Early Origins of Chronic Airflow Limitation: Outcomes Into the 4th Decade of Life

 描述(申请人提供)：哮喘和慢性阻塞性肺病(COPD)是世界范围内发病率和死亡率的主要原因。因此，制定初级预防战略是一项重大的公共卫生优先事项。图森儿童呼吸研究(TCRS)和其他出生队列的最新发现表明，大多数成人哮喘始于童年。这些队列还发现了一种特殊的成人哮喘表型，它是由与呼吸道合胞病毒(RSV)或人类鼻病毒(HRV)相关的早期下呼吸道疾病(LRIS)引发的，随后发展为儿童时期的持续性喘息和成年后的气流受限。虽然COPD通常被认为是一种与吸烟相关的肺功能快速下降的疾病，但最近的研究表明，多达一半的COPD患者并没有表现出这种快速下降，而是以轻/中度的气道阻塞开始成年生活，随着年龄的增长，肺功能下降，导致临床上显著的气流受限。我们已经证明，新生儿后肺功能、3岁前肺炎发作和严重的儿童哮喘是在生命的第三个十年中最大限度地获得肺功能减退的主要危险因素。综上所述，这些数据有力地表明，相当大比例的成人哮喘和COPD病例的根源可以在早期生活中找到。该应用程序的目标是对36-40岁的TCRS参与者进行功能、临床和分子评估，以确定上述两种主要COPD亚型的早期生活事件与临床前阶段之间的联系机制。与此同时，我们将继续评估决定儿童哮喘持续存在到成年生活的因素。我们推测，对呼吸道病毒的异常反应可能是哮喘和COPD早期起源的主要原因。TCRS队列提供了一个独特的载体，我们现在可以通过它来解决三个特定的目标：1.确定早期生活中预测肺功能缺陷、哮喘持续存在和中年空气流动受限发展的宿主和环境因素；2.确定RSV LRI在早期生活中的作用及其与主动吸烟的相互作用，作为肺功能缺陷的决定因素，并表征诱导痰细胞和暴露于RSV的PBMC中基因表达的相关变化。3.确定鼻病毒感染后鼻上皮细胞产生的分子内型，以区分受试者 患有成人哮喘的人，以及那些患有成人哮喘但没有这种病史的人在早期生活中有持续喘息史。作为唯一的出生队列跟踪大量未选择的受试者进入生命的第四个十年，TCRS提供了一个独特的机会来调查成人生活中哮喘和COPD的早期生命风险因素和潜在的疾病机制。

 DESCRIPTION (provided by applicant): Asthma and (COPD) are major causes of morbidity and mortality worldwide. The development of primary prevention strategies is thus a major public health priority. Recent findings from the Tucson Children's Respiratory Study (TCRS) and other birth cohorts have shown that most asthma in adults begins in childhood. These cohorts have also identified a specific adult asthma phenotype which is initiated by early lower respiratory illnesses (LRIs) associated with respiratory syncytial virus (RSV) or human rhinovirus (HRV) and that subsequently progresses into both persistent wheezing in childhood and airflow limitation in adult life. Although COPD is commonly considered a disease of rapid decline in lung function associated with smoking, recent studies have shown that up to half of all patients with COPD do not show this rapid decline but rather, start adult life with mild/moderate airway obstruction which, with age-related decline in lung function, results in clinically significnt airflow limitation. We have shown that post-neonatal lung function, episodes of pneumonia by age 3, and severe childhood asthma are major risk factors for diminished maximally attained lung function in the third decade of life. Taken together, these data strongly suggest that the roots of a significant proportion of cases of asthma and COPD in adult life can be found during early life. The objective of this application is to perform functional, clinical, and molecular assessments in TCRS participants at 36-40 years of age to identify the mechanisms that connect early life events with the preclinical phase for the two major subtypes of COPD described above. Concomitantly, we will continue to assess the factors that determine persistence of childhood asthma into adult life. We hypothesize that abnormal responses to respiratory viruses may be major contributors to the early origins of asthma and COPD. The TCRS cohort provides a unique vehicle through which we can now address 3 specific aims: 1.To identify host and environmental factors in early life that predict lung function deficits, persistence of asthma, and development of airflow limitation in mid-adult life; 2. To determine the role of RSV LRI in early life and its interaction with active smoking as determinants of lung function deficits, and to characterize associated alterations in gene expression in induced sputum cells and in PBMCs exposed to RSV. 3. To determine the molecular endotype generated in nasal epithelial cells in response to rhinovirus infection that distinguishes subjects with adult asthma and a history of persistent wheezing in early life from those with adult asthma but without such history. As the only birth cohort that has followed a large number of nonselected subjects into the 4th decade of life, the TCRS offers a unique opportunity to investigate the early life risk factors for and the potential disease mechanisms involved in the origin of asthma and COPD in adult life.