Cigarette Smoke Exposure and Acute Lung Injury After Severe Blunt Trauma

描述（由申请人提供）：急性肺损伤（ALI）是危重成人呼吸衰竭的常见原因，仅在美国每年的发病率就接近20万例，死亡率为30-40% 1急性呼吸道感染经常发生在重大创伤之后，创伤本身就是全国1至44岁人群死亡的主要原因；此外，创伤后急性脑损伤的发生使死亡率增加了3倍我们最近发现，主动吸烟和中度至重度二手烟暴露与严重钝性创伤后发生ALI的几率增加近3倍有关，与酒精滥用无关。在本文提出的研究中，我们将验证一个中心假设，即创伤前主动吸烟和二手烟暴露均可通过损伤肺上皮和内皮以及增强对感染的易感性使患者易患ALI。我们将利用我们在旧金山总医院建立的、正在进行的严重钝性创伤患者前瞻性队列的基础设施，收集600名新患者的必要临床数据和生物标本，以研究三个具体目标。对于所有目标，主动和被动的香烟烟雾暴露都将通过经过充分验证的生物标志物进行严格量化：特别是血浆可替宁和尿液总4-（甲基亚硝胺）-1-（3-吡啶基）-1-丁醇（NNAL）。在Aim 1中，我们将测试低水平二手烟暴露与严重钝性创伤后ALI易感性之间的关系，因为我们之前的研究规模不够大，无法解决这种暴露水平，这与公共卫生有重大关系，因为它在美国和国际上仍然很常见。在目的2中，我们将确定主动吸烟和/或二手烟暴露在多大程度上导致患者通过内皮和肺上皮损伤而发生ALI。内皮和肺上皮损伤将通过测量血浆和支气管肺泡灌洗液中特异性的、先前研究和验证的蛋白质生物标志物来量化。在Aim 3中，我们将确定主动吸烟和/或二手烟暴露在多大程度上通过增强感染易感性导致患者发生ALI，这反映在肺部微生物组的变化中。我们的研究小组完全有资格开展这项研究，因为我们在招募严重受伤的创伤患者队列、测量香烟烟雾暴露和肺损伤的生物标志物、描述微生物群方面的专业知识，以及我们成功合作的历史。该项目将通过深入了解吸烟如何促使患者发展为急性脑损伤，为针对性和/或预防性治疗奠定基础，从而显著推进急性脑损伤研究领域。此外，它可能会对二手烟暴露的监管产生重要的公共卫生影响。我们的方法特别具有创新性，因为它专注于慢性环境对急性呼吸道感染病因的影响，这一点尚未得到很好的研究；使用生物标志物来测量危重患者的暴露；它对预防急性呼吸道感染的潜在影响，这是最近NHLBI工作组的一个主要优先事项；它将提供暴露在香烟烟雾中对肺部微生物群的影响的见解。

DESCRIPTION (provided by applicant): Acute lung injury (ALI) is a common cause of respiratory failure in critically ill adults, with an incidence of nearly 200,000 cases/year in the US alone and a mortality of 30-40%.1 ALI frequently follows major trauma, which is itself the leading cause of mortality nationally between the ages of 1 and 44;2 further, the development of ALI following trauma increases mortality by 3-fold.3 We recently discovered that both active smoking and moderate to heavy secondhand smoke exposure are associated with a nearly 3-fold increase in the odds of developing ALI after severe blunt trauma, independent of alcohol abuse. In the research proposed here, we will test the central hypothesis that both active smoking and secondhand smoke exposure prior to trauma predispose patients to develop ALI via injury to the lung epithelium and endothelium and enhanced susceptibility to infection. We will use the infrastructure of our established, ongoing prospective cohort of severely injured blunt trauma patients at San Francisco General Hospital to collect the necessary clinical data and biologic specimens in 600 new patients to study three specific aims. For all aims, both active and passive cigarette smoke exposure will be rigorously quantified by well-validated biomarkers: specifically, plasma cotinine and urine total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL). In Aim 1, we will test the association between low-level secondhand smoke exposure and susceptibility to ALI after severe blunt trauma, since our prior studies were not large enough to address this level of exposure, which has major relevance to public health since it remains common in the US and internationally. In Aim 2, we will determine the extent to which active smoking and/or secondhand smoke exposure prime patients to develop ALI via endothelial and lung epithelial injury. Endothelial and lung epithelial injury will be quantified by measurement of specific, previously studied and validated protein biomarkers in plasma and bronchoalveolar lavage. In Aim 3, we will determine the extent to which active smoking and/or secondhand smoke exposure prime patients to develop ALI via enhanced susceptibility to infection, as reflected by changes in the lung microbiome. Our research group is well-qualified to conduct this research by virtue of our expertise in enrolling cohorts of severely injured trauma patients, measuring biomarkers of cigarette smoke exposure and of lung injury, characterizing the microbiome, and our history of successful collaboration. This project will significantly advance the field of ALI research by providing insight into how cigarette smoke primes patients to develop ALI, laying the groundwork for targeted and/or preventative therapies. In addition, it will likely have important public health implications regarding the regulation of secondhand smoke exposure. Our approach is especially innovative because of its focus on chronic environmental influences on the etiology of ALI, which have not been well studied; the use of biomarkers to measure exposure in critically ill subjects; its potential implications for prevention of ALI, a major priority of a recent NHLBI Working Group; and the insights it will provide into the effects of cigarette smoke exposure on the lung microbiome.