HIV and Emphysema _ Role of Pulmonary Vascular Dysfunction

 描述(申请人提供)：慢性阻塞性肺病现在是HIV感染(HIV+)患者中最常见的诊断合并症之一。在HIV+患者中，COPD的主要表型是肺气肿，即使调整了吸烟史，这种情况也比未感染(HIV-)患者更常见。在放射学上，我们发现肺气肿比HIV患者更严重和弥漫，下叶受累更多。人类免疫缺陷病毒感染背景下的肺气肿的发病机制和临床病程是否与人类免疫缺陷病毒感染者的肺气肿不同尚不完全清楚。然而，慢性炎症、免疫激活和相关的内皮激活介导了HIV+患者的其他终末器官损伤，可能是主要因素。与此一致，我们发现在HIV+患者中，可溶性CD14水平的升高与肺气肿和肺功能下降有关，但在HIV携带者中没有。我们对外周血白细胞转录信号的评估表明，与具有相似肺弥散能力(DLCO)的HIV+患者相比，具有低肺弥散能力(DLCO)的HIV+患者的内皮通路发生了扰动。综上所述，我们的初步发现表明，在HIV+的个体中，导致低DLCO和肺气肿的途径是不同的。在这个项目中，我们将检验这一假设，即HIV阳性的肺气肿患者与HIV阳性的肺气肿患者相比，有更严重的肺血管功能障碍。我们怀疑这将表现为肺血管疾病患病率和表型的生理学差异，从生物学上讲，这将与内皮激活和功能障碍的生物标志物的差异有关，并可能被其解释。为了验证这一假设，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。这项横断面研究涉及150名HIV+患者和150名艾滋病毒携带者和曾经吸烟者。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；并描述运动受限的原因是否因艾滋病毒而不同。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包括microRNAs在内的循环标志物进行新的分析。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学差异，调整放射学肺气肿的存在和严重程度；2.确定与HIV+患者相比，肺泡和循环内皮细胞激活和功能障碍的生物标志物是否与肺气肿相关。这些研究的结果将使我们能够全面描述与HIV+患者相比，HIV+患者肺气肿的临床和生物学差异，重点放在肺血管功能障碍的作用上。了解肺气肿是否在艾滋病毒感染的背景下是不同的，对于定制患者管理、开发新的预防和治疗目标以及改善患者结果至关重要。

 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.