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: 7618456
• 负责人: Debra L Laskin
• 金额: $ 29.79万
• 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 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7618456
• 关键词: Acute Lung Injury; Alveolar; Biological; Carcinogens; Caveolae; Cell Proliferation; Cell membrane; Cells; Cyclin D1; Development; Down-Regulation; Endogenous Mitogens; 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; TNF gene; TNFRSF1A gene; TNFRSF1B gene; Testing; Therapeutic; Time; Tissues; Toxic effect; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Type II Epithelial Receptor Cell; Wound Healing; carcinogenesis; caveolin 1; cytokine; cytotoxic; cytotoxicity; design; human MPP1 protein; innovation; interest; keratinocyte growth factor; lung injury; macrophage; occupational hazard; receptor; repaired; research study; response; 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））的肺毒性的炎症机制。使用模型肺毒物，我们发现巨噬细胞对急性肺损伤做出反应，释放出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)，它在损伤后的早期直接导致细胞毒性，而在此过程的后期，参与调节祖细胞增殖，这是二氧化硅诱导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)，其位于含有小窝蛋白 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组织中 Cav-1 的显着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。我们假设 TNFa 对 Cav-1 的下调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而启动祖细胞增殖。 Cav-1 的下调与 β-catenin/cyclin D1 促有丝分裂信号通路的激活相关。我们推测这对于二氧化硅诱导的损伤后导致祖细胞增殖的途径很重要。本提案中描述的实验旨在分析 Cav-1 和 TNFa 在二氧化硅诱导的毒性中的作用。计划开展研究评估小鼠给予二氧化硅后祖细胞中 Cav-1 下调的机制，并阐明 TNFa 在此过程中的作用。我们还将确定 TNFa 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。这些研究的结果将为导致肺癌发展的途径提供新的机制线索，并可能提出创新的治疗方法来消除与暴露于环境污染物相关的组织损伤。