HIV and Emphysema _ Role of Pulmonary Vascular Dysfunction

HIV 和肺气肿 _ 肺血管功能障碍的作用

• 批准号: 9109018
• 负责人: Kristina Anne Crothers
• 金额: $ 69.84万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9109018
• 关键词: Address; Alveolar; Area; Biological; Biological Markers; Blood Vessels; Bronchoalveolar Lavage Fluid; CD14 Antigen; CD14 gene; Cardiac; Cardiopulmonary; Chest; Chronic; Chronic Obstructive Airway Disease; Clinical; Comorbidity; Cross-Sectional Studies; Data; Diagnosis; Diffuse; Dimensions; EFRAC; Epidemic; Etiology; Exercise; Exercise stress test; Forced expiratory volume function; Fractals; Functional disorder; Future; Gases; Gene Expression Profile; HIV; HIV Infections; Health; Individual; Inflammation; Leukocytes; Lobe; Lung; Lung diseases; Magnetic Resonance Imaging; Measures; Mediating; MicroRNAs; Molecular; Obstruction; Organ; Outcome; Pathogenesis; Pathway interactions; Patient-Focused Outcomes; Patients; Pattern; Phenotype; Physiological; Physiology; Prevalence; Proteome; Proteomics; Pulmonary Emphysema; Pulmonary Function Test/Forced Expiratory Volume 1; Pulmonary function tests; Resistance; Respiratory physiology; Rest; Right ventricular structure; Risk; Risk Factors; Role; Severities; Smoker; Smoking History; System; Testing; Vascular Diseases; Ventricular; X-Ray Computed Tomography; antiretroviral therapy; circulating biomarkers; circulating microRNA; clinically relevant; exercise capacity; immune activation; improved; injured airway; new therapeutic target; novel; patient stratification; peripheral blood; programs; public health relevance; pulmonary function; therapeutic target

 DESCRIPTION (provided by applicant): COPD is now one of the most commonly diagnosed comorbidities in HIV infected (HIV+) patients. The predominant phenotype of COPD in HIV+ patients is emphysema, which occurs more frequently than in uninfected (HIV-) patients, even when adjusted for smoking history. Radiographically, we have found that emphysema appears more severe and diffuse with greater lower lobe involvement than in HIV- patients. Whether the pathogenesis and clinical course of emphysema in the context of HIV infection are distinct from emphysema in HIV- individuals is not fully understood. However, chronic inflammation, immune activation and associated endothelial activation mediate other end-organ damage in HIV+ patients and are likely to be major contributors. Consistent with this, we found that elevated levels of soluble CD14 are associated with emphysema and decline in lung function in HIV+, but not in HIV- individuals. Our assessment of transcriptional signatures in peripheral blood leukocytes suggested perturbations in endothelial pathways in HIV+ patients with low lung diffusing capacity (DLCO) compared to HIV- patients with similar DLCO. Taken together, our preliminary findings suggest that pathways leading to a low DLCO and emphysema are distinct in HIV+ individuals. In this project, we will test the hypothesis that HIV+ patients with emphysema, compared to HIV- patients with emphysema, have a greater degree of pulmonary vascular dysfunction. We suspect that this will manifest as physiologic differences in the prevalence and phenotype of pulmonary vascular disease, and biologically, will be associated with and potentially explained by differences in biomarkers of endothelial activation and dysfunction. To test this hypothesis, we will evaluate differences in cardiopulmonary function and pulmonary vascular physiology using pulmonary function tests, chest CT scans, cardiac MRI and cardiopulmonary exercise testing in a cross-sectional study of 150 HIV+ and 150 HIV- current and former smokers. We will determine abnormalities in the cardiac, pulmonary vascular and ventilatory systems; their relationship to exercise capacity; and delineate whether the cause for exercise limitation differs by HIV. To determine biologic differences associated with emphysema by HIV status, we will conduct novel analyses of the bronchoalveolar lavage fluid proteome and circulating markers including microRNAs. Our aims are to: 1. Compare physiologic differences related to pulmonary vascular disease in HIV+ and HIV- patients, adjusting for the presence and severity of radiographic emphysema; 2. Determine whether alveolar and circulating biomarkers of endothelial activation and dysfunction are associated with emphysema in HIV+ compared to HIV- patients. Results of these studies will allow us to comprehensively characterize clinical and biological differences in emphysema in HIV+ compared to HIV- patients with a focus on the role of pulmonary vascular dysfunction. Understanding whether emphysema is distinct in the context of HIV infection is crucial to tailoring patient management; developing novel preventative and therapeutic targets; and improving patient outcomes.

 描述（由申请人提供）：COPD 目前是 HIV 感染 (HIV+) 患者中最常诊断的合并症之一 HIV+ 患者中 COPD 的主要表型是肺气肿，甚至比未感染 (HIV-) 患者更常见。根据吸烟史进行调整后，我们发现，与 HIV 患者相比，肺气肿显得更加严重和弥漫，下肺叶受累程度也更大。 HIV感染者的肺气肿与HIV-个体的肺气肿不同，但尚不完全清楚，慢性炎症、免疫激活和相关的内皮激活介导HIV+患者的其他终末器官损伤，并且可能是主要因素。我们发现，可溶性 CD14 水平升高与 HIV 阳性个体的肺气肿和肺功能下降有关，但与 HIV 阴性个体无关。我们对外周血白细胞转录特征的评估表明，内皮细胞受到干扰。与具有相似 DLCO 的 HIV-患者相比，具有低肺扩散能力 (DLCO) 的 HIV+ 患者的途径 综上所述，我们的初步研究结果表明，导致低 DLCO 和肺气肿的途径在 HIV+ 个体中是不同的。与患有肺气肿的艾滋病毒患者相比，患有肺气肿的艾滋病毒阳性患者具有更大程度的肺血管功能障碍，我们怀疑这将表现为肺血管疾病的患病率和表型的生理差异。从生物学上讲，这些差异与内皮激活和功能障碍的生物标志物的差异有关，并可能由其解释。为了检验这一假设，我们将使用肺功能测试、胸部 CT 扫描、心脏 MRI 和心肺运动测试来评估心肺功能和肺血管生理学的差异。对 150 名 HIV 感染者和 150 名 HIV 感染者进行横断面研究，我们将确定其心脏、肺血管和通气系统异常与运动能力的关系；为了确定 HIV 状态与肺气肿相关的生物学差异，我们将对支气管肺泡灌洗液蛋白质组和包括 microRNA 在内的循环标记物进行新的分析。 2. 确定肺泡和循环内皮细胞激活的生物标志物是否存在；与 HIV- 患者相比，HIV+ 和功能障碍与肺气肿相关。这些研究结果将使我们能够全面描述 HIV+ 与 HIV- 患者肺气肿的临床和生物学差异，重点了解肺血管功能障碍是否在其中发挥作用。肺气肿在艾滋病毒感染的情况下是独特的，这对于制定新的预防和治疗目标以及改善患者的治疗效果至关重要；