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（由应用提供）：我们的实验室一直在研究介导环境和职业危害的肺毒性，例如结晶二氧化硅，一种已知的人类致癌物。使用模型肺有毒物质，我们发现巨噬细胞响应急性肺损伤释放介质，从而有助于致病过程。特别令人感兴趣的是肿瘤坏死因子A（TNFA），它直接有助于受伤后的早期细胞毒性，而在此过程的后期，涉及祖细胞细胞增殖，这是硅胶诱导的肿瘤发生的关键步骤。介导TNFA的促丝分裂作用的主要接收器是TNFR1（p55），它位于含有小窝蛋白-1（CAV-1）的含有质膜的质膜脂质筏或小窝中。这些是隔离和负调节各种细胞信号分子的专门细胞器。在啮齿动物模型中，我们观察到肺损伤与组织中CAV-1的明显抑制有关，以及介导祖细胞增殖的信号分子的释放，包括II型肺泡上皮细胞和支气管藻类病房细胞。在初步研究中，我们将TNFA确定为主要的调节器CAV-1表达。我们假设通过TNFA对CAV-1的下降来启动祖细胞的增殖，从而使这些细胞敏感以对炎症反应期间释放的内源性有损伤剂反应。 Cav-1的下调与�-蛋白神经蛋白/细胞周期蛋白D1 pro有水裂信号通路的激活有关。我们推测这在导致二氧化硅诱导损伤后导致祖细胞增殖的途径中很重要。该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。计划进行研究来评估二氧化硅对小鼠施用后祖细胞中Cav-1在祖细胞中下调的机制，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 - 帕宁信号传导和祖细胞细胞增殖的激活。这些研究的结果将为导致肺癌发展的途径提供新的机械线索，并可能提出创新的治疗方法，以消除与暴露于环境污染物相关的组织损伤。