Project 4: Quantification and Biomarkers of Short-Term Pulmonary Effect p302-340

吸烟的健康后果主要被认为是癌症、心血管疾病和 慢性肺部疾病，但暴露在香烟烟雾中的急性肺部后果可能会 在吸烟的总体发病率和死亡率方面同样重要或更重要。然而，有 关于吸烟与急性肺损伤(ALI)的研究很少，ALI是#年急性呼吸衰竭的常见原因 危重病人。吸烟和二手烟暴露与近三年的- 严重钝性创伤后发生ALI的几率成倍增加，但吸烟的影响 最常见的ALI类型--感染相关性ALI的易感性暴露情况尚不清楚。这 该项目将通过量化烟草使用的不良健康后果增加我们对烟草使用的了解 感染相关性ALI易感性增加。了解吸烟和二手烟的影响 与感染相关的ALI的烟雾暴露将对烟草产品的监管产生重大影响 由于阿里的巨大直接成本负担以及卷烟变化的潜在快速影响 吸烟暴露对ALI及其相关死亡负担和成本的影响。我们假设 感染前的香烟烟雾暴露使患者发生急性肺损伤的急性呼吸衰竭。我们 将利用我们正在进行的具有严重感染的危重患者队列的基础设施 我们在ALI和香烟烟雾暴露的动物模型上的经验1)量化了强度， 剂量-反应曲线，以及测量的香烟烟雾暴露之间的关联的时间进程 经验证的生物标志物与入院重症患者ALI的发展 2)测试香烟烟雾暴露和不同尼古丁含量对糖尿病发展的影响 小鼠感染相关ALI模型，重点是确定烟草相关肺的血浆生物标志物 上皮或内皮损伤，然后可以在危重患者中进行测试；以及3)验证ASSO(：；关系 烟草相关肺上皮和内皮细胞损伤生物标志物与ALI发生发展的关系 患有严重感染的危重病人。该项目的结果将为更准确的模型提供信息 香烟烟雾暴露对经济和公共健康的影响。该项目还将确定 烟草相关性肺损伤的生物标志物，可用于未来的毒性研究，并采取关键 确定烟草烟雾的哪些成分会促进肺损伤的第一步，包括对 尼古丁和丙烯醛在烟草烟雾毒性中的作用，具有重要的调控意义。 相关性(请参阅说明！： 通过促进我们对香烟烟雾暴露与常见和 代价高昂的ALI综合征，这项研究将对FDA模型的变化产生重大影响 香烟烟雾暴露对医疗保健成本和公共健康结果的影响。这项研究还将 量化可转化为有意义变化的暴露生物标志物的变化幅度 在ALI风险中，并确定反映烟草短期肺毒性的功能生物标志物 产品，以供将来的研究使用。最后，这项研究将采取必要的第一步，以确定 香烟烟雾中对肺损伤影响最大的成分。

The health consequences of smoking are primarily perceived to be cancer, cardiovascular disease, and chronic pulmonary disease, but acute pulmonary consequences of exposure to cigarette smoke are likely to be as or more important with respect to overall morbidity and mortality from smoking. However, there has been little research on smoking and acute lung injury (ALI), a common cause of acute respiratory failure in critically ill patients. Cigarette smoking and secondhand smoke exposure are associated with a nearly three- fold increase in the odds of developing ALI after severe blunt trauma, but the effects of cigarette smoke exposure on susceptibility to infection-associated ALI, the most common type of ALI, are unknown. This project will increase our understanding ofthe adverse health consequences of tobacco use by quantifying the increased susceptibility to infection-related ALI. Understanding the impact of smoking and secondhand smoke exposure on infection-related ALI will have major implications forthe regulation of tobacco products because ofthe large immediate cost burden of ALI and the potentially rapid impact of changes in cigarette smoke exposure on the incidence of ALI and its associated mortality burden and costs. We hypothesize that cigarette smoke exposure before infection primes patients to develop acute respiratory failure from ALI. We will leverage the infrastructure of our ongoing prospective cohort of critically ill patients with severe infection and our experience with animal models of ALI and cigarette smoke exposure to 1) quantify the strength, dose-response curve, and time course of the association between cigarette smoke exposure, as measured by validated biomarkers, and the development of ALI in patients admitted to the hospital with severe infection; 2) test the effects of cigarette smoke exposure and varying nicotine content on the development of infection-related ALI in mouse models, with a focus on identifying plasma biomarkers of tobacco-related lung epithelial or endothelial injury that can then be tested in critically ill patients; and 3) validate the asso(:;iation between biomarkers of tobacco-related lung epithelial and endothelial injury and the development of ALI in critically ill human subjects with severe infection. The results ofthis project will inform more accurate models ofthe economic and public health effects of cigarette smoke exposure. This~project will also identify biomarkers of tobacco-related lung injury that can be used in future studies of toxicity and take the critical first steps towards determining which constituents of tobacco smoke promote lung injury, including studies of the roles of nicotine and acrolein in tobacco smoke toxicity, with important regulatory implications. RELEVANCE (See instructions'!: By advancing our understanding of the association between cigarette smoke exposure and the common and costly syndrome of ALI, this research will have major implications for FDA models ofthe impact of changes in cigarette smoke exposure on health care costs and public health outcomes. This research will also quantify the magnitude of change of biomarkers of exposure that can be translated into meaningful changes in ALI risk and identify functional biomarkers that reflect the short-term pulmonary toxicity of tobacco products, for use in future studies. Finally, this research will take the essential first steps towards identifying the constituents of cigarette smoke with the greatest impact on lung injury.