Metabolic mechanisms of naphthalene toxicity in lung

 说明(申请人提供)：萘(NA)是一种急性呼吸道毒物，也是一种潜在的人类肺癌致癌物质。人类对NA的暴露很普遍，但人类对NA毒性的敏感性却知之甚少。关于人类对NA毒性易感性的裁决将对公众健康产生重大影响，可能会拯救许多人的生命，但涉及经济成本。该VICKTER计划的总体主题是研究NA诱导的包括耐受性在内的肺毒性的机制，以改进对NA和其他相关毒物引起的人类肺癌风险的评估。有三个目的被提出，1)通过直接机制确定NA是否是一种遗传毒性致癌物；2)测试炎性细胞雌激素产生在NA诱导的肺毒性和耐受性中的作用；3)确定NA诱导的肺毒性和耐受性的细胞应激反应。这些目的是通过研究初始生物激活步骤下游的分子和细胞事件来显著扩大当前项目的范围，而父母的赠款则侧重于NA生物激活步骤。该联盟允许参与者在分享动物模型、独特技能(例如，呼吸道解剖)、仪器以及分子、细胞和遗传毒性观点方面进行广泛的合作。来自AIMS的数据将为NA诱导的组织损伤和修复的复杂、多步骤过程提供补充观点，这些过程导致癌前病变和最终致癌。目的1将提供关于NA是否在活体内诱导肺内稳定的DNA加合物的急需的数据，并将把我们的研究转化为更接近人类的模型系统。这些结果将推动风险评估，指导未来的机制研究，并为测试其他致癌物提供方法和途径。目的2将建立一种新的基因敲除小鼠模型，并建立巨噬细胞衍生雌激素在NA诱导的过度增殖反应和耐受中的作用，该反应和耐受先于增生性/异常增生性结节的发展。目标3将确定导致急性肺毒性的特定活性氧物种损伤和允许NA诱导耐受的信号通路。这一结果将为未来识别和保护高危个体的转译研究提供潜在的缓解剂和生物标记物。

 DESCRIPTION (provided by applicant): Naphthalene (NA) is an acute respiratory toxicant and a potential human lung carcinogen. Human exposure to NA is widespread, but human susceptibility to NA toxicity is poorly understood. The verdict on human susceptibility to NA toxicity will have a significant impact on public health, could save many lives, but involves economic costs. The overall theme of this ViCTER program is to study mechanisms of lung toxicity, including tolerance, induced by NA, in order to improve assessment of human lung cancer risks from NA and other related toxicants. Three Aims are proposed, 1) to define whether NA is a genotoxic carcinogen through a direct mechanism; 2) to test the role of inflammatory cell estrogen production in NA-induced lung toxicity and tolerance; and 3) to identify cellular stress response for NA-induced lung toxicity and tolerance. These Aims significantly expand the scope of the current project by studying molecular and cellular events downstream of the initial bio-activation step, while the parent grant is focused on the NA bio-activation step. The consortium allows extensive collaborations among the participants, in sharing of animal models, unique skills (e.g., airway dissection), instruments, and molecular, cellular, and genotoxic perspectives. Data from the Aims will provide complementary views of the complex, multi-step process of NA-induced tissue damage and repair that lead to preneoplastic changes and eventual carcinogenesis. Aim 1 will provide much needed data on whether NA induces stable DNA adducts in the lung in vivo, and will translate our studies to a more human-like model system. The results would drive risk estimation, guide future mechanistic studies, and provide methodology and approaches for testing other carcinogens. Aim 2 will produce a novel knockout mouse model and establish role of macrophage-derived estrogen in NA-induced hyper proliferative response and tolerance, which precedes development of hyperplastic/dysplastic nodules. Aim 3 will identify the specific reactive oxygen species damage driving acute lung toxicity and signaling pathways that allow for NA-induced tolerance. The results would provide insight for potential mitigating agents and biomarkers for future translational studies to identify and protect at-risk individuals.