HIV+ Alveolar Macrophage Oxidant-mediated Apoptosis of Pulmonary Endothelium

HIV肺泡巨噬细胞氧化介导的肺内皮细胞凋亡

• 批准号: 9338282
• 负责人: RONALD G CRYSTAL
• 金额: $ 74.49万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-26 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9338282
• 关键词: Adverse effects; Age; Alveolar Macrophages; Anti-Retroviral Agents; Apoptosis; Apoptotic; Biological Markers; Blood capillaries; Bronchoalveolar Lavage Fluid; Cells; Cellular biology; Characteristics; Chronic; Chronic Obstructive Airway Disease; Coculture Techniques; Computational Biology; Crystallization; Data; Development; Endothelial Cells; Endothelium; Epithelial; Flow Cytometry; Funding; Generations; Genetic Medicine; Goals; HIV; HIV Infections; HIV-1; High Resolution Computed Tomography; Highly Active Antiretroviral Therapy; Human; In Vitro; Incidence; Individual; Inflammatory; Knowledge; Liquid substance; Lower respiratory tract structure; Lung; Mass Spectrum Analysis; Mediating; Medicine; Methodology; Modeling; Molecular Target; Mononuclear; Morbidity - disease rate; Oxidants; Oxides; Pathogenesis; Peptide Hydrolases; Phagocytes; Pharmaceutical Preparations; Pharmacology; Phenotype; Plasma; Population; Process; Proteins; Pulmonary Emphysema; Recording of previous events; Respiratory physiology; Risk; Sampling; Signal Transduction; Smoker; Smoking; Sorting - Cell Movement; System; United States National Institutes of Health; alveolar destruction; base; capillary; cigarette smoking; cohort; drug testing; experience; interdisciplinary approach; metabolome; metabolomics; non-smoker; oxidant stress; oxidation; prevent; programs; public health relevance; statistics; tool; transcriptome

DESCRIPTION (provided by applicant): Despite the increased survival of individuals with HIV-1 (HIV) infection resulting from the use of highly active antiretroviral therapy (HAART), individuals infected with HIV have an increased risk for the development of chronic obstructive pulmonary disease, manifesting as emphysema. The emphysema occurs at an earlier age than in HIV- smokers, and is recognized as an increasing cause of morbidity in the HAART-treated HIV+ population. The pathogenesis of HIV-associated emphysema has been hypothesized to result from an exaggerated lower respiratory tract burden of inflammatory cell-derived proteases and/or oxidants, direct effects of HIV proteins, or adverse effects of anti- retroviral therapy. Despite evidence to support each of these mechanisms, there is limited data in humans pointing to specific molecular targets that contribute to the destruction of the lower respiratory tract leading to emphysema. Based on preliminary data generated from HIV+ individuals, we will use a multidisciplinary approach to explore the hypothesis that the combination of HIV infection and smoking activates alveolar macrophages (AM) to create chronic oxidant stress in the lower respiratory tract that promotes apoptosis of the pulmonary capillary endothelium, contributing to progressive alveolar destruction. We will study this hypothesis by sampling HIV+ and HIV- subjects for AM and lower respiratory tract epithelial lining fluid (ELF) by bronchoalveolar lavage, and by assessing plasma pulmonary capillary-derived endothelial microparticles (EMPs) as a biomarker for ongoing pulmonary capillary endothelial apoptosis. Using newly developed mass spectrometry methodologies, we will quantify the oxidant stress of AM, ELF and plasma EMPs, and identify specific oxidized metabolites within each of these compartments. Finally, we will model the AM-pulmonary capillary endothelial interaction in vitro to tease apart the contribution of each component of the interaction. We will assess HIV+ and HIV- nonsmokers, smokers, smokers with early and GOLD criteria emphysema using 3 specific aims. Aim 1. To explore the extent of oxidant stress in the lower respiratory tract of HIV+ and HIV- subjects by assessing spontaneous AM generation of oxidants, together with mass spectrometry-based assessment of the oxidation state of AM and lower respiratory tract ELF. Aim 2. To evaluate the plasma levels of pulmonary capillary apoptosis-derived EMPs of HIV+ nonsmokers and smokers, and to assess the oxidation state of the components of these EMPs. Aim 3. To examine the interaction of pulmonary capillary endothelium with AM of HIV+ and HIV- subjects, using apoptosis and the oxidation state of endothelial metabolites as the phenotype of the interaction. As we develop data to solidify our hypothesis, we expect to uncover a new class of targets to test drugs aimed at preventing HIV-associated emphysema.

描述（由申请方提供）：尽管使用高效抗逆转录病毒治疗（HAART）可增加HIV-1（HIV）感染个体的存活率，但HIV感染个体发生慢性阻塞性肺疾病（表现为肺气肿）的风险增加。肺气肿发生的年龄比HIV-吸烟者更早，并且被认为是HAART治疗的HIV+人群中发病率增加的原因。HIV相关性肺气肿的发病机制被假设是由炎性细胞衍生的蛋白酶和/或氧化剂的过度下呼吸道负荷、HIV蛋白的直接作用或抗逆转录病毒治疗的不良反应引起的。尽管有证据支持这些机制中的每一种，但在人类中，指向导致下呼吸道破坏导致肺气肿的特定分子靶点的数据有限。基于从HIV+个体产生的初步数据，我们将使用多学科方法来探讨HIV感染和吸烟的组合激活肺泡巨噬细胞（AM）在下呼吸道中产生慢性氧化应激，促进肺毛细血管内皮细胞凋亡，导致进行性肺泡破坏的假设。我们将研究这一假设采样的AM和下呼吸道上皮衬里液（ELF）的艾滋病毒+和艾滋病毒-受试者的支气管肺泡灌洗，并通过评估血浆肺毛细血管衍生的内皮微粒（EMP）作为一个生物标志物进行肺毛细血管内皮细胞凋亡。使用新开发的质谱分析方法，我们将量化AM，ELF和血浆EMP的氧化应激，并确定这些隔室中的每一个特定的氧化代谢物。最后，我们将在体外模拟AM-肺毛细血管内皮相互作用，以梳理出相互作用的每个组件的贡献。我们将使用3个特定目标评估HIV+和HIV-非吸烟者、吸烟者、吸烟者伴早期和GOLD标准肺气肿。目标1。通过评估氧化剂的自发AM生成，以及基于质谱的AM和下呼吸道ELF氧化状态评估，探索HIV+和HIV-受试者下呼吸道氧化应激的程度。目标二。评价HIV+非吸烟者和吸烟者的肺毛细血管炎源性EMP的血浆水平，并评估这些EMP组分的氧化态。目标3.以细胞凋亡和内皮代谢产物的氧化状态作为相互作用的表型，研究HIV+和HIV-受试者肺毛细血管内皮与AM的相互作用。当我们开发数据来巩固我们的假设时，我们希望发现一类新的靶点来测试旨在预防HIV相关肺气肿的药物。