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

Cathelicidin 和维生素 D：对高危人群和 COPD 患者的影响

• 批准号: 9043948
• 负责人: Michael Bradley Drummond
• 金额: $ 1.9万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9043948
• 关键词: Acute; Acute respiratory infection; Address; African American; Area; Behavioral; Blood; Bronchoalveolar Lavage; Chemotactic Factors; Cholecalciferol; Chronic Obstructive Airway Disease; Chronic lung disease; Clinical; Cohort Studies; Collection; Cross-Sectional Studies; Data; Data Collection; Development; Enrollment; Epithelial Cells; Etiology; Evaluation; Forced expiratory volume function; Funding; HIV; HIV Infections; Health; Human; Immune response; Impairment; Individual; Infection; Inflammatory; Intervention; Intervention Studies; Investigation; Laboratories; Lead; Lung; Lung diseases; Measurable; Measurement; Measures; Mediating; Mediator of activation protein; Morbidity - disease rate; Multicenter Studies; National Heart, Lung, and Blood Institute; Obstructive Lung Diseases; Oral; Outcome; Outcome Measure; Participant; Pathway interactions; Physiological; Plasma; Population; Populations at Risk; Prevalence; Production; Pulmonary Function Test/Forced Expiratory Volume 1; Recruitment Activity; Research Design; Respiratory Tract Infections; Respiratory physiology; Risk; Role; Sampling; Severities; Skin; Smoker; Spirometry; Testing; Therapeutic; Therapeutic Intervention; Visit; Vitamin D; Vitamin D supplementation; Vitamins; bactericide; cathelicidin; cathelicidin antimicrobial peptide; cohort; follow-up; high risk; improved; macrophage; mortality; neutrophil; prevent; prospective

 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.

 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病（COPD）在内的阻塞性肺病的生理标志，对于改善肺部健康的干预措施来说是必要的。在此应用中，我们打算研究抗菌肽导管素及其主要调节剂维生素 D 在肺功能损伤、呼吸道感染和慢性阻塞性肺病急性加重中的作用，并评估口服维生素 D 补充剂对人类肺导管素水平的影响。 Cathelicidin 在肺部具有杀菌和炎症活性，并受维生素 D 水平调节。我们的假设是，导管素水平降低与肺功能加速下降有关，该途径部分由感染增加和慢性阻塞性肺病恶化介导。我们假设维生素 D 不足的患者中，导管素对肺功能的影响更大，口服维生素 D 补充剂将提高肺室中导管素的水平，从而恢复肺导管素缺乏症。具体来说，通过一项正在进行的队列研究中的纵向调查，该研究对患有老年痴呆症高风险的城市人群（主要是非洲裔美国人）进行研究，我们将描述 380 名参与者的肺功能下降率，并随后进行长达六年的连续肺功能测定。导管素和维生素 D 的基线和重复测量将作为肺功能下降和呼吸道感染的独立预测因子进行检查。另外，使用参加 COPD 研究亚群和中间结果测量 (SPIROMICS) 研究的 2100 名已确诊 COPD 参与者的纵向数据，将检查血液导管素和维生素 D 的基线测量，作为三年内纵向 FEV1 下降和 COPD 恶化的独立预测因子。在这两个队列中，同时进行维生素 D 测量将允许评估导管素与肺结果关系的前因和修饰因素。最后，我们将在口服维生素 D 补充剂八周之前和之后测量 40 名维生素 D 不足个体的血液和肺灌洗导管素水平，以确定维生素 D 补充剂对导管素水平的影响。完成这些目标将为我们的作用提供强有力的确定。 导管素在高危和患病个体的独特人群中导致肺功能下降和不良肺部结果。此外，本申请的目的直接或间接地致力于最终了解易于测量的血液标记物导管素是否可以告知谁可以从补充维生素 D 中受益以预防慢性肺病。该应用的结果将导致一项治疗干预研究，该研究将为提高我们对维生素 D、导管素和肺功能之间关系的理解提供进一步的机会。