TOXIC INTERACTIONS OF AIR POLLUTANT COMPOUNDS

空气污染物的毒性相互作用

• 批准号: 8168075
• 负责人: MICHAEL P DOHM
• 金额: $ 23.9万
• 依托单位: UNIVERSITY OF HAWAII AT MANOA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8168075
• 关键词: Acute; Adult; Affect; Air Pollutants; Air Pollution; Alveolar Macrophages; Antioxidants; Asthma; Binding; Binding Proteins; Cardiovascular Diseases; Cell Adhesion; Cell Nucleus; Cell Surface Proteins; Cell membrane; Cells; Cessation of life; Chronic Obstructive Airway Disease; Complex; Computer Retrieval of Information on Scientific Projects Database; Coronary; Cytoplasm; DNA; Epidemiologic Studies; Epithelial Cells; Event; Family; Free Radicals; Funding; Gene Expression; Gene Expression Regulation; Gene Targeting; Genes; Genetic; Genetic Enhancer Element; Genetic Transcription; Goals; Grant; Heat-Shock Response; Homo; Hour; Human; IL8 gene; In Vitro; Inflammatory Response; Institution; Link; Lipids; Lung; MAPK14 gene; Membrane; Molecular; NF-kappa B; Nuclear; Osmotic Shocks; Oxidants; Ozone; Pathway interactions; Pattern; Populations at Risk; Protein Biosynthesis; Proteins; Reactive Oxygen Species; Research; Research Personnel; Resources; Rodent Model; SAPK; Signal Transduction; Source; Stimulus; Stress; Sunlight; TNFRSF5 gene; Testing; Tissues; Translating; United States; United States National Institutes of Health; Work; activating transcription factor; cell type; chemokine; cytokine; environmental agent; exhaust; immune function; in vivo; innate immune function; lipid metabolism; macrophage; middle age; mitogen-activated protein kinase p38; oxidative damage; ozone exposure; p65; premature; promoter; receptor; repaired; respiratory; surfactant; transcription factor; ultraviolet irradiation

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Despite significant improvement in control of point source emissions during the past 30 years, air pollution continues to contribute to thousands of premature deaths each year in the United States. Recent epidemiological studies also link O3 to acute coronary events in otherwise healthy, middle-aged adults. Asthmatics and other at-risk populations are known to be particularly sensitive to O3, which has recently (June 2007) prompted the EPA to recommend amending the federal standards from 80 ppb to 70 ppb (8 hour standard). Ozone (O3), produced at ground levels from an interaction between sunlight and vehicle exhaust emissions, is highly reactive with human respiratory tissues. Exposure leads to reduced respiratory and altered immune function. O3 is known to cause or exacerbate many pulmonary conditions, including asthma and chronic obstructive pulmonary disease. Ozone may induce its adverse affects directly by oxidizing cell surface proteins and lipids which act to promote cellular repair and inflammatory responses. Alternatively, or in combination, O3 may act indirectly via reactive oxygen species (ROS) pathways which leads to oxidative damage. In rodent models, the effects of O3 are strain-specific, suggesting genetic background is significant. Most studies also implicate modulation by cytokines/chemokines signaling among different cell types (resident macrophages, alveolar epithelial cells, etc.). Thus, we seek to elucidate how oxidant air pollutants may exacerbate or trigger proinflammatory molecular mechanisms that contribute to pulmonary and cardiovascular disease. We combine in vivo and in vitro approaches to analyze complex gene expression and regulation patterns between experimental and control subjects. All cells that respond to external stimuli share the same challenge; how to translate recognition of a stimulus into changes within the cell. Recognition of stimuli is typically via receptors on the outside of the cells, and extra cellular signals then must be transmitted across the cell membrane. These receptors, typically integral or membrane-bound proteins, are required for signal transduction, the conversion from one form of a signal into another. SAPK and p38 are responsive to stress stimuli, such as cytokines, ultraviolet irradiation, heat shock, and osmotic shock, and regulate many cellular activities. SAPK and p38 affect transcription of genes via activation of transcription factors, with the transcription factor NF-kB perhaps the most essential (e.g., for IL-8 gene expression). The NF-kB family of transcription factors consists of homo- or hetero-dimeric subunits of the Rel family including p50, p52, p65/RelA, c-Rel, and Rel-B. Induction of NF-kB activity does not require protein synthesis. Instead, in unstimulated cells, most of NF-kB is inactive and localized in the cytoplasm bound by an inhibitory protein, IkB. When the cell is stimulated, both proinflammatory cytokines (e.g., TNF-a) and free radical intermediates (ROS and RNS), IkB is phosphorylate, then degraded, allowing NF-kB to move to the nucleus and bind to DNA targets, thus activating transcription of specific target genes. The result of ozone exposure on lung epithelial cells is rapid expression of 100's of genes; these genes can be grouped into clusters of known function within the lung cells, including those that affect innate immune function, cell adhesion, surfactant protein and lipid metabolism, and the antioxidant status of the cell. Ozone is among the numerous environmental agents that activates the transcription factor NF-kB nuclear binding activity in lung macrophage and epithelial cells. Many of the genes that are expressed within hours of ozone exposure are controlled by NF-kB (i.e., have binding regions in promoter or enhancer elements). However, it is unclear whether ozone activates NF-kB via SAPK or p38, or whether both are activated and essential; therefore, one of the primary goals of this proposed work is to test whether SAPK, p38, or both are essential for ozone-induced activation of NF-kB pathway in lung epithelial cells.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 尽管在过去30年中，对点源排放的控制有了显着改善，但在美国，空气污染每年仍会导致数千个过早死亡。 最近的流行病学研究还将O3与其他健康的中年成年人的急性冠状动脉事件联系起来。 众所周知，哮喘患者和其他高危人群对O3特别敏感，最近（2007年6月）促使EPA建议将联邦标准从80 ppb到70 ppb（8小时标准）修改。 臭氧（O3）是由于阳光与媒介物排气排放之间的相互作用而在基础水平上产生的，它与人呼吸道组织具有高反应性。 暴露导致呼吸道减少和免疫功能改变。 已知O3会引起或加剧许多肺部状况，包括哮喘和慢性阻塞性肺部疾病。 臭氧可以通过氧化细胞表面蛋白和脂质直接诱导其不良影响，这些蛋白和脂质起促进细胞修复和炎症反应。 另外，O3可以通过活性氧（ROS）途径间接起作用，从而导致氧化损伤。 在啮齿动物模型中，O3的作用是特异性的，表明遗传背景很重要。 大多数研究还暗示了不同细胞类型（驻留巨噬细胞，肺泡上皮细胞等）中细胞因子/趋化因子信号传导的调节。 因此，我们试图阐明氧化剂空气污染物如何加剧或触发促炎性分子机制，从而导致肺和心血管疾病。 我们结合了体内和体外方法，以分析实验和对照受试者之间的复杂基因表达和调节模式。 所有对外部刺激反应的细胞都有同样的挑战；如何将刺激的识别转化为细胞内的变化。刺激的识别通常是通过细胞外部的受体进行的，然后必须在整个细胞膜上传播额外的细胞信号。这些受体（通常是积分或膜结合的蛋白）是信号转导所必需的，从一种信号的一种形式转换为另一种信号。 SAPK和p38对应力刺激有反应，例如细胞因子，紫外线照射，热休克和渗透性休克，并调节许多细胞活性。 SAPK和p38通过转录因子的激活影响基因的转录，转录因子NF-KB可能是最重要的（例如，对于IL-8基因表达）。 NF-KB转录因子家族由RER家族的同型或异二聚亚基组成，包括P50，P52，P65/RELA，C-REL和REL-B。 NF-KB活性的诱导不需要蛋白质合成。取而代之的是，在未刺激的细胞中，大多数NF-KB都是不活跃的，并将其局部定位于受抑制蛋白IKB结合的细胞质中。当细胞刺激细胞时，促炎细胞因子（例如TNF-A）和自由基中间体（ROS和RNS）均具有磷酸化，然后降解，允许NF-KB移动到原子核并结合到DNA靶标，从而激活特定靶基因的特定靶基因转录。在肺上皮细胞上暴露臭氧的结果是100个基因的快速表达。这些基因可以分为肺部细胞中已知功能的簇，包括影响先天免疫功能，细胞粘附，表面活性剂蛋白和脂质代谢以及细胞的抗氧化剂状态。臭氧是激活肺巨噬细胞和上皮细胞中转录因子NF-KB核结合活性的众多环境药物之一。臭氧暴露时间内表达的许多基因都由NF-KB控制（即在启动子或增强子元素中具有结合区域）。但是，目前尚不清楚臭氧是否通过SAPK或P38激活NF-KB，还是两者都被激活和必不可少的。因此，这项提出的工作的主要目标之一是测试SAPK，p38还是两者都是臭氧诱导的肺上皮细胞中NF-KB途径的激活所必需的。