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造成1100万人死亡和3.5亿人伤残调整寿命年损失。 2017年(较2007年大幅增加)。呼吸道树是抵御这些无处不在的有害物质的第一道防线 而且，根据教科书，它有相当标准的解剖学。 在第一个资助期，我们确认了我们的主要假设，并发现大约25%的一般 人群中有改变对香烟烟雾易感性的呼吸道分支变体(发表在PNAS上)。进一步 多个队列中呼吸道树结构的CT流行病学调查显示 天然气道树口径的变异(“呼吸困难”)是常见的，并可预测慢性阻塞性肺疾病的发生。 (COPD)比吸烟好(发表在《美国医学会杂志》上)，并延伸到终末细支气管炎。这些新的发现表明 自然呼吸道树口径是COPD风险的基础，可能会改变吸入颗粒物的易感性，包括 香烟味。因此，这一更新建议1)建立呼吸道树口径的早期起源，以确定 可能的可改变因素，2)调查吸入性有害物质易感性增加的病理生理学 成人，以及3)根据临床结果确定有弹性的与易受影响的气道树结构 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利用无辐射的创新mr肺成像，我们将建立早期生命起源的气道树口径。 在具有良好特征的多民族出生队列中的青少年(n=100)中具有生理相关性的变异。 探索较小的气道树口径是否与预期确定的和可修改的早期生命因素相关。 目的2研究两种候选的病理生理学机制，将呼吸道树口径与增加的易感性联系起来。 烟草烟雾和其他有害污染物： 2A：机制1(高剂量注射)：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聚(n=554)，以及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相关 不吸烟者(n=40)的基本祖细胞表达特征和“疲惫”的基本细胞基因表达 对吸烟的反应与呼吸道炎症的高表达(n=207)。 目的3确定定义弹性与易感气道树口径的阈值 心脏和全肺CT测量和临床结果，随访长达21年(n=9,664)。 3A：测试呼吸道树口径是否改变与吸烟相关的死亡风险。 建议的R01更新建立在高影响的先前工作的基础上，并寻求了解并最终瞄准弹性气道 树木的发展和维护跨越了寿命，并改善了21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.