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，仅在美国的发病率就接近200，000例/年，死亡率为30- 40%。1 ALI通常发生在严重创伤之后，其本身是全国1至44岁人群死亡的主要原因; 2此外，创伤后发生ALI的死亡率增加了3倍。3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倍相关，独立于酒精滥用。在这里提出的研究中，我们将检验中心假设，即创伤前主动吸烟和二手烟暴露使患者易于通过损伤肺上皮和内皮细胞以及增强对感染的易感性而发生ALI。我们将使用我们在旧金山弗朗西斯科总医院建立的、正在进行的严重钝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，以研究三个特定目标。对于所有目的，主动和被动香烟烟雾暴露将通过经过充分验证的生物标志物进行严格量化：具体而言，血浆可替宁和尿液总4-（甲基亚硝胺）-1-（3-吡啶基）-1-丁醇（NNAL）。在目标1中，我们将测试低水平二手烟暴露与严重钝性创伤后ALI易感性之间的关联，因为我们之前的研究不足以解决这种暴露水平，这与公共卫生具有重大相关性，因为它在美国和国际上仍然很常见。在目标2中，我们将确定主动吸烟和/或二手烟暴露导致患者通过内皮和肺上皮损伤发展ALI的程度。将通过测量血浆和支气管肺泡灌洗液中的特异性、先前研究和验证的蛋白质生物标志物来定量内皮和肺上皮损伤。在目标3中，我们将确定主动吸烟和/或二手烟暴露导致患者通过增强对感染的易感性（如肺部微生物组的变化所反映的）发展ALI的程度。我们的研究小组完全有资格进行这项研究，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，表征微生物组以及我们成功合作的历史方面具有专业知识。 该项目将通过深入了解香烟烟雾如何引发患者发展ALI，为靶向和/或预防性治疗奠定基础，从而显着推进ALI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ALI病因学的影响，尚未得到很好的研究;使用生物标志物来测量重症受试者的暴露;其对预防ALI的潜在影响，这是最近NHLBI工作组的主要优先事项;以及它将提供香烟烟雾暴露对肺部微生物组的影响。 公共卫生相关性：急性肺损伤仍然是危重患者急性呼吸衰竭的常见和经常致命的原因，没有具体的预防策略或治疗方法。研究香烟烟雾暴露在急性肺损伤发展中的作用可能有助于开发新的治疗方法，包括预防方法，并将为消除被动和主动香烟烟雾暴露的公共卫生措施提供进一步的理论依据和支持。

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. PUBLIC HEALTH RELEVANCE: Acute lung injury remains a common and frequently fatal cause of acute respiratory failure in critically ill patients, with no specific preventative strategies or therapies available. Studying the role of cigarette smoke exposure in the development of acute lung injury may help develop new therapies, including preventative approaches, and will provide further rationale and support for public health measures to eliminate passive and active cigarette smoke exposure.