Tlp2/COT Regulation of ERK1/2 and NF-kB in Response to Particulates

描述(申请人提供)：自上世纪70年代《S报告》以来，一直有报告称，空气中的颗粒物污染浓度出乎意料地低，对健康造成了不利影响，这使得科学家和公共卫生官员得出结论，长期暴露在与燃烧相关的细颗粒物污染中，是心肺疾病的一个重要环境风险因素。尽管许多研究考察了石油柴油(石油柴油)废气排放对呼吸系统的影响，但报告的对人类健康不利影响的机制以及这些颗粒物的哪些特征启动了不利过程仍然难以捉摸。在美国和欧洲，由植物油或动物脂肪制成的生物柴油正在成为未来的能源。生物柴油通常被掺入常规柴油中，排放测试表明，生物柴油排放的碳氢化合物、一氧化碳和颗粒物(PM)水平较低，但可溶有机成分浓度较高。需要检验的假设是，与石油柴油相比，生物柴油燃烧产生的颗粒物对肺部的不良影响较小。生物效应包括细胞死亡、代偿性细胞生长和炎症反应，这些反应受体外人肺上皮细胞和巨噬细胞的丝裂原活化蛋白激酶(MAPK)和核因子-kappaB(NF-(B))信号通路的激活以及体内小鼠吸入肺损伤模型的调节。COT(癌大阪甲状腺和大鼠同源，肿瘤进展基因2或TPL2)是一种人类原癌基因，是MAPK3K家族中的一种丝氨酸/苏氨酸激酶，表达于造血和肺组织中。COT/Tpl2可诱导ERK1/2和NF-B的表达，并在T细胞活化中发挥作用。我们计划测试石油和生物柴油燃烧的颗粒物是否会以不同的方式激活CoT/Tpl2，并随后以不同的方式激活ERK1/2和NF-(B)通路，导致典型的细胞因子/趋化因子反应和细胞凋亡与增殖之间的平衡改变。这项提案中将获得的数据将为今后的研究奠定基础，这些研究旨在确定导致肺损伤的废气排放的特定成分，以及可能减弱致病反应的潜在干预措施。 与公共健康相关：生物柴油被吹捧为在农业生产和减少交通部门对环境的影响方面实现能源独立和可持续发展的重要战略，但与石油柴油一样，生物柴油燃烧会产生颗粒物空气污染。据报道，空气污染中颗粒物的浓度出人意料地低，这对健康造成了不利影响，这使得科学家和公共卫生官员得出结论，长期暴露在与燃烧相关的颗粒物空气污染中，是心肺疾病的一个重要环境风险因素。尽管人们相信生物燃料可能对环境和人类健康更好，但关于生物柴油排放的生物和健康影响的信息非常有限，因此该项目将比较和对比石油和生物柴油燃烧产生的排放颗粒物的生物影响，努力为未来的研究奠定基础，这些研究旨在阐明空气颗粒物与肺病和心脏病之间的重要关系的机制，并开发减少空气污染对健康不利影响的方法。

DESCRIPTION (provided by applicant): Since the 1970's, adverse health effects have been reported at unexpectedly low concentrations of particulate air pollution, leading scientists and public health officials to conclude that long-term exposure to combustion-related fine particulate air pollution is a significant environmental risk factor for heart and lung diseases. Despite numerous studies examining the effects of petroleum diesel (petrodiesel) exhaust emissions on the respiratory system, the mechanisms responsible for the reported adverse human health effects and which features of the particles initiate adverse processes remain elusive. Biodiesel fuel made from vegetable oil or animal fat is gaining momentum as the energy source of the future both in the U.S. and Europe. Biodiesel is typically blended into conventional diesel fuel, and emission testing has shown that biodiesel emissions contain reduced levels of hydrocarbons, carbon monoxide and particulate matter (PM) but a higher concentration of soluble organic fraction. The hypothesis to be tested is that particulates from biodiesel combustion will have less adverse lung effects compared to those from petrodiesel. The biological effects will include cell death and compensatory cell growth and inflammatory responses, regulated by the activation of the Mitogen-activated Protein Kinase (MAPK) and Nuclear Factor-kappa B (NF-(B) signaling pathways in human lung epithelial cells and macrophages in vitro and an in vivo murine inhalation model of lung injury. Cot (cancer osaka thyroid and rat homologue, tumor progression locus 2 or Tpl2), a human proto-oncogene, is a serine/threonine kinase in the MAP Kinase kinase kinase (MAPK3K) family that is expressed in hematopoietic and lung tissues. COT/Tpl2 has been shown to induce ERK1/2 and NF-(B and play a role in T cell activation. We plan to test whether particulates from petro- and biodiesel combustion will differentially activate COT/Tpl2 and subsequently differentially activate ERK1/2 and NF-(B pathways leading to characteristic cytokine/chemokine responses and a shift in the balance between cell apoptosis and proliferation. The data to be obtained in this proposal will lay the groundwork for future studies aimed at identifying the specific components of exhaust emissions that lead to lung injury and the potential interventions that may attenuate the pathogenic responses. PUBLIC HEALTH RELEVANCE: Biodiesel has been touted as an important strategy for energy independence as well as sustainability in terms of agricultural production and reduced environmental impact from the transportation sector, but as with petrodiesel, combustion of biodiesel produces particulate air pollution. Adverse health effects have been reported at unexpectedly low concentrations of particulate matter in air pollution, leading scientists and public health officials to conclude that long-term exposure to combustion-related particulate air pollution is a significant environmental risk factor for heart and lung diseases. Despite the belief that biofuels may be better for the environment and for human health, there is very limited information about the biological and health effects of biodiesel emissions so this project will compare and contrast the biological effects of emission particles from the combustion of petro- and biodiesel in an effort to lay the groundwork for future studies aimed at elucidating the mechanisms responsible for the significant relationship between airborne particulates and lung and heart disease and at developing approaches to reduce the adverse health consequences of air pollution.