Airway trees in the Anthropocene: Defining resilient airway trees and identifying the candidate mechanisms and etiologic factors that increase susceptibility to tobacco smoke and air pollution

年，烟草烟雾和其他有毒污染物导致1100万人死亡和3.5亿残疾调整生命年损失 2017年（较2007年大幅增加）。气道树是抵御这些无处不在的有毒物质的第一道防线 而且根据教科书的说法，它的解剖结构相当标准 在第一个资助期内，我们证实了我们的主要假设，并发现大约25%的一般 人群中有气道分支变异，改变了对香烟烟雾的敏感性（发表在PNAS上）。进一步 在多个队列中对计算机断层扫描（CT）上的气道树结构的流行病学调查表明， 天然气道树口径的变化（“呼吸困难”）是常见的，并预测慢性阻塞性肺疾病的发生 （COPD）比吸烟更好（发表在JAMA），并延伸到终末细支气管。这些新发现表明， 天然气道树口径是COPD风险的基础，并可能改变吸入颗粒物的易感性，包括 香烟烟雾。因此，本次更新建议1）建立气道树口径的早期起源，以确定 可能的可改变因素，2）研究对吸入性有害物质敏感性增加的病理生理学， 成人，和3）使用临床结果定义弹性与易感气道树结构 我们将使用新的和现有的数据，以及在队列流行病学，肺部成像，烟草和空气污染方面经过验证的专业知识 评估和基因表达，以实现以下目标： 目的1利用无辐射的磁共振肺部成像技术，建立气道树口径的早期起源 在一个特征良好的多种族出生队列中，青少年（n=100）的生理相关变异。 1a探索较小的气道树口径是否与前瞻性确定和可改变的早期生命因素相关。 目的2：研究两种将气道树口径与气道狭窄易感性增加联系起来的候选病理生理机制。 烟草烟雾和其他有害污染物： 2a：机制1（输送的剂量较高）：确定较小的气道树口径是否与i）较高的基线相关 和肺巨噬细胞黑碳含量的预期积累（n=554），和ii）更高的全身生物标志物水平 烟草烟雾暴露和炎症（n= 6，570）。 2b：机制2（气道内稳态受损）：确定较小的气道树口径是否与衰减的 从不吸烟者（n=40）的基底祖细胞表达特征和“耗尽”基底细胞基因表达 对吸烟的反应与气道炎症的较高表达（n=207）。 目的3：使用现有的气道树口径识别定义弹性与敏感气道树口径的阈值。 心脏和全肺CT测量和临床结局，随访时间长达21年（n= 9，664）。 3a：测试气道树口径是否改变与吸烟相关的死亡风险。 拟议的R01更新建立在高影响力的前期工作基础上，旨在了解并最终瞄准弹性气道 树木的发展和维护贯穿整个生命周期，并改善世纪的人口健康。

11 million lives and 350 million disability-adjusted life-years were lost to tobacco smoke and other noxious pollutants in 2017 (significant increases from 2007). The airway tree is the first line of defense against these ubiquitous noxious agents and, according to textbooks, has a fairly standard anatomy. During the first funding period, we confirmed our primary hypothesis and found that approximately 25% of the general population have airway branch variants that modify susceptibility to cigarette smoke (published in PNAS). Further epidemiologic investigation of airway tree structure on computed tomography (CT) in multiple cohorts demonstrated that variation in native airway tree caliber (“dysanapsis”) is common and predicts incident chronic obstructive pulmonary disease (COPD) better than smoking (published in JAMA) and extends to the terminal bronchioles. These new findings suggest that native airway tree caliber is fundamental to COPD risk and may modify susceptibility to inhale particulates including cigarette smoke. This renewal therefore proposes to 1) establish the early-life origins of airway tree caliber to identify possible modifiable factors, 2) investigate the pathophysiology of increased susceptibility to inhaled noxious agents in adults, and 3) define resilient vs susceptible airway tree structure using clinical outcomes We will use new and existing data, and proven expertise in cohort epidemiology, lung imaging, tobacco and air pollution assessment and gene expression to address the following aims: Aim 1 Using radiation-free innovative MR lung imaging, we will establish the early-life origin of airway tree caliber variation that is physiologically relevant among adolescents (n=100) in a well-characterized mulit-ethnic birth cohort. 1a Explore if smaller airway tree caliber is associated with prospectively ascertained and modifiable early-life factors. Aim 2 Investigate two candidate pathophysiologic mechanisms linking airway tree caliber to increased susceptibility to tobacco smoke and other noxious pollutants: 2a: Mechanism 1 (higher dose delivered): Determine if smaller airway tree caliber is associated with i) higher baseline and prospective accumulation of lung macrophage black carbon content (n=554), and ii) higher systemic biomarker levels of tobacco smoke exposure and inflammation (n=6,570). 2b: Mechanism 2 (impaired airway homeostasis): Determine if smaller airway tree caliber is associated with attenuated basal progenitor cell expression signature among never smokers (n=40) and an ‘exhausted’ basal cell gene expression response to smoking with higher expression of airway inflammation (n=207). Aim 3 Identify the threshold of airway tree caliber that defines resilient versus susceptible airway tree caliber using existing cardiac and full-lung CT measures and clinical outcomes with up to 21 years of follow-up (n=9,664). 3a: Test whether airway tree caliber modifies the risk of death associated with tobacco smoking. The proposed R01 renewal builds upon high-impact prior work and seeks to understand and ultimately target resilient airway tree development and maintenance across the lifespan and improve population health in the 21st century.