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

吸烟对健康的影响主要被认为是癌症、心血管疾病和 慢性肺病，但暴露于香烟烟雾的急性肺部后果可能 对于吸烟导致的总体发病率和死亡率来说，这一点同样重要，甚至更为重要。但一直 关于吸烟和急性肺损伤（ALI）的研究很少，ALI是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个- 严重钝伤后发生ALI的几率增加了一倍，但吸烟的影响 暴露对感染相关ALI（最常见的ALI类型）易感性的影响尚不清楚。这 该项目将通过量化烟草使用对健康的不良影响， 感染相关性ALI的易感性增加。了解吸烟和二手烟的影响 吸烟对感染相关性ALI的影响将对烟草制品的监管产生重大影响， 由于急性肺损伤的巨大直接成本负担和卷烟变化的潜在快速影响， 烟雾暴露对ALI发病率及其相关死亡负担和费用的影响。我们假设 在感染前暴露于香烟烟雾使患者容易发展为急性呼吸衰竭。我们 将利用我们正在进行的重症感染患者前瞻性队列的基础设施， 我们对ALI和香烟烟雾暴露的动物模型的经验是：1）量化强度， 剂量-反应曲线，以及香烟烟雾暴露之间的相关性的时间过程，如测量的 通过验证的生物标志物，以及严重急性肺损伤患者入院后的ALI发展， 感染; 2）测试香烟烟雾暴露和不同尼古丁含量对发展的影响， 小鼠模型中感染相关的ALI，重点是鉴定烟草相关肺的血浆生物标志物 然后可以在危重患者中测试上皮或内皮损伤;以及3）验证该阿索（：;iation 烟草相关的肺上皮和内皮损伤的生物标志物与急性肺损伤的发生之间的关系， 严重感染的危重人类受试者。该项目的结果将为更准确的模型提供信息 吸烟对经济和公众健康的影响。该~项目还将确定 烟草相关肺损伤的生物标志物，可用于未来的毒性研究， 确定烟草烟雾中哪些成分会促进肺损伤的第一步， 尼古丁和丙烯醛在烟草烟雾毒性中的作用，具有重要的监管意义。 相关性（参见注意事项！： 通过提高我们对香烟烟雾暴露与常见和 昂贵的ALI综合征，这项研究将对FDA模型的变化产生重大影响 吸烟对医疗保健成本和公共卫生结果的影响。这项研究也将 量化暴露生物标志物的变化幅度，并将其转化为有意义的变化 在急性肺损伤的风险和识别功能生物标志物，反映了烟草的短期肺毒性 产品，用于未来的研究。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.