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（由适用提供）：COPD现在是受HIV感染（HIV+）患者最常见的合并症之一。 HIV+患者COPD的主要表型是肺气肿，即使在接受吸烟史进行调整时，它的频率比未感染（HIV-）患者的频率更高。从射线照相上，我们发现肺气肿显得比HIV患者更严重，较低的叶片受累。在艾滋病毒感染的背景下，肺气肿的发病机理和临床过程是否与HIV-个体中的肺气肿不同。然而，慢性感染，免疫反应和相关的内皮激活介导HIV+患者的其他最终器官损伤，可能是主要贡献者。与此相一致，我们发现固体CD14水平升高与HIV+中的肺气肿和肺功能下降有关，而在HIV个体中则无关。我们对外周血白细胞中的转录特征的评估表明，与患有类似DLCO的HIV患者相比，HIV+肺部分化能力低的HIV+患者的内皮途径受到扰动。综上所述，我们的初步发现表明，导致低DLCO和肺气肿的途径在HIV+个体中是不同的。在该项目中，我们将检验以下假设：与HIV-肺气肿患者相比，HIV+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，并且在生物学上将与内皮激活和功能障碍的生物标志物的差异有关，并可能与并有可能解释。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和心肺运动测试评估心肺功能和肺血管生理学的差异，并在150 HIV+和150 HIV+和150 HIV的HIV - 当前和前吸烟者中。我们将确定心脏，肺血管和通气系统的异常。他们与运动能力的关系；并描述艾滋病毒的运动限制差异是否存在。为了确定与HIV状态相关的生物学差异，我们将对支气管肺泡灌洗液蛋白质组和包括microRNA的循环标记进行新的分析。我们的目的是：1。比较HIV+和HIV患者与肺血管疾病有关的生理差异，以调整放射线性肺气肿的存在和严重程度； 2.与HIV患者相比，确定内皮激活和功能障碍的肺泡和循环生物标志物是否与HIV+的肺气肿有关。与HIV患者相比，这些研究的结果将使我们能够全面地表征HIV+肺气肿的临床和生物学差异，该患者侧重于肺血管功能障碍的作用。了解肺气肿是否在HIV感染的背景下是不同的，对于调整患者管理至关重要。开发新颖的预防和治疗靶标；并改善患者预后。