Translational evaluation of aging, inflammation, and HIV in lung dysfunction

肺功能障碍中衰老、炎症和 HIV 的转化评估

• 批准号: 8877628
• 负责人: Alison Morris
• 金额: $ 67.85万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-04 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8877628
• 关键词: AIDS/HIV problem; Affect; Age; Aging; Anti-Retroviral Agents; Biological; Biological Markers; Blood; C-reactive protein; CD4 Lymphocyte Count; Carbon Monoxide; Cell Aging; Cells; Chest; Chronic; Chronic Obstructive Airway Disease; Clinical Data; Complication; Controlled Study; Cytokine Network Pathway; Data; Decision Trees; Development; Diffuse; Disease; Drug usage; Enrollment; Epidemiology; Epithelial Cells; Evaluation; Functional disorder; Goals; HIV; Health; Illicit Drugs; Immune; Immunosuppression; Individual; Infection; Inflammation; Inflammatory; Injury; Interleukin-6; Interleukin-8; Knowledge; Length; Link; Lung; Lung diseases; Lymphocyte; Obstructive Lung Diseases; Outpatients; Participant; Pathogenesis; Pattern; Peripheral; Persons; Phenotype; Physiological; Play; Positioning Attribute; Prevalence; Prevention; Public Health; Pulmonary function tests; Recruitment Activity; Relative (related person); Research; Respiratory physiology; Risk; Risk Factors; Sampling; Site; Smoker; Smoking; Specimen; Symptoms; T-Lymphocyte; Telomere Shortening; Testing; Time; Translating; Tumor Necrosis Factor-alpha; Up-Regulation; Work; X-Ray Computed Tomography; age effect; age related; airway obstruction; body system; cell age; cigarette smoking; clinically relevant; co-infection; cohort; cytokine; disease phenotype; human TNF protein; immune activation; lung development; mortality; multidisciplinary; never smoker; normal aging; novel; personalized care; personalized medicine; prevent; pulmonary function; repaired; respiratory; response; senescence; telomere; therapy development; treatment effect

DESCRIPTION: Despite a long list of organ systems adversely affected by aging in HIV, the lung remains relatively understudied, and combined effects of aging and HIV on the lung are unknown. Development of chronic obstructive pulmonary disease (COPD) may be accelerated in HIV despite antiretroviral treatment (ART). Average age of HIV+ individuals with COPD in our cohorts is 51 years compared to 61 years in our HIV- controls (p<0.001 adjusted for smoking). Lung disease may be a novel HIV-associated non-AIDS (HANA) complication related to aging, but rigorously controlled studies have not been performed. Aging in HIV is linked to cellular senescence and maladaptive inflammation. Senescence of lung and immune cells has been implicated in COPD in persons without HIV, but has not been investigated in HIV COPD. Our preliminary data demonstrate 1) increases in senescent and activated systemic T cells, 2) telomere shortening in blood lymphocytes, and 3) increases in peripheral and lung cytokines in HIV COPD; therefore, we hypothesize that aging is important in HIV COPD. Distinct phenotypes are increasingly being recognized as critical in understanding COPD pathogenesis. Our work indicates that HIV+ individuals commonly have different COPD phenotypes. Over 70% of outpatients manifest at least one abnormality with certain abnormalities associated with a greater burden of respiratory symptoms and with mortality. The relative importance of aging and inflammation in these phenotypes has not been examined, and peripheral biomarkers of phenotypes are unknown. Overall goals of the proposal are to evaluate the impact of aging on lung function in HIV, to test the novel hypothesis that COPD in HIV is a manifestation of immune cell and lung cell aging, and to determine peripheral biomarkers of aging and inflammation in HIV COPD. We will test these hypotheses with the following aims: Aim 1. To test the hypothesis that aging modifies the risk of pulmonary dysfunction in HIV+ individuals. Aim 2. To test the hypothesis that immune cell and lung cellular aging are increased in HIV COPD. Aim 3. To establish the significance of patterns of peripheral inflammatory cytokines (the "inflammome") in HIV-associated lung disease. We will recruit HIV+ and HIV- participants from ongoing cohorts with enrichment of individuals over the age of 50. We will examine pulmonary function changes over time and the relationship of pulmonary function to peripheral and pulmonary markers of senescence and inflammation. We are uniquely positioned to investigate lung aging in HIV as we have established cohorts of >600 HIV+ and HIV- participants with thorough physiologic characterization and biological samples. The proposal will fill the gap in knowledge of pulmonary effects of physiologic and cellular aging in HIV and is directly responsive to PA-12-175 (Multidisciplinary Studies of HIV/AIDS and Aging). Results will enhance understanding of pulmonary aging and translate into improvements in prevention and management of HIV pulmonary disease.

描述：尽管有很多器官系统对艾滋病毒的衰老不利影响，但肺部仍然相对研究，并且衰老和艾滋病毒对肺部的综合作用尚不清楚。尽管抗逆转录病毒治疗（ART），慢性阻塞性肺疾病（COPD）仍可能在HIV中加速。我们队列中患有COPD的HIV+个体的平均年龄为51岁，而在我们的HIV对照中为61岁（P <0.001进行了吸​​烟调整）。肺部疾病可能是与衰老有关的新型HIV相关的非AID（HANA）并发症，但尚未进行严格控制的研究。 HIV衰老与细胞衰老和适应不良的炎症有关。肺和免疫细胞的衰老与没有HIV的人有关COPD，但尚未在HIV COPD中进行研究。我们的初步数据表明1）衰老和活化的全身T细胞增加，2）血液淋巴细胞的端粒缩短，3）HIV COPD中周围和肺细胞因子的增加；因此，我们假设衰老在HIV COPD中很重要。不同的表型越来越多地被认为是理解COPD发病机理的关键。我们的工作表明HIV+个体通常具有不同的COPD表型。超过70％的门诊患者至少表现出一种异常，并且与更大的呼吸道症状和死亡率负担相关。尚未研究这些表型中衰老和炎症的相对重要性，并且表型的外周生物标志物尚不清楚。该提案的总体目标是评估衰老对HIV中肺功能的影响，以检验新的假设，即HIV中的COPD是免疫细胞和肺部衰老的表现，并确定HIV COPD中衰老和炎症的外围生物标志物。我们将以以下目的检验这些假设：目的1。测试衰老会改变HIV+个体肺功能障碍的风险的假设。 目的2。测试HIV COPD中免疫细胞和肺细胞衰老增加的假设。 目的3。建立周围炎症细胞因子（“炎症”）在与HIV相关的肺部疾病中的重要性。我们将招募来自正在进行的人群中的HIV+和HIV参与者，其中50岁以上的个体富集。我们将随着时间的推移检查肺功能变化，以及肺功能与衰老和炎症的外周和肺标志物的关系。由于我们已经建立了> 600 HIV+和HIV参与者的同类，因此我们可以独特地研究HIV中的肺老化。该提案将填补HIV生理和细胞衰老肺影响的知识的差距，并直接对PA-12-175（HIV/AIDS和衰老的多学科研究）直接反应。结果将增强对肺衰老的理解，并转化为预防和治疗HIV肺部疾病的改善。