Endothelial mechanisms of impaired lung gas exchange by HIV

HIV导致肺气体交换受损的内皮机制

• 批准号: 9109811
• 负责人: Kristina Anne Crothers
• 金额: $ 11.07万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-11 至 2016-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9109811
• 关键词: Endothelial; mechanisms; impaired; lung; gas

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.

描述（由申请方提供）：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%。HIV现在被认为是COPD的一个危险因素，与吸烟无关。然而，艾滋病毒相关的慢性肺部疾病的机制仍然知之甚少。慢性炎症和相关的内皮活化介导HIV+患者终末器官疾病的发展，可能是COPD发病机制的主要因素。HIV感染的最早检测到的肺部表现之一是通过肺泡毛细血管膜的气体转移减少，这反映在肺对一氧化碳（DLCO）的扩散能力降低，即使在接受抗逆转录病毒治疗（ART）的个体中也存在这种情况。影像学上，HIV+患者DLCO较低的主要原因是肺气肿，与HIV-患者相比，HIV+患者肺气肿更严重、更弥漫，下叶受累更严重。这种分布与α-1抗胰蛋白酶（A1 AT）缺乏患者中发现的分布相似，后者也在相对年轻的年龄出现肺气肿，并因吸烟而恶化。由于除了抗弹性蛋白酶活性外，我们和其他人已经证明A1 AT对内皮细胞具有保护作用，相对A1 AT缺乏与HIV诱导的内皮活化结合可能导致内皮功能障碍、DLCO降低、早期肺气肿和对肺功能下降的易感性增强。因此，HIV阳性患者肺气肿的发病机制可能主要在血管室中启动，并且可能与HIV阴性患者不同。我们将检验以下假设：HIV+患者的肺气体交换受损是由吸烟协同加重的肺微血管功能障碍解释的，并由内皮活化和功能障碍的生物标志物鉴定。为了验证这一假设，我们将使用一种互补的翻译方法，利用我们多个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上相似的HIV+和HIV-患者的临床数据进行有效的研究设计，并辅之以相关人类肺微血管内皮损伤模型的研究，这些模型将与空气空间的蛋白质组学分析协同作用。这项建议将测试新的范式，即内皮细胞活化是一个启动器受损的气体交换和发展的慢性肺部疾病的艾滋病毒感染。了解气体交换受损的机制至关重要，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性化治疗的目标，为未来的验证研究确定潜在的生物标志物，并为临床试验的设计提供信息，以改善HIV+慢性肺病患者的健康。HIV感染与肺部气体交换受损有关;这种缺陷与死亡风险增加有关。拟议的研究将促进我们对艾滋病毒气体交换异常发展机制的理解，并将为制定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生存。