WORKSITE-ASSOCIATED VANADIUM AND IMMUNOMODULATION

工人在工业环境中接触含钒烟雾和粉尘 会降低他们对许多肺部疾病的抵抗力。 肺 巨噬细胞是肺内的细胞， 维持器官不育以及启动免疫反应， 消除任何抗原挑战。 因为肺部是 在钒进入体内的过程中，巨噬细胞可能是 毒性免疫调节 先前的体内和体外研究， 肺和其他组织巨噬细胞已经证明， 巨噬细胞活性方面，包括受体介导的结合， 吞噬作用和细胞内杀死细菌、细胞因子和 前列腺素释放、活性氧中间体生成和表面 Fc-受体表达在暴露于钒后改变。 的 本提案的目标是描绘一个可能的统一的基本 观察到的免疫抑制机制。 特别是 假设肺巨噬细胞产生，结合， 和/或负责早期和晚期的过程细胞因子 巨噬细胞（干扰素-α和-γ [IFN α和IFN γ]）的活化 IFN γ）通过暴露于钒而被修饰。 三个具体目标是 建议证实这一点：（1）评估诱导水平 肺巨噬细胞（和其他辅助细胞）的IFN α和IFN γ 在完整的大鼠肺中吸入钒金属后， 在工作场所条件下遇到的形式/浓度;（2） 确定吸入钒是否改变巨噬细胞IFN α/γ表面 受体表达或IFN结合，细胞内递送和 随后受体-IFN复合物的解离，或再循环/解离， 表面IFN受体的从头合成;和（3）将表面IFN受体的任何变化 这些测量参数与巨噬细胞反应性的总体变化 外源性IFN γ，即，IFN γ诱导的II类MHC表达 表面抗原和增强的活性氧中间体的产生。 这项研究的结果将有助于澄清精确的 钒引起免疫抑制的机制是通过干扰关键的 巨噬细胞-细胞因子相互作用。

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.