Role of Alveolar Macrophages in the Accelerated Emphysema of HIV-1 Positive

肺泡巨噬细胞在 HIV-1 阳性加速肺气肿中的作用

• 批准号: 7231215
• 负责人: Robert J Kaner
• 金额: $ 29.63万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-12-01 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7231215
• 关键词: Advertisements; Age; Alveolar; Alveolar Macrophages; Alveolar Pattern; Alveolus; Animal Model; Animals; Area; Biological; Biological Assay; Blood; CD4 Lymphocyte Count; Cations; Chest; Chronic; Chronic Disease; Chronic Obstructive Airway Disease; Cigarette smoke-induced emphysema; Clinical; Code; Complement component C1s; Conditioned Culture Media; Control Groups; Data; Development; Disease; Effectiveness; Elastases; Endopeptidases; Enzyme-Linked Immunosorbent Assay; Epithelial; Evaluation; Gelatinase B; Gene Chips; Gene Expression; Gene Expression Profile; Genes; Genome; HIV; HIV-1; Highly Active Antiretroviral Therapy; In Vitro; Incidence; Individual; Infection; Injury; Interferons; Interstitial Collagenase; Knowledge; Link; Liquid substance; Lung; Matrix Metalloproteinases; Measures; Mediating; Mediator of activation protein; Messenger RNA; Methods; Mining; Modeling; Molecular; Numbers; Opportunistic Infections; Pancreatic Elastase; Pathogenesis; Pathway interactions; Patients; Pattern; Peptide Hydrolases; Pharmaceutical Preparations; Phenotype; Plasma; Play; Polymerase Chain Reaction; Population; Population Study; Protein C Inhibitor; Protein Overexpression; Proteins; Pulmonary Emphysema; RNA; Recording of previous events; Recruitment Activity; Research Personnel; Resolution; Respiratory physiology; Role; Screening procedure; Series; Signal Transduction; Smoke; Smoker; Smoking; Smoking History; Standards of Weights and Measures; Structure of parenchyma of lung; Testing; Transcription Coactivator; Transcriptional Activation; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Up-Regulation; Virus; Work; X-Ray Computed Tomography; antiretroviral therapy; base; cell type; cigarette smoking; cigarette smoking; clinical phenotype; cohort; disease phenotype; human TNF protein; improved; in vivo; macrophage; metropolitan; non-smoker; prevent; programs; therapy development

With the advent of highly active antiretroviral therapy (HAART), the survival of individuals infected with HIV-1 has dramatically improved. However, recent recognition of the markedly accelerated development of emphysema in this population at an early age and with a minimal smoking history provides an opportunity to study the molecular basis for this problem. In this context, the emphysema of HIV-1/AIDS joins a1-antitrypsin deficiency as a clinical model of an accelerated form of lung destruction, and thus HIV-1+ individuals that smoke can serve as a model to understand the pathogenesis of emphysema. Based on the knowledge that the alveolar macrophage (AM) is the primary cell type of the lung that is chronically infected by HIV-1, and that the AM plays a central role in releasing mediators that mediate the lung destruction in smoking-ind.uced emphysema, we hypothesize that HIV-1 and cigarette smoke synergize to activate AM to express a transcriptome that is highly dangerous to the lung parenchyma. Its evaluation will help to identify the activation pathways that are most critical in the development of emphysema and represent pharmacologic targets. Based on this background, we propose to assess 3 specific aims. Aim 1. To test the hypothesis that HIV-1 infection and cigarette smoking act in concert to create a pattern of AM gene expression indicative of up-regulated expression of genes relevant to the pathogenesis of emphysema and that these changes are in excess of, or in addition to, that induced by smoking or HIV-1 alone. Aim 2. Based on the knowledge that HIV-1 infection is associated with elevated systemic and lung levels of tumor necrosis factor-a (TNF-a) and interferon-Y (IFN-v), and that expression of TNF-a or IFN-v in the lungs of experimental animals is associated with the development of emphysema, we will examine the hypothesis that the exaggerated program of emphysema-related mediators expressed by AM of HIV-1+ smokers is linked to the overexpression of TNF-a and/or IFN-y in the lung. Aim 3. To examine the hypothesis that while HAART therapy effectively suppresses replication of HIV-1 in the AM, it does not entirely suppress the pattern of gene expression of the AM relevant to the pathogenesis of emphysema, and that the persistence of the subset of up-regulated genes in the AM is linked to TNF-a or INF-v in the milieu of the alveolus.

随着高效抗逆转录病毒疗法（HAART）的出现，感染艾滋病病毒的个体的存活率 HIV-1已经有了显著的改善。然而，最近认识到， 肺气肿在这个人群中的早期年龄和最低限度的吸烟史提供了一个 研究这个问题的分子基础。在这方面，艾滋病毒1/艾滋病肺气肿 加入α 1-抗胰蛋白酶缺乏作为肺破坏加速形式的临床模型，因此 吸烟的HIV-1+个体可以作为一个模型来了解 肺气肿基于肺泡巨噬细胞（AM）是肺泡巨噬细胞的主要细胞类型的知识， 肺是慢性感染HIV-1，AM在释放介质中起着核心作用， 在吸烟引起的肺气肿中，HIV-1介导肺的破坏，我们假设HIV-1和 香烟烟雾协同激活AM表达转录组， 肺实质它的评估将有助于确定最关键的激活途径， 肺气肿的发展，并代表药理学目标。基于这一背景，我们 提出三个具体目标。目标1.为了验证HIV-1感染和吸烟 吸烟共同作用产生AM基因表达模式，表明表达上调 与肺气肿的发病机制相关的基因的变化，这些变化超过，或 除此之外，还有吸烟或单独的HIV-1。目标二。基于HIV-1 感染与肿瘤坏死因子-α（TNF-α）的全身和肺水平升高有关， 干扰素-γ（IFN-v），并在实验动物肺中表达TNF-α或IFN-v， 与肺气肿的发展相关，我们将研究夸大的 HIV-1+吸烟者AM表达的肺气肿相关介质程序与 肺中TNF-α和/或IFN-γ的过度表达。目标3。为了检验HAART的假设， 虽然治疗有效地抑制了AM中HIV-1的复制，但它并不完全抑制AM中HIV-1的模式。 AM的基因表达与肺气肿的发病机制有关， AM中上调基因的一个子集与肺泡环境中的TNF-α或INF-γ相关。