HIV and Emphysema _ Role of Pulmonary Vascular Dysfunction

 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，其发生频率高于未感染（HIV-）患者，即使在调整吸烟史后也是如此。放射学上，我们发现肺气肿比HIV-1患者表现得更严重，更弥漫，下叶受累更严重。HIV感染背景下肺气肿的发病机制和临床过程是否与HIV感染者的肺气肿不同，目前还不完全清楚。然而，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，并且可能是主要贡献者。与此一致，我们发现可溶性CD 14水平升高与HIV+患者的肺气肿和肺功能下降有关，但与HIV-患者无关。我们对外周血白细胞中转录特征的评估表明，与具有类似DLCO的HIV-患者相比，具有低肺弥散能力（DLCO）的HIV+患者的内皮途径存在扰动。总之，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。在这个项目中，我们将检验这样一个假设，即与HIV-肺气肿患者相比，HIV+肺气肿患者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，将与内皮活化和功能障碍的生物标志物的差异相关并可能由其解释。为了验证这一假设，我们将在一项横断面研究中评估150名HIV阳性和150名HIV-当前和既往吸烟者的心肺功能和肺血管生理学差异，包括肺功能检查、胸部CT扫描、心脏MRI和心肺运动试验。我们将确定心脏，肺血管和呼吸系统的异常;它们与运动能力的关系;并描述运动限制的原因是否因HIV而异。为了通过HIV状态确定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循环标志物（包括microRNA）进行新的分析。我们的目标是：1.比较HIV+和HIV-患者与肺血管疾病相关的生理差异，调整放射学肺气肿的存在和严重程度; 2.确定肺泡和循环内皮细胞活化和功能障碍的生物标志物是否与HIV+患者和HIV-患者的肺气肿相关。这些研究的结果将使我们能够全面表征HIV+与HIV-患者肺气肿的临床和生物学差异，重点关注肺血管功能障碍的作用。了解肺气肿在艾滋病毒感染的背景下是否是独特的是至关重要的定制患者管理;开发新的预防和治疗目标;并改善患者的结果。

 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.