertain if the RSV-smoking interaction explains why only a minority of smokers develop COPD. Finally, we will investigate the hypothesis that major risk factors for RSP are nutritional problems in- utero and during childhood. We will address 3 specific aims: 1. To assess the cellular and molecular endotypes and the continued influence of early life risk factors on phenotypes of asthma from childhood into mid-adult life. 2. To assess the continued influence of early life risk factors and the clinical, physiological, and airway structural alterations of incipient early COPD in mid-adult life. 3. To assess the influence of early life risk factors on plethysmography-defined lung restriction in mid-adult life. As the only birth cohort with hundreds of non- selected participants followed from birth into the fifth decade of life, the TCRS offers a unique opportunity to investigate the potential disease mechanisms for the early origins of asthma, COPD, and RSP in adult life.