WORKSITE-ASSOCIATED VANADIUM AND IMMUNOMODULATION

工业环境中工人接触含钒烟雾和粉尘 已知会降低它们对许多肺部疾病的抵抗力。肺 巨噬细胞是肺内主要负责 用于维持器官不孕不育以及启动免疫反应 去除任何抗原性挑战。因为肺是主要途径 将钒输送到体内，巨噬细胞可能是 毒性免疫调节。先前的体内和体外研究 肺和其他组织的巨噬细胞已经证明各种不同的 巨噬细胞活动的各个方面，包括受体介导的结合， 吞噬和细胞内杀灭细菌、细胞因子和 前列腺素的释放、活性氧中间产物的产生和表面 Fc受体的表达，在接触钒后发生改变。这个 这项提案的目标是勾勒出一个可能的统一基础 观察到的免疫抑制的机制。尤其是，它是 这里假设肺巨噬细胞产生、结合、 和/或处理与早期和晚期有关的细胞因子 巨噬细胞的激活(干扰素-α和-γ[干扰素-α和-γ IFNGamma)通过暴露在钒中进行修饰。三个具体目标是 建议证实这一点：(1)评估可诱导的水平 肺巨噬细胞(及其他辅助细胞)产生的干扰素α和干扰素γ 吸入金属钒对大鼠完整肺组织的影响 工作场所条件下遇到的形式/浓度；(2)至 确定吸入的钒是否改变巨噬细胞的IFNα/伽马表面 受体表达或干扰素结合，细胞内递送和 随后解离受体-干扰素复合体，或回收/去离子化 表面干扰素受体的新合成；以及(3)与 这些测量参数反映了巨噬细胞反应性的总体变化 对外源干扰素，即干扰素诱导的第II类MHC的表达 表面抗原和增加活性氧中间体的产生。 这项研究的结果将有助于澄清 钒通过干扰关键分子而引起免疫抑制的机制 接触工人巨噬细胞-细胞因子的相互作用。

Worker exposure to vanadium-bearing fumes and dusts in industrial settings is known to reduce their resistance to many pulmonary diseases. Pulmonary macrophages are the cells within the lungs that are primarily responsible for maintaining organ sterility as well as initiating immune responses to remove any antigenic challenges. Because the lungs are the major route for delivery of vanadium into the body, the macrophages are likely targets for toxic immunomodulation. Previous in vivo and in vitro studies with pulmonary and other tissue macrophages have demonstrated that various aspects of macrophage activity, including receptor-mediated binding, phagocytosis and intracellular killing of bacteria, cytokine and prostaglandin release, reactive oxygen intermediate generation, and surface Fc-receptor expression, are altered following exposure to vanadium. The goal of this proposal is to delineate a possible unifying underlying mechanism for the observed immunosuppression. In particular, it is hypothesized here that the pulmonary macrophage capacity to produce, bind, and/or process cytokines responsible for the early- and late-stage activation of macrophage (interferons-alpha and -gamma [IFNalpha and IFNgamma) are modified by exposure to vanadium. Three specific aims are proposed to substantiate this: (1) to assess the levels of inducible IFNalpha and IFNgamma by pulmonary macrophage (and other accessory cells) in the intact rat lung following inhalation of vanadium metal in the forms/concentrations encountered under workplace conditions; (2) to determine if the inhaled vanadium alters macrophage IFNalpha/gamma surface receptor expression or IFN binding, the intracellular delivery and subsequent dissociation of the receptor-IFN complex, or the recycling/de novo synthesis of surface IFN receptors; and (3) to relate any changes in these measured parameters to overall changes in macrophage responsiveness to exogenous IFNgamma, i.e., IFNgamma-induced expression of Class II MHC surface antigens and enhanced production of reactive oxygen intermediates. The results from this study will be useful in clarifying the precise mechanisms by which vanadium causes immunosuppression by disturbing crucial macrophage-cytokine interactions in exposed workers.