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

 描述（由申请人提供）：COPD是一种HIV相关肺部疾病，是发病率和死亡率的主要原因。艾滋病毒相关慢性阻塞性肺病（HIV+COPD）的潜在机制尚不完全清楚，但已提出艾滋病毒特异性或艾滋病毒增强因素，因为很大一部分艾滋病毒+COPD发生在非吸烟者中，并且该疾病通常比COPD发病年龄更早。未感染艾滋病毒的个体。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。我们将使用由已从肺炎中恢复的HIV+受试者组成的IHOP队列，因为研究表明这些患者的肺功能下降和COPD的风险特别高。我们的中心假设是，系统性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+个体的肺功能更大程度地下降，并且微生物易位可能有助于这一过程。我们的初步数据表明，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。目标1：为了检验PBMCs和BAL中端粒长度短和/或端粒长度/端粒酶活性（TL/TA）比值低与COPD患病率增加相关的假设。目标二：检验血浆和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设。目标3：在正在进行的多中心、前瞻性HIV+队列中验证目标1和目标2中确定的标志物，并检验以下假设：确定的标志物与肺功能（FEV 1和FEV 1/FVC）的更大下降相关，并且作为次要目标，DLco的下降幅度更大并发展为COPD。目标1和2将利用现有的旧金山弗朗西斯科IHOP队列（>300例HIV+受试者）。我们将对70例COPD受试者和140例非COPD受试者进行一项横断面、巢式病例对照研究，并分析门诊研究访视的库存血液的端粒长度、TL/TA和12种免疫激活和炎症标志物，这些标志物是根据其与HIV未感染人群中COPD的相关性而选择的。我们将研究与HIV+COPD的相关性，调整年龄、性别和吸烟以及多重比较，并推导出一组候选生物标志物进行前瞻性验证。作为子目标，我们还将分析BAL中的这些标志物，并将其与IHOP研究中接受系列支气管镜检查的50例HIV+ IHOP受试者（伴或不伴COPD）的血液进行比较。目标3将使用正在进行的在旧金山弗朗西斯科、西雅图和乌干达坎帕拉的IHOP队列。我们将对600名从肺炎中恢复的HIV+受试者进行纵向队列研究，并在肺炎治疗完成后>3个月开始分析目标1和2中确定的标志物。（基线），然后每年一次直至研究完成，并将这些测量结果与在相同时间点进行的肺功能检查和胸部CT相关联，加强目标1和2中的因果推论，并为今后的治疗干预试验奠定基础。(End摘要）

 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)