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

描述（由申请人提供）：自20世纪70年代以来，报道了意想不到的低浓度颗粒空气污染对健康的不利影响，主要科学家和公共卫生官员得出结论，长期暴露于与燃烧有关的细颗粒空气污染是心脏和肺部疾病的重要环境风险因素。尽管有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，但所报告的对人类健康造成不利影响的机制以及颗粒的哪些特征引发了不利过程，仍然难以理解。在美国和欧洲，从植物油或动物脂肪中提取的生物柴油正在成为未来的能源。生物柴油通常与传统柴油混合，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）含量较低，但可溶性有机组分的浓度较高。要测试的假设是，与石油柴油相比，生物柴油燃烧产生的微粒对肺部的不良影响更小。生物效应将包括细胞死亡、代偿性细胞生长和炎症反应，由丝裂原活化蛋白激酶（MAPK）和核因子- κ B (NF-(B)信号通路的激活调节，在体外的人肺上皮细胞和巨噬细胞和体内的小鼠肺损伤吸入模型中。Cot （cancer osaka thyroid and rat homologue, tumor progression locus 2 or Tpl2）是一种人类原癌基因，是MAP激酶激酶激酶（MAPK3K）家族中的丝氨酸/苏氨酸激酶，在造血和肺组织中表达。COT/Tpl2已被证明可诱导ERK1/2和NF-(B)，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产生的颗粒是否会不同地激活COT/Tpl2，随后不同地激活ERK1/2和NF- B通路，从而导致特征性的细胞因子/趋化因子反应，并改变细胞凋亡和增殖之间的平衡。本提案中获得的数据将为未来的研究奠定基础，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轻致病反应的潜在干预措施。

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.