Biomarkers predictive of Lung Function Decline in physiologically Normal Smokers

 描述(由申请人提供)：烟草相关的肺部疾病，包括慢性阻塞性肺疾病(COPD)，是美国主要的死亡原因和医疗费用的主要贡献者。COPD病例传统上是用气流阻塞的肺活量阈值来定义的。虽然烟草烟雾可能会启动这些过程，但肺功能或其他与烟草相关的表型下降的易感性是高度可变的。此外，由于免疫耐受性改变等机制，肺功能可能会继续加速下降，这些机制在戒烟后仍会继续。COPD患者肺功能减退率的变化没有得到很好的描述。由于疾病的定义是基于单个肺功能的测量，而不是基于人群的标准，所以即使在肺功能研究“正常”的患者中，肺功能的下降也可能是显著的。相比之下，使用传统疾病定义被归类为肺功能异常的人可能会有反映童年甚至宫内事件的生理异常，这些异常不再活跃或进展。该项目的总体目标是开发一个综合临床、人口学、放射学和生理学参数以及生物标志物水平的模型，用于预测肺活量正常的受试者的长期肺功能下降。这一目标将通过利用基础肺功能正常的大型纵向队列吸烟者(N=1024)和中位数9年(范围4-12)的长期随访来实现。我们将根据有无长期快速肺功能下降将受试者定义为病例和对照。我们将分析一组基于队列初步数据选择的生物标记物，并进行为期2年的随访。我们将验证我们的假设，即外周血生物标志物(Ccp、C-反应蛋白、白介素6、肿瘤坏死因子α、PTX3、sFas、MMP1、TIMP1、TIMP2、TNFRI和TNFRII)与肺功能下降的比率有关，人口统计学和临床特征、外周蛋白生物标志物和其他可用的放射和生理参数相结合，将构成一套强大的预测快速肺功能下降的指标。这项研究的积极结果将使我们能够定义肺活量正常吸烟者的生物标志物特征和其他预测肺功能下降的特征。经过验证的识别战略将用于制定和测试对那些面临快速下降风险的个人的干预措施。

 DESCRIPTION (provided by applicant): Tobacco associated diseases of the lung, including chronic obstructive pulmonary disease (COPD), are a leading cause of death and a major contributor to health care costs in the United States. COPD cases are traditionally defined using spirometric thresholds of airflow obstruction. While tobacco smoke may initiate these processes, the susceptibility to decline in lung function or other tobacco associated phenotypes is highly variable. Furthermore, accelerated decline in lung function may continue due to mechanisms such as altered immune tolerance which continue after smoking cessation. The variation in the rate of lung function decline in patients with COPD is poorly described. Because disease definitions are based on single lung function measurements compared to population based standards, lung function decline may be significant even in patients with "normal" lung function studies. By contrast, individuals classified as having abnormal lung function using traditional disease definitions may have physiologic abnormalities reflective of events during childhood or even in utero which are no longer active or progressive. The project's overall goal is to develop a model integrating clinical, demographic, radiologic and physiological parameters and biomarker levels for the prediction of long-term lung function decline in spirometrically normal subjects. The goal will be accomplished by leveraging a large longitudinal cohort (N=1024) of smokers with normal baseline lung function and median long-term follow up of 9 years (range 4 -12). We will define the subjects as cases and controls based on the presence or absence of rapid long-term lung function decline. We will analyze a set of biomarkers selected based on preliminary data in a cohort with 2-year follow-up. We will test our hypotheses that peripheral blood biomarkers (CCP, CRP, IL6, TNFα, PTX3, sFAS, MMP1, TIMP1, TIMP2, TNFRI and TNFRII) are associated with rate of lung function decline and that demographic and clinical characteristics, peripheral protein biomarkers, and other available radiologic and physiologic parameters, in combination, will constitute a powerful set of predictors for rapid lung function decline. Positive results from this study will allow us to define biomarker signatures and other features in spirometrically normal smokers that predict lung function decline. The validated identification strategy will be used for development and testing of interventions in those individuals at risk for rapid decline.