CYTOKINE DYSFUNCTION AND LUNG 5LO METABOLISM IN AIDS

艾滋病中的细胞因子功能障碍和肺 5LO 代谢

• 批准号: 6184593
• 负责人: MICHAEL J. COFFEY
• 金额: $ 30.43万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-30 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6184593
• 关键词: AIDS; HIV infections; alveolar macrophages; bactericidal immunity; clinical research; colony stimulating factor; cytokine; eicosanoid metabolism; eicosanoids; enzyme activity; genetically modified animals; helper T lymphocyte; human subject; laboratory mouse; lipoxygenase; lymphocyte; monocyte; neutrophil; opportunistic infections; respiratory infections

Infection with the HIV leads to the development of AIDS. The alveolar macrophage (AM), which is the main resident inflammatory cell and defender of the lung against foreign microbes, can be affected by HIV disease. AM function is altered in HIV disease through direct infection with HIV, but also by the altered environmental milieu in AIDS. Although not infected by HIV, PMN dysfunction also occurs in AIDS. One group of Thl cytokines, granulocyte-macrophage colony stimulating factor (GM-CSF), interleukin (IL)-3, interferon (IFN)gamma, as well as G-CSF have decreased levels in AIDS. Furthermore, there is an increase in the Th2 cytokines levels. The objective of this proposal is to examine the role of cytokine dysfunction in the regulation of AM, PBM and PMN dysfunction. Preliminary data suggests that synthesis of LT, which are 5-lipoxygenase (5-LO) metabolites of arachidonic acid, are reduced in AM, PBM, and PMN from HIV-infected subjects. We have evidence that cytokine dysfunction in HIV disease results in decreased 5-LO product synthetic capacity and is associated with reduced cellular killing of M. avium and BCG. Augmentation of LT levels in AM, PBM, and PMN following therapy with GM-CSF and G-CSF increases antimicrobial activity against M.avium and BCG. The hypothesis is that reduced colony stimulating factor levels, along with increased IL-4 levels suppress LT synthesis in AM, PBM, and PMN from HIV-infected subjects. This dysfunction in turn reduces phagocytic antimycobacterial activity. The specific aims are (1) to determine the mechanisms by which CD4 T cell dysfunction reduce AM, PBM, and PMN 5-LO metabolism in AIDS. In addition, (2) we will investigate the mechanisms by which G-CSF expression in AM and PBM is regulated in HIV disease, and its impact on PMN 5-LO metabolism. Furthermore, (3) we will examine the role of LT in the increased antimycobacterial activity of AM, PBM, and PMN following GM-CSF and G-CSF therapy. The experimental approach will be to examine the role of depletion of CD4 T cells and Thl/Th2 cytokine dysfunction on 5-LO metabolism in AM, PBM, and PMN. We will characterize the regulation of G-CSF expression in macrophages in AIDS. Finally, we will examine the role LT play in the increased antimycobacterial activity of AM, PBM, and PMN following CSF therapy. In summary, we will characterize a crucial defect in cytokine and subsequent 5-LO metabolism in AM, PBM, and PMN which occurs in AIDS. This proposal will further enhance our ability to correct this defect and help boost AM, PBM, and PMN defenses against opportunistic infections in the lung in HIV disease.

感染艾滋病毒会导致艾滋病的发展。牙槽骨 巨噬细胞(AM)，这是主要驻留的炎症细胞和 肺抵御外来微生物的卫士，可受艾滋病毒影响 疾病。AM功能在HIV疾病中通过直接感染而改变 艾滋病毒携带者，但也与艾滋病的环境变化有关。 虽然没有感染艾滋病毒，但艾滋病患者也会出现PMN功能障碍。一 Th1类细胞因子、粒细胞-巨噬细胞集落刺激因子 粒-巨噬细胞集落刺激因子、白细胞介素3、干扰素-γ和粒细胞集落刺激因子 已经降低了艾滋病的水平。此外，还增加了 Th2细胞因子水平。这项建议的目的是研究 细胞因子功能障碍在AM、PBM和PMN调节中的作用 功能障碍。初步数据表明，LT的合成是 花生四烯酸的5-脂氧合酶(5-LO)代谢产物在 来自HIV感染者的AM、PBM和PMN。我们有证据表明 HIV疾病中细胞因子功能障碍导致5-LO产物减少 合成能力，并与减少细胞杀灭 阿维菌素和卡介苗。AM、PBM和PMN中LT水平的增加 GM-CSF和G-CSF治疗后抗菌活性增强 对抗M.avium和BCG。假设是减少的蜂群 刺激因子水平与IL-4水平升高一起抑制LT HIV感染者AM、PBM和PMN的合成。这 功能障碍反过来会降低吞噬细胞的抗分枝杆菌活性。这个 具体目标是：(1)确定CD4T细胞 功能障碍降低了艾滋病患者AM、PBM和PMN 5-LO代谢。在……里面 此外，(2)我们将研究G-CSF的作用机制 AM和PBM在HIV疾病中的表达受到调节，及其对 PMN 5-LO代谢。此外，(3)我们将研究LT的作用 AM、PBM和PMN的抗分枝杆菌活性增强 在GM-CSF和G-CSF治疗后。实验方法将是 CD4T细胞耗竭与Th1/Th2细胞因子的关系 AM、PBM和PMN的5-LO代谢功能障碍。我们会 探讨艾滋病患者巨噬细胞中G-CSF表达的调节。 最后，我们将考察LT在增加的 脑脊液治疗后AM、PBM和PMN的抗分枝杆菌活性。 综上所述，我们将描述细胞因子和 艾滋病患者AM、PBM和PMN中随后的5-LO代谢。 这项建议将进一步增强我们纠正这一缺陷的能力 并帮助增强AM、PBM和PMN防御以抵御机会主义 艾滋病毒感染中的肺部感染。