CYTOKINE DYSFUNCTION AND LUNG 5LO METABOLISM IN AIDS

感染艾滋病毒会导致艾滋病的发展。 肺泡 巨噬细胞（AM），是主要的常驻炎症细胞 肺部抵御外来微生物的卫士，可能会受到艾滋病毒的影响 疾病。 HIV 疾病中的 AM 功能通过直接感染而改变 与艾滋病毒有关，而且还与艾滋病发生的环境环境的改变有关。 尽管未感染艾滋病毒，但艾滋病患者也会出现中性粒细胞功能障碍。 一 Thl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)gamma 以及 G-CSF 艾滋病感染率有所下降。 此外，还有增加 Th2 细胞因子水平。 该提案的目的是审查 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 花生四烯酸的 5-脂氧合酶 (5-LO) 代谢物在 来自 HIV 感染者的 AM、PBM 和 PMN。 我们有证据表明 HIV 疾病中的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 鸟分枝杆菌和卡介苗。 AM、PBM 和 PMN 中 LT 水平升高 GM-CSF 和 G-CSF 治疗后可增加抗菌活性 抗 M.avium 和 BCG。 假设是菌落减少 刺激因子水平以及 IL-4 水平升高抑制 LT HIV 感染者的 AM、PBM 和 PMN 中的合成。 这个 功能障碍反过来会降低吞噬细胞的抗分枝杆菌活性。 的 具体目标是 (1) 确定 CD4 T 细胞 艾滋病患者的功能障碍会降低 AM、PBM 和 PMN 5-LO 代谢。 在 此外，（2）我们将研究G-CSF的机制 AM 和 PBM 的表达在 HIV 疾病中受到调节，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 GM-CSF 和 G-CSF 治疗后。 实验方法将是 检查 CD4 T 细胞和 Thl/Th2 细胞因子消耗的作用 AM、PBM 和 PMN 中 5-LO 代谢功能障碍。 我们会 描述艾滋病巨噬细胞中 G-CSF 表达的调节。 最后，我们将研究 LT 在增加的过程中所扮演的角色。 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和 随后在 AIDS 中发生的 AM、PBM 和 PMN 中的 5-LO 代谢。 该提案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 防御机会主义行为 HIV 疾病中的肺部感染。

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.