Macrophages and Inflammatory Mediators in Silica-Induced Carcinogenesis

二氧化硅诱发癌变中的巨噬细胞和炎症介质

• 批准号: 8253758
• 负责人: Debra L Laskin
• 金额: $ 28.49万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8253758
• 关键词: Acute Lung Injury; Alveolar; Biological; Carcinogens; Caveolae; Cell Proliferation; Cell membrane; Cells; Cyclin D1; Development; Down-Regulation; Endogenous Mitogens; Environmental Hazards; Environmental Pollutants; Epithelial; Epithelial Cell Proliferation; Epithelial Cells; Epithelium; Event; Exposure to; Human; Inflammation Mediators; Inflammatory; Inflammatory Response; Injury; Laboratories; Lung; Lung Adenocarcinoma; Lung Neoplasms; Malignant neoplasm of lung; Mediating; Mediator of activation protein; Membrane Lipids; Membrane Microdomains; Mitogens; Modeling; Mus; Nitrogen; Organelles; Oxygen; Pathology; Pathway interactions; Play; Process; Proliferating; Rodent; Rodent Model; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Silicon Dioxide; Stem cells; TNFRSF1A gene; TNFRSF1B gene; Testing; Therapeutic; Time; Tissues; Toxic effect; Tumor Necrosis Factor-alpha; Type II Epithelial Receptor Cell; carcinogenesis; caveolin 1; cytokine; cytotoxic; cytotoxicity; design; human MPP1 protein; human TNF protein; innovation; interest; keratinocyte growth factor; lung injury; macrophage; occupational hazard; receptor; repaired; research study; response; tissue repair; toxicant; tumorigenesis

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.

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（例如结晶二氧化硅，一种已知的人类致癌物）的肺部毒性的炎症机制。使用模型肺部毒物，我们发现巨噬细胞对急性肺损伤会释放介质。特别令人感兴趣的是肿瘤坏死因子-a (TNFa)，它在损伤后的早期直接导致细胞毒性，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的关键步骤，介导 TNFa 促有丝分裂作用的主要受体是 TNFR1 (p55)，它位于含有小窝蛋白 1 (Cav-1) 的质膜脂筏或小窝中。这些是特殊的细胞器，可以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 Cav-1 的显着抑制有关。在初步研究中，我们发现 TNFa 是调节 Cav-1 表达的主要介质。 TNFa 通过使这些细胞对炎症反应期间释放的内源有丝分裂原敏感来启动祖细胞增殖。Cav-1 的下调与 ¿ 的激活有关。 -连环蛋白/细胞周期蛋白 D1 促有丝分裂信号通路。我们推测这在二氧化硅诱导损伤后导致祖细胞增殖的通路中很重要。本提案中描述的实验旨在分析 Cav-1 和 TNFa 在细胞增殖中的作用。计划研究评估给予小鼠二氧化硅后祖细胞中 Cav-1 下调的机制，并阐明 TNFa 在这一过程中的作用。 TNFa 诱导的 Cav-1 抑制导致 ¿ 的激活-连环蛋白信号传导和祖细胞增殖。这些研究的结果将为肺癌发展的主要途径提供新的机制线索，并可能提出消除与环境污染物暴露相关的组织损伤的创新治疗方法。