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

随着高效抗逆转录病毒疗法(HAART)的出现，感染者的存活率 HIV-1病毒有了显著的改善。然而，最近对明显加速发展的认识 在这个年龄较小且吸烟史最少的人群中发生肺气肿提供了一个 有机会研究这个问题的分子基础。在这方面，艾滋病毒-1/艾滋病的肺气肿 加入A1抗胰蛋白酶缺乏症作为加速形式的肺破坏的临床模型，因此 吸烟的HIV-1+个体可作为了解艾滋病发病机制的模型 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 被HIV-1慢性感染的肺，AM在释放介质方面起着中心作用 介导吸烟所致肺气肿的肺破坏，我们假设HIV-1和 香烟烟雾协同激活AM表达高度危险的转录组 肺实质。它的评估将有助于确定最关键的激活途径 肺气肿的发生和代表药理作用的靶点。基于这样的背景，我们 建议评估3个具体目标。目的1.检验HIV-1感染与香烟 吸烟共同作用，产生AM基因表达模式，表明表达上调 与肺气肿发病相关的基因，并且这些变化超过或超过 此外，吸烟或单独感染HIV-1也会导致这种情况。目标2.基于对艾滋病毒-1的了解 感染与全身和肺部肿瘤坏死因子-a(TNF-a)水平升高和 实验动物肺组织中肿瘤坏死因子-a或干扰素-v的表达 与肺气肿的发展有关，我们将检验这样一种假设，即 HIV-1+吸烟者AM表达的肺气肿相关介质程序与 肺组织中肿瘤坏死因子-α和/或干扰素-γ过度表达。目标3.检验假设：虽然HAART 治疗有效地抑制了HIV-1在AM中的复制，但不能完全抑制 AM的基因表达与肺气肿的发病机制有关，而肺气肿的持续性 AM中上调基因的子集与肺泡周围环境中的肿瘤坏死因子-a或干扰素-v有关。

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.