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

哮喘、慢性阻塞性肺疾病(COPD)和限制性肺活量测定模式(RSP)的发病率很高 与发病率和死亡负担增加有关。最近的发现有力地表明， 许多成年期的哮喘、COPD和RSP病例可以在生命的早期发现。防止这些情况的发生 目前尚不存在治愈方法的异质性疾病，需要对自然的 其独特的临床表型的病史和机制途径。图森儿童之家 呼吸系统研究(TCRS)已经为我们理解人类的自然历史做出了重大贡献。 哮喘和肺功能轨迹的研究，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 他们独特的临床表型。虽然特应性哮喘(T2)的起源已经确定，但 非T2型哮喘，在严重哮喘患者中比例过高，没有有效的治疗方法 但不太为人所知。我们最近发现，高血清胰岛素和非特应性鼻炎在 从儿童到36岁，6岁是哮喘的独立预测因素。这些发现 提供激动人心的新途径，以了解非T2哮喘的发病机制，基于其自然历史。 在这里，我们建议使用最先进的单细胞表观遗传学和基因表达技术来比较 有无这两个早期生命危险因素的参与者的痰中细胞类型分布。关于 COPD，我们最近的发现表明，至少有一半被诊断为COPD的患者没有表现出 成年后肺功能加速衰退，提示气流受限起源于低气道。 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点。此外，我们还向吸烟者展示了 早期因呼吸道合胞病毒(RSV)确诊的下呼吸道疾病正在增加 在生命的第三个十年中出现慢性呼吸道症状的风险。我们现在建议将数据用于 第五个十年的生命来确定RSV与吸烟的相互作用是否解释了为什么只有一小部分吸烟者患上了 慢性阻塞性肺疾病（慢阻肺）。最后，我们将研究关于可吸入颗粒物的主要危险因素是营养问题的假设。 子宫和儿童时期。我们将解决三个具体目标：1.评估细胞和分子内型 早期生活危险因素对儿童至中年哮喘表型的持续影响。 2.评估早期生命危险因素对临床、生理和呼吸道的持续影响 早期慢性阻塞性肺疾病患者中年的结构改变。3.评估早期生命危险因素的影响 关于体积描记术定义的中年生活中的肺限制。作为唯一的出生队列，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 研究成人生活中哮喘、COPD和RSP早期发生的潜在疾病机制。

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.