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: 8915896
• 负责人: Kristina Anne Crothers
• 金额: $ 57.29万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 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 2015-06-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8915896
• 关键词: Accounting; Acute-Phase Proteins; Age; Alveolar; Apoptosis; Apoptotic; Area; Biological Markers; Blood Vessels; Blood capillaries; Carbon Monoxide; Cells; Cessation of life; Chest; Chronic; Chronic Obstructive Airway Disease; Chronic lung disease; Clinical Data; Clinical Trials Design; Complement; Data; Defect; Development; Diffuse; Disease; Elastases; Endothelial Cells; Epithelial Cells; Functional disorder; Future; Gases; HIV; HIV Infections; Health; Homeostasis; Human; Impairment; Individual; Inflammation; Inflammatory; Injury; Lead; Link; Lobe; Lung; Lung Capacity; Mediating; Membrane; Microvascular Dysfunction; Modeling; Morbidity - disease rate; Obstruction; Organ; Pathogenesis; Pathway interactions; Patients; Peptide Hydrolases; Phenotype; Plasma; Play; Post-Translational Protein Processing; Predisposition; Protein C Inhibitor; Proteome; Proteomics; Publishing; Pulmonary Emphysema; Pulmonary Function Test/Forced Expiratory Volume 1; Pulmonary Gas Exchange; Relative (related person); Reporting; Research Design; Respiratory physiology; Risk; Risk Factors; Role; Serpins; Smoking; Testing; Therapeutic Intervention; alveolar destruction; antiretroviral therapy; capillary; cigarette smoking; cigarette smoking; endothelial dysfunction; functional loss; improved; injured airway; novel; respiratory gas; translational approach; validation studies

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（由申请人提供）：HIV血清阳性（HIV+）患者中最普遍的病因之一是慢性阻塞性肺疾病（COPD），例如肺气肿，含量为约20％。现在，艾滋病毒被公认为COPD的危险因素，独立于吸烟（CS）。然而，艾滋病毒相关的慢性肺疾病的机制仍然鲜为人知。慢性炎症和相关的内皮激活，介导HIV+患者最终器官疾病发展的相关内皮激活可能是COPD发病机理的主要因素。 HIV感染最早检测到的肺部表现之一是跨肺泡毛细血管膜的气体转移减少，这反映出，即使在抗逆转录病毒疗法（ART）上，肺肺部肺部的扩散能力（DLCO）也会降低。从射线照相上，在HIV+患者中解释低DLCO的主要发现是肺气肿，与HIV患者相比，在HIV+较低的HIV+参与度更高，并且比HIV患者更低。该分布与α-抗抗胰蛋白酶（A1AT）缺乏的患者相似，他们在相对年轻的年龄也出现肺气肿，并随着吸烟而恶化。由于除了其抗冲突活性外，我们和其他人还证明了A1AT对内皮细胞具有保护性，因此相对A1AT缺乏与HIV诱导的内皮内皮激活相结合可能会导致内皮功能障碍，DLCO降低，早期肺气肿和对肺功能下降的易感性增强。因此，HIV+患者中肺气肿的发病机理可能主要在血管室中启动，并且可能与HIV患者不同。我们将检验以下假设：HIV+患者中肺气交换受损的假设通过肺部微血管功能障碍协同散发出烟雾烟雾，并由内皮激活和功能障碍的生物标志物鉴定出来。为了检验这一假设，我们将使用一种互补的翻译方法来利用我们多个PI团队的独特优势。我们将利用现有的生物测量和来自人口统计学相似的HIV+和HIV患者的临床数据来利用有效的研究设计，并通过对相关的人类肺微血管内皮损伤模型的研究补充，这些模型将通过空域的蛋白质组学分析协同作用。该提案将测试新的范式，即内皮激活是一种引发剂O受损的气体交换和HIV感染中慢性肺部疾病的发展。理解气体交换受损的机制至关重要，因为低DLCO是艾滋病毒+患者死亡的危险因素，我们的结果可以识别新的个性化治疗方法的靶标，确定潜在的生物标志物，用于未来的验证研究，并为临床试验的设计提供了改善HIV+患者健康的临床试验。相关性艾滋病毒感染与肺气交换中的损伤有关；该缺陷与死亡风险增加有关。提出的研究将促进我们对HIV中气体交换异常发展机制的理解，并将告知量身定制的治疗干预措施的发展，以改善HIV感染者的长期功能和生存。