Inflammation, Aging, Microbes, and Obstructive Lung Disease (I AM OLD) Study

 描述(由申请人提供)：慢性阻塞性肺病是一种与艾滋病毒相关的肺部疾病，是导致发病率和死亡率的主要原因。艾滋病毒相关性慢性阻塞性肺疾病(HIV+COPD)的发病机制尚不完全清楚，但已经提出了艾滋病毒特有或艾滋病毒增强因素，因为相当大比例的艾滋病毒+COPD发生在不吸烟的人中，而且在未感染艾滋病毒的人中，这种疾病通常比COPD发展得更早。我们的研究将调查广泛的潜在机制和一套全面的生物标志物。我们将使用我们的IHOP队列，该队列由肺炎康复的HIV+患者组成，因为研究表明，这些患者肺功能下降和慢性阻塞性肺病的风险特别高。我们的中心假设是，系统免疫激活和炎症以及以端粒缩短为特征的功能性PBMC缺陷导致HIV+患者肺功能的更大下降，微生物易位可能参与了这一过程。我们的初步数据显示，在我们的IHOP队列中，PBMC端粒长度缩短和血浆IL-6水平升高与COPD相关的强烈趋势。目的1：验证PBMCs和BAL中端粒长度较短和/或端粒长度/端粒酶活性(TL/TA)比值较低与COPD患病率增加的假设。目的：验证血浆和BAL中选定的免疫激活和炎症标志物与COPD患病率增加相关的假说。目的3：在一个正在进行的多中心预期HIV+队列中验证AIMS 1和2中确定的标志物，并检验已确定的标志物与肺功能(FEV1和FEV1/FVC)的更大下降相关的假设，以及作为次要目标的DLCO更大的下降和COPD的发展。AIMS 1和2将利用旧金山IHOP现有的&gt；300名HIV+受试者。我们将对70名COPD患者和140名非COPD患者进行横断面嵌套病例对照研究，并分析从门诊研究访问中收集的血液端粒长度、TL/TA和12个免疫激活和炎症标记物，以确定它们与HIV非感染人群中COPD的相关性。我们将调查与HIV+COPD的相关性，调整年龄、性别、吸烟和多重比较，并得出一组候选生物标记物，以进行前瞻性验证。作为一个子目标，我们还将分析BAL中的这些标志物，并将它们与50名患有和不患有COPD的HIV+IHOP患者的血液进行比较，这些患者接受了IHOP研究的连续支气管镜检查。AIM 3将使用正在进行的IHOP在旧金山、西雅图和乌干达坎帕拉的队列。我们将对600名肺炎康复者进行纵向队列研究，并分析AIMS 1和2中确定的标志物，从肺炎治疗完成后3个月(基线)开始，然后每年分析，直到研究完成，并将这些测量与同时进行的肺功能测试和胸部CT相关联，加强AIMS 1和2中的因果推断，为未来的治疗干预试验奠定基础。(摘要结束)

 DESCRIPTION (provided by applicant): COPD is an HIV-associated lung disease and a leading cause of morbidity and mortality. The mechanisms underlying HIV-associated COPD (HIV+COPD) are incompletely understood but HIV-specific or HIV-enhanced factors have been suggested as a substantial proportion of HIV+COPD occur in non-smokers and the disease typically develops at an earlier age than COPD in HIV-uninfected individuals. Our study will investigate a wide- range of potential mechanisms and a comprehensive set of biomarkers. We will use our IHOP cohort composed of HIV+ subjects who have recovered from pneumonia as studies indicate that these patients are at an especially high-risk for a greater decline in lung function and COPD. Our central hypothesis is that systemic immune activation and inflammation and functional PBMC defects characterized by shortened telomeres contribute to a greater decline in lung function in HIV+ individuals, and that microbial translocation may contribute to this process. Our preliminary data demonstrate a strong trend for shortened PBMC telomere length and elevated plasma IL-6 levels to be associated with COPD in our IHOP cohort. Aim 1: To test the hypothesis that short telomere length and/or low telomere length/telomerase activity (TL/TA) ratio in PBMCs and BAL are associated with an increased prevalence of COPD. Aim 2: To test the hypothesis that selected markers of immune activation and inflammation in plasma and BAL are associated with an increased prevalence of COPD. Aim 3: To validate the markers identified in Aims 1 & 2 in an ongoing multicenter, prospective HIV+ cohort and to test the hypothesis that the identified markers are associated with a greater decline in lung function (FEV1 and FEV1/FVC) and, as secondary aims, with a greater decline in DLco and development of COPD. Aims 1 & 2 will leverage the existing San Francisco IHOP cohort of >300 HIV+ subjects. We will conduct a cross-sectional, nested case-control study of 70 subjects with COPD and 140 subjects without COPD and analyze banked blood from an outpatient study visit for telomere length, TL/TA, and 12 markers of immune activation and inflammation, selected for their association with COPD in HIV- uninfected populations. We will investigate associations with HIV+COPD, adjusting for age, sex, and smoking and for multiple comparisons, and derive a set of candidate biomarkers to validate prospectively. As a sub-aim, we will also analyze these markers in BAL and compare them to blood from 50 HIV+ IHOP subjects with and without COPD undergoing serial bronchoscopies for an IHOP study. Aim 3 will use the ongoing IHOP cohorts in San Francisco, Seattle, and Kampala, Uganda. We will conduct a longitudinal cohort study of 600 HIV+ subjects recovered from pneumonia and analyze the markers identified in Aims 1 & 2 beginning >3 months after completion of pneumonia treatment (baseline) and then annually until study completion and correlate these measurements with lung function tests and chest CT performed at the same time-points, strengthening the causal inferences in Aims 1 & 2 and setting the foundation for future trials of therapeutic interventions. (End of Abstract)