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: 6056608
• 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/6056608
• 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HIV会导致艾滋病的发展。 肺泡 巨噬细胞（AM），其是主要的常驻炎性细胞， 肺抵抗外来微生物的防御者，可能受到艾滋病毒的影响 疾病 AM功能在HIV疾病中通过直接感染而改变 艾滋病病毒感染者，也受到艾滋病环境改变的影响。 虽然没有被HIV感染，但PMN功能障碍也发生在AIDS中。 一 Th 1类细胞因子，粒细胞-巨噬细胞集落刺激因子 （GM-CSF）、白细胞介素（IL）-3、干扰素（IFN）γ以及G-CSF 艾滋病的发病率有所下降。 此外， Th 2细胞因子水平。 这项建议的目的是审查 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， 5-花生四烯酸的脂氧合酶（5-LO）代谢产物，在 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，并与减少细胞杀伤有关， M. avium和BCG。 AM、PBM和PMN中LT水平的增加 在用GM-CSF和G-CSF治疗后增加抗微生物活性 抗鸟分枝杆菌和卡介苗。 假设减少的蜂群 刺激因子水平，沿着IL-4水平的升高抑制LT HIV感染者AM、PBM和PMN中的合成。 这 功能障碍反过来降低吞噬抗分枝杆菌活性。 的 具体目标是（1）确定CD 4 T细胞 AIDS中AM、PBM和PMN 5-LO代谢降低。 在 此外，（2）我们还将探讨G-CSF在肿瘤细胞中的作用机制。 AM和PBM中的表达在HIV疾病中受到调节， 中性粒细胞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加 在GM-CSF和G-CSF治疗之后。 实验方法将是 检测CD 4 T细胞和Th 1/Th 2细胞因子的耗竭的作用 AM、PBM和PMN中5-LO代谢功能障碍。 我们将 表征AIDS中巨噬细胞中G-CSF表达的调节。 最后，我们将研究LT在增加的 CSF治疗后AM、PBM和PMN的抗分枝杆菌活性。 总之，我们将描述细胞因子的一个关键缺陷， 随后在AM、PBM和PMN中的5-LO代谢，其发生在AIDS中。 这项建议将进一步加强我们纠正这一缺陷的能力 帮助增强AM、PBM和PMN防御机会主义 艾滋病病毒感染的肺部疾病。