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

Tlp2/COT 对 ERK1/2 和 NF-kB 响应颗粒物的调节

• 批准号: 8013037
• 负责人: NAOMI K FUKAGAWA
• 金额: $ 7.45万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-11 至 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8013037
• 关键词: Agriculture; Air Pollution; Animals; Apoptosis; Area; Aromatic Compounds; Attenuated; Belief; Biological; Breathing; Caliber; Carbon Monoxide; Cardiopulmonary; Cardiovascular Diseases; Cardiovascular system; Cell Death; Cells; Characteristics; Chemistry; Data; Development; Diesel Exhaust; Diesel Fuels; Disease; Distal; Endotoxins; Energy-Generating Resources; Engineering; Environment; Environmental Impact; Environmental Risk Factor; Epidemiology; Epithelial Cells; Equilibrium; Europe; Exposure to; Family; Fatty acid glycerol esters; Fibrosis; Future; Health; Heart Diseases; Homologous Gene; Human; Human Cell Line; Hydrocarbons; In Vitro; Inflammation Mediators; Inflammatory Response; Intervention; Lead; Letters; Link; Lung; Lung diseases; MAP Kinase Kinase Kinase; MAP3K8 gene; MAPK3 gene; Malignant Neoplasms; Malignant neoplasm of lung; Mitogen-Activated Protein Kinases; Modeling; Morbidity - disease rate; Mus; NF-kappa B; Nose; Particle Size; Particulate; Particulate Matter; Pathogenesis; Pathway interactions; Petroleum; Play; Pneumonia; Process; Production; Property; Protein-Serine-Threonine Kinases; Proto-Oncogenes; Public Health; Pulmonary Heart Disease; Rattus; Regulation; Reporting; Research; Respiratory System; Role; Schools; Scientist; Signal Pathway; Source; Structure of parenchyma of lung; Sulfur; T-Cell Activation; Testing; Thyroid Gland; Transportation; Ultrafine; Universities; Vegetable Oils; Vermont; base; cell growth; chemokine; cytokine; design; exhaust; hematopoietic tissue; in vivo; lung injury; macrophage; mortality; particle; planetary Atmosphere; public health relevance; response

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.

描述（由申请人提供）：自1970年代以来，以意外浓度低的颗粒空气污染报道了不良健康影响，领先的科学家和公共卫生官员得出结论，长期暴露于燃烧相关的细颗粒空气污染是一项重大心脏和肺部疾病的环境风险因素。尽管许多研究检查了石油柴油（石油）排气排放对呼吸系统的影响，但导致报告的不良人类健康效应的机制以及颗粒的哪些特征引发了不良过程仍然难以捉摸。由植物油或动物脂肪制成的生物柴油燃料正在获得动力，这是美国和欧洲未来的能源。生物柴油通常混合到常规的柴油燃料中，发射测试表明，生物柴油排放含有降低的碳氢化合物水平，一氧化碳和颗粒物（PM），但可溶性有机分数较高。要测试的假设是，与石油柴油相比，来自生物柴油燃烧的颗粒将具有较少的不良肺作用。生物学作用将包括细胞死亡和补偿性细胞生长和炎症反应，受丝分裂原激活蛋白激酶（MAPK）（MAPK）和核因子-Kappa B（NF-（B）信号通路的激活调节）体外和体内鼠吸入肺损伤模型。 ）在造血和肺组织中表达的家族已显示出诱导ERK1/2和NF-（B中的TPL2（B），我们计划在T细胞激活中起作用。激活COT/TPL2，然后随后差异激活ERK1/2和NF-（B途径导致特征性细胞因子/趋化因子反应以及细胞凋亡和增殖之间的平衡发生变化。该提案中要获得的数据将为将来提供构成目标。旨在确定导致肺损伤的排气排放的特定组成部分以及可能减轻致病反应的潜在干预措施。 公共卫生相关性：生物柴油已被吹捧为能源独立性以及在农业生产方面的可持续性的重要策略，并减少了运输部门的环境影响，但是与石油柴油一样，生物柴油的燃烧会产生颗粒空气污染。在空气污染中，据报道，在意外浓度的颗粒物浓度下，不良健康的影响，导致科学家和公共卫生官员得出结论，长期暴露于燃烧相关的颗粒空气污染是心脏和肺部疾病的重要环境风险因素。尽管认为生物燃料可能对环境和人类健康更好，但有关生物柴油排放的生物学和健康影响的信息非常有限，因此该项目将比较和对比发射颗粒的生物学作用生物柴油为了为未来的研究奠定基础，旨在阐明负责空气颗粒与肺与心脏病之间显着关系的机制，以及开发方法以减少空气污染的不利健康后果。

项目成果

Soy biodiesel and petrodiesel emissions differ in size, chemical composition and stimulation of inflammatory responses in cells and animals.

• DOI: 10.1021/es403146c
• 发表时间: 2013
• 期刊: ENVIRONMENTAL SCIENCE & TECHNOLOGY
• 影响因子: 11.4
• 作者: Fukagawa, Naomi K.;Li, Muyao;Poynter, Matthew E.;Palmer, Brian C.;Parker, Erin;Kasumba, John;Holmen, Britt A.
• 通讯作者: Holmen, Britt A.

Sex-specific metabolic adaptations from in utero exposure to particulate matter derived from combustion of petrodiesel and biodiesel fuels.

• DOI: 10.1016/j.chemosphere.2023.140480
• 发表时间: 2023-10
• 期刊: Chemosphere
• 影响因子: 8.8
• 作者: T. Jetton;Oban T. Galbraith;Mina Peshavaria;Elizabeth A. Bonney;B. Holmén;Naomi K. Fukagawa