Endothelial mechanisms of impaired lung gas exchange by HIV

描述(申请人提供)：HIV血清阳性(HIV+)患者中最常见的疾病之一是慢性阻塞性肺疾病(COPD)，如肺气肿，约占20%。艾滋病毒现在被认为是COPD的危险因素，独立于吸烟(CS)。然而，HIV相关慢性肺部疾病的发病机制仍然知之甚少。慢性炎症和相关的内皮激活介导了HIV+患者终末器官疾病的发展，可能是COPD发病的主要因素。HIV感染最早的肺部表现之一是通过肺泡毛细血管膜的气体转移减少，反映为肺对一氧化碳(DLCO)的扩散能力降低，即使在接受抗逆转录病毒治疗(ART)的患者中也存在这种情况。在放射学上，HIV+患者的DLCO低的主要原因是肺气肿，与HIV+患者相比，肺气肿看起来更严重和弥漫，并且有更多的下叶受累。这种分布类似于在α-1抗胰蛋白酶(A1AT)缺乏的患者中发现的，这些患者在相对年轻的时候也会出现肺气肿，并随着吸烟而恶化。由于A1AT除了其抗弹性蛋白酶活性外，我们和其他人已经证明了A1AT对内皮细胞具有保护作用，相对A1AT缺陷与HIV诱导的内皮激活可能导致内皮功能障碍、DLCO减少、早期肺气肿和肺功能下降的易感性增加。因此，HIV阳性患者肺气肿的发病机制可能主要始于血管间隙，可能与HIV阳性患者的肺气肿不同。我们将检验这一假设，即HIV+患者的肺气体交换受损是由香烟烟雾协同加剧的肺微血管功能障碍解释的，并由内皮激活和功能障碍的生物标志物确定。为了验证这一假设，我们将使用一种互补的翻译方法，该方法利用了我们的多PI团队的独特优势。我们将利用现有的生物标本和来自人口统计学相似的HIV+和HIV患者的临床数据的有效研究设计，并辅之以相关的人类肺微血管内皮损伤模型的研究，这将与空气空间的蛋白质组分析相协同。这一提议将检验内皮细胞激活是气体交换受损和HIV感染中慢性肺部疾病发展的始发者这一新范式。了解气体交换受损的机制是至关重要的，因为低DLCO是HIV+患者死亡的风险因素，我们的结果可以确定新的个体化治疗的靶点，确定未来验证研究的潜在生物标志物，并为改善HIV+慢性肺病患者健康的临床试验设计提供信息。相关声明艾滋病毒感染与肺部气体交换障碍有关；这种缺陷与死亡风险增加有关。建议的研究将促进我们对艾滋病毒气体交换异常发生机制的理解，并将为开发量身定制的治疗干预措施提供信息，以改善艾滋病毒感染者的长期功能和存活率。

DESCRIPTION (provided by applicant): One of the most prevalent morbidities in HIV seropositive (HIV+) patients is chronic obstructive pulmonary disease (COPD), such as emphysema, present in ~20%. HIV is now recognized as a risk factor for COPD, independent of cigarette smoking (CS). However, the mechanisms of HIV associated chronic lung disease remain poorly understood. Chronic inflammation and the associated endothelial activation that mediate the development of end-organ disease in HIV+ patients are likely to be major contributors to COPD pathogenesis. One of the earliest detected pulmonary manifestations of HIV infection is a decrease in gas transfer across the alveolar-capillary membrane, reflected by a reduced diffusing capacity of the lung for carbon monoxide (DLCO) that is present even in individuals on antiretroviral therapy (ART). Radiographically, the predominant finding to account for low DLCO in HIV+ patients is emphysema, which appears more severe and diffuse, and with greater lower lobe involvement in HIV+ compared to HIV- patients. This distribution is similar to that found in alpha-one antitrypsin (A1AT) deficient patients, who also present with emphysema at relatively young ages and worsen with smoking. Since in addition to its antielastase activity, we and others have demonstrated that A1AT is protective to endothelial cells, relative A1AT deficiency combined with HIV induced endothelial activation may cause endothelial dysfunction, reduced DLCO, early emphysema and enhanced susceptibility to a decline in lung function. Thus, the pathogenesis of emphysema in HIV+ patients may be initiated primarily in the vascular compartment and may be distinct from that in HIV- patients. We will test the hypothesis that the impaired pulmonary gas exchange in HIV+ patients is explained by lung microvascular dysfunction synergistically aggravated by cigarette smoke and identified by biomarkers of endothelial activation and dysfunction. To test this hypothesis, we will use a complementary translational approach that takes advantage of the unique strengths of our multiple PI team. We will leverage an efficient study design using existing biospecimens and clinical data from demographically similar HIV+ and HIV- patients, complemented by studies of relevant human lung microvascular endothelial injury models that will synergize with proteomic analysis of airspaces. This proposal will test the novel paradigm that endothelial activation is an initiator o impaired gas exchange and of the development of chronic lung disease in HIV infection. Understanding the mechanisms of impaired gas exchange is essential as a low DLCO is a risk factor for death in HIV+ patients, and our results can identify targets for new individualized treatments, identify potential biomarkers for future validation studies, and inform the design of clinical trials to improve the health of HIV+ patients with chronic lung disease. Statement of Relevance HIV infection is associated with impairment in gas exchange in the lung; this defect is associated with an increased risk of death. The studies proposed will advance our understanding of the mechanisms for the development of gas exchange abnormalities in HIV, and will inform the development of tailored therapeutic interventions to improve the long-term function and survival of HIV infected individuals.