Macrophages and Inflammatory Mediators in Silica-Induced Carcinogenesis

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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.