Macrophages and Inflammatory Mediators in Silica-Induced Carcinogenesis

描述（由申请人提供）：我们的实验室一直在研究炎症机制，介导环境和职业危害的肺毒性，如晶体二氧化硅，一种已知的人类致癌物。使用模型肺毒物，我们发现巨噬细胞对急性肺损伤的反应释放有助于致病过程的介质。特别令人感兴趣的是肿瘤坏死因子-a (TNFa)，它在损伤后早期直接参与细胞毒性，而在稍后的过程中，参与调节祖细胞增殖，这是硅诱导肿瘤发生的关键步骤。介导TNFa有丝分裂作用的主要受体是TNFR1 (p55)，其定位于含有Cav-1的质膜脂筏或小泡中。这些是专门的细胞器，隔离和负调节各种细胞信号分子。在啮齿动物模型中，我们观察到肺损伤与组织中Cav-1的明显抑制以及介导祖细胞（包括II型肺泡上皮细胞和支气管肺泡干细胞）增殖的信号分子的释放有关。在初步研究中，我们确定TNFa是调节Cav-1表达的主要介质。我们推测，tnf对Cav-1的下调通过使这些细胞对炎症反应中释放的内源性有丝分裂原敏感来启动祖细胞增殖。Cav-1的下调与-catenin/cyclin D1促有丝分裂信号通路的激活有关。我们推测这在二氧化硅诱导损伤后导致祖细胞增殖的途径中是重要的。本提案中描述的实验旨在分析Cav-1和TNFa在硅致毒性中的作用。研究计划评估在给小鼠二氧化硅后，Cav-1在祖细胞中下调的机制，并阐明TNFa在这一过程中的作用。我们还将确定tnfa诱导的Cav-1的抑制是否会导致¿-catenin信号的激活和祖细胞的增殖。这些研究结果将为肺癌发展的途径提供新的机制线索，并可能为消除与暴露于环境污染物相关的组织损伤提供创新的治疗方法。

DESCRIPTION (provided by applicant): Our laboratories have been investigating inflammatory mechanisms mediating the pulmonary toxicity of environmental and occupational hazards such as crystalline silica, a known human carcinogen. Using model pulmonary toxicants, we have discovered that macrophages responding to acute lung injury release mediators that contribute to the pathogenic process. Of particular interest is tumor necrosis factor-a (TNFa) which directly contributes to cytotoxicity at early times after injury, while later in the process, is involved in regulating progenitor cell proliferation, a key step in silica-induced tumorigenesis. The major receptor mediating the mitogenic actions of TNFa is TNFR1 (p55), which is localized in caveolin-1 (Cav-1)-containing plasma membrane lipid rafts, or caveolae. These are specialized organelles that sequester and negatively regulate various cell-signaling molecules. In rodent models, we observed that lung injury is associated with a marked suppression of Cav-1 in the tissue, and the release of signaling molecules mediating proliferation of progenitor cells including Type II alveolar epithelial cells and bronchoalveolar stem cells. In preliminary studies we identified TNFa as a major mediator regulating Cav-1 expression. We hypothesize that down regulation of Cav-1 by TNFa initiates progenitor cell proliferation by sensitizing these cells to respond to endogenous mitogens released during the inflammatory response. Down-regulation of Cav-1 is associated with activation of the ¿-catenin/cyclin D1 pro-mitogenic signaling pathway. We speculate that this is important in the pathway leading to progenitor cell proliferation following silica-induced injury. The experiments described in this proposal are designed to analyze the role of Cav-1 and TNFa in silica-induced toxicity. Studies are planned to assess mechanisms by which Cav-1 is down-regulated in progenitor cells following silica administration to mice and to elucidate the role of TNFa in this process. We will also determine if TNFa-induced suppression of Cav-1 leads to activation of ¿-catenin signaling and progenitor cell proliferation. The results of these studies will provide new mechanistic clues about the pathways leading to the development of lung cancer and may suggest innovative therapeutic approaches for abrogating tissue injury associated with exposure to environmental pollutants.