Cathelicidin and Vitamin D: Impact on Populations At-Risk and with COPD

 描述(由申请人提供)：了解导致肺功能下降的机制，这是包括慢性阻塞性肺疾病(COPD)在内的阻塞性肺疾病的生理特征，对于为改善肺健康的干预措施提供信息是必要的。在这项应用中，我们建议研究抗菌肽长春花素及其主要调节因子维生素D在COPD的肺功能损害、呼吸道感染和急性加重中的作用，并评价口服维生素D对人类肺长春花素水平的影响。放线菌素在肺部具有杀菌和炎症活性，并受维生素D水平的调节。我们的假设是，尽管感染增加和COPD加重部分介导了这一途径，但放线菌素水平的降低与肺功能加速下降有关。我们假设在维生素D缺乏的人中，长春花碱对肺功能的影响更大，口服维生素D补充剂将提高肺间室的长春花素水平，从而恢复肺的长春花素缺乏症。具体地说，通过在一项正在进行的队列研究中嵌套的纵向调查，我们将描述380名参与者的肺功能减退率，并进行长达六年的一系列肺活量测量。基线和重复测量长春新碱和维生素D将被视为肺功能下降和呼吸道感染的独立预测因子。另外，使用2100名参加COPD研究中的亚群和中间结果测量(SPIROMICS)研究的参与者的纵向数据，基线的血液去甲肾上腺素和维生素D测量将被检验为三年内纵向FEV1下降和COPD恶化的独立预测因素。在这两个队列中，同步的维生素D测量将允许评估先行因素和调节剂对放线菌素-肺结局关系的影响。最后，我们将测定40名维生素D缺乏者口服维生素D补充剂8周前后的血液和肺灌洗液中的青蒿素水平，以确定补充维生素D对青蒿素水平的影响。这些目标的实现将有力地确定 卡西西丁在高危和患病个体的独特人群中的肺功能下降和不良肺结局。此外，这项应用的目的直接或间接地是为了最终了解一种容易测量的血液标记物是否可以告知谁可以从维生素D补充剂中受益，以预防慢性肺部疾病。这一应用的结果将导致一项治疗性干预研究，这将为我们进一步了解维生素D、长春花碱和肺功能之间的关系提供进一步的机会。

 DESCRIPTION (provided by applicant): Understanding mechanisms leading to decrements in lung function, the physiologic hallmark of obstructive lung diseases including chronic obstructive pulmonary disease (COPD), are necessary to inform interventions to improve lung health. In this application, we propose to examine the role of the antimicrobial peptide cathelicidin, and its primary regulator vitamin D, in lung function impairment, respiratory infections and acute exacerbations of COPD as well as evaluate the effect of oral vitamin D supplementation on lung cathelicidin levels in humans. Cathelicidin has bactericidal and inflammatory activities in the lung and is regulated by vitamin D levels. Our hypothesis is that reduced cathelicidin levels are associated with accelerated lung function decline though a pathway partially mediated by increased infections and COPD exacerbations. We hypothesize the effect of cathelicidin on lung function is greater in those with vitamin D insufficiency and that oral vitamin D supplementation will raise cathelicidin levels in the pulmonary compartment, thereby restoring lung cathelicidin deficiency. Specifically, through longitudinal investigation nested within an ongoing cohort study of urban, predominantly African-American individuals at high risk for development of OLDs, we will characterize the rate of lung function decline in 380 participants followed with serial spirometry measures for up to six years. Baseline and repeated measures of cathelicidin and vitamin D will be examined as independent predictors of lung function decline and respiratory infections. Separately, using longitudinal data from 2100 participants enrolled in the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) study with established COPD, baseline measures of blood cathelicidin and vitamin D will be examined as an independent predictor of longitudinal FEV1 decline and COPD exacerbations over three years. In both cohorts, concurrent vitamin D measurements will permit evaluation of antecedent and modifier on the cathelicidin-lung outcomes relationships. Finally, we will measure blood and lung lavage cathelicidin levels in 40 vitamin D insufficient individuals before and after eight weeks of oral vitamin D supplementation to determine the effect of vitamin D supplementation on cathelicidin levels. Completion of these aims will provide a robust determination of the role of cathelicidin in lung function decline and adverse pulmonary outcomes in unique populations of at-risk and diseased individuals. Moreover, the aims of this application directly or indirectly wor towards ultimately understanding if a readily measurable blood marker, cathelicidin, can inform who may benefit from vitamin D supplementation to prevent chronic lung disease. The results from this application would lead to a therapeutic intervention study that will provide further opportunities to improve our understanding of the relationship between vitamin D, cathelicidin and lung function.