Cigarette Smoke and the Acute Respiratory Distress Syndrome: The Role of Alveolar Epithelial Injury and Inflammation

 描述（由申请人提供）：急性呼吸窘迫综合征（ARDS）是发病率和死亡率的主要来源，在美国每年有近20万例病例，死亡率为30- 40%。尽管进行了大量研究，但尚未确定有效的治疗方法;因此，人们对预防策略的兴趣越来越大。吸烟暴露最近已被确定为发展为ARDS的危险因素。然而，很少有研究直接研究这种关系的潜在机制。我的初步数据表明，吸烟与基线肺泡上皮损伤增加和炎症反应加剧有关。鉴于肺泡上皮损伤和炎症在ARDS发病机制中的重要作用，这些发现鼓励我进一步研究吸烟者的这些途径。拟议的项目旨在通过研究四个不同队列中肺泡上皮损伤和炎症的血浆和支气管肺泡灌洗（BAL）生物标志物来研究香烟烟雾使患者易患ARDS的机制，其中三个队列已完成招募。我假设香烟烟雾与基线肺泡上皮损伤有关，在“二次打击”的情况下，肺泡上皮损伤使肺产生过度损伤和炎症。“在目标1中，我将测量两组健康受试者的肺泡上皮损伤和炎症的基线水平。我假设，在我的第一个队列中，这是由健康的慢性酗酒者和匹配的对照组，香烟烟雾将与基线肺泡上皮损伤（假设1a）。我假设在我的第二个队列中，由吸入脂多糖（LPS）的健康志愿者组成，香烟烟雾将与肺泡上皮损伤和炎症增加相关（假设1b）。在目标2中，我将在两个不同的有ADS风险的重症患者队列中测量肺泡上皮损伤和炎症的生物标志物，以确定香烟烟雾是否与“二次打击”（如创伤，吸入，肺炎或败血症）存在下的损伤和炎症增加相关。我假设在存在ARDS危险因素的情况下，香烟烟雾暴露与肺泡上皮损伤和炎症增加有关（假设2a和2b）。此外，我假设在继续发展为ARDS的患者中，吸烟者的上皮损伤和炎症的严重程度将更大（假设2a和2b）。这些研究有可能深入了解香烟烟雾使患者易患ARDS的机制，为未来预防和针对性治疗ARDS策略奠定基础。

 DESCRIPTION (provided by applicant): The acute respiratory distress syndrome (ARDS) is a major source of morbidity and mortality, with nearly 200,000 cases annually in the US and a mortality of 30-40%. Despite significant research, no effective treatments have been identified; consequently, there has been increased interest in preventative strategies. Cigarette smoke exposure has recently been identified as a risk factor for the development of ARDS. However, few studies have directly examined the potential mechanisms that underlie this relationship. My preliminary data suggests that cigarette smoke is associated with increased baseline alveolar epithelial injury and an exaggerated inflammatory response. Given the significant role that alveolar epithelial injury and inflammation play in the pathogenesis of ARDS, these findings have encouraged me to further study these pathways in cigarette smokers. The proposed project aims to investigate the mechanisms through which cigarette smoke predisposes patients to develop ARDS by studying plasma and bronchoalveolar lavage (BAL) biomarkers of alveolar epithelial injury and inflammation in four distinct cohorts, three of which have completed enrollment. I hypothesize the cigarette smoke is associated with baseline alveolar epithelial injury that primes the lung to develop excessive injury and inflammation in the presence of a "second-hit." In Aim 1, I will measure baseline levels of alveolar epithelial injury and inflammation in two cohorts of healthy subjects. I hypothesize that in my first cohort, which is comprised of otherwise healthy chronic alcoholics and matched controls, that cigarette smoke will be associated with baseline alveolar epithelial injury (Hypothesis 1a). I hypothesize that in my second cohort, which consists of healthy volunteers undergoing inhalation of lipopolysaccharide (LPS), cigarette smoke will be associated with increased alveolar epithelial injury and inflammation (Hypothesis 1b). In Aim 2, I will measure biomarkers of alveolar epithelial injury and inflammation in two distinct cohorts of critically ill patients at risk for ADS to determine if cigarette smoke is associated with increased injury and inflammation in the presence of a "second-hit," such as trauma, aspiration, pneumonia or sepsis. I hypothesize that in the presence of a risk factor for ARDS, cigarette smoke exposure will be associated with increased alveolar epithelial injury and inflammation (Hypotheses 2a & 2b). In addition, I hypothesize that in patients who go on to develop ARDS, the severity of epithelial injury and inflammation will be greater amongst cigarette smokers (Hypotheses 2a & 2b). These studies have the potential to provide insight into the mechanisms by which cigarette smoke predisposes patients to ARDS, laying the groundwork for future prevention and targeted treatment strategies for ARDS.