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介导环境和职业危害（如结晶二氧化硅，一种已知的人类致癌物）的肺毒性的炎症机制。使用模型肺毒物，我们已经发现，巨噬细胞响应急性肺损伤释放介质，有助于致病过程。特别令人感兴趣的是肿瘤坏死因子-a（TNFa），其在损伤后的早期直接有助于细胞毒性，而在该过程的后期，参与调节祖细胞增殖，这是二氧化硅诱导的肿瘤发生中的关键步骤。介导TNF α的促有丝分裂作用的主要受体是TNFR 1（p55），其位于含有小窝蛋白-1（Cav-1）的质膜脂筏或小窝中。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的显著抑制以及介导祖细胞增殖的信号分子的释放相关，所述祖细胞包括II型肺泡上皮细胞和支气管肺泡干细胞。在初步研究中，我们确定TNF α作为调节Cav-1表达的主要介质。我们假设TNF α下调Cav-1通过使祖细胞对炎症反应期间释放的内源性有丝分裂原敏感而启动祖细胞增殖。Cav-1的下调与β-连环蛋白/细胞周期蛋白D1促有丝分裂信号通路的激活有关。我们推测，这是重要的途径，导致祖细胞增殖后二氧化硅诱导的损伤。本提案中描述的实验旨在分析Cav-1和TNF α在二氧化硅诱导的毒性中的作用。研究计划评估Cav-1在小鼠施用二氧化硅后在祖细胞中下调的机制，并阐明TNF α在该过程中的作用。我们还将确定TNF α诱导的Cav-1抑制是否会导致β-连环蛋白信号传导和祖细胞增殖的激活。这些研究的结果将提供新的机制线索的途径，导致肺癌的发展，并可能提出创新的治疗方法，消除组织损伤与暴露于环境污染物。

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.