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(申请人提供)：我们的实验室一直在研究调节环境和职业危害的肺部毒性的炎症机制，如已知的人类致癌物质结晶二氧化硅。利用模型肺毒物，我们发现对急性肺损伤做出反应的巨噬细胞释放促进致病过程的介质。尤其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起到细胞毒性作用，而在这个过程的后期，参与调控祖细胞的增殖，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)，它定位于含小窝蛋白-1(Cav-1)的质膜脂筏或小窝中。这些是专门的细胞器，可以隔离和负向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包括II型肺泡上皮细胞和支气管肺泡干细胞在内的前体细胞增殖的信号分子的释放有关。在初步研究中，我们发现TNFa是调节Cav-1表达的主要介质。我们假设，TNFa下调Cav-1的表达，通过使这些细胞对炎症反应中释放的内源性有丝分裂原做出反应，从而启动这些细胞的增殖。Cav-1的下调与-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，这在二氧化硅诱导的损伤后导致祖细胞增殖的途径中是重要的。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。研究计划评估在给小鼠注射二氧化硅后Cav-1在祖细胞中下调的机制，并阐明TNFa在这一过程中的作用。我们还将确定TNFa诱导的Cav-1抑制是否导致连接蛋白信号的激活和祖细胞的增殖。这些研究的结果将提供导致肺癌发展的新的机制线索，并可能为消除暴露在环境污染物中的组织损伤提供创新的治疗方法。