Exposure and biological response biomarkers of cigarette smoke

香烟烟雾的暴露和生物反应生物标志物

基本信息

批准号：
7847893
负责人：
Ian Alexander Blair
金额：
$ 0.79万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-15 至 2009-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7847893
关键词：
11p 2&apos -deoxyadenosine 8-Oxo-2&apos -Deoxyguanosine Acids Anabolism Antibodies Antioxidants Arachidonic Acids Aromatic Polycyclic Hydrocarbons Arts Atmospheric Pressure Basic Science Benzo(a)pyrene Binding Biological Biological Assay Biological Markers Bronchoconstriction Bronchoconstrictor Agents Carcinogens Cardiovascular Diseases Cardiovascular system Cause of Death Cell Line Cells Chemicals Chronic Obstructive Airway Disease Cigarette Cigarette Smoker Comet Assay Complex Mixtures Cotinine Coupled Cytochrome P450 DNA DNA Adduction DNA Adducts DNA Damage Deoxyguanosine Digestion Dinoprost Disease Electrons Environment Environmental Exposure Environmental Tobacco Smoke Enzymes Epithelial Epithelial Cells Epoxide hydrolase Excretory function Exhalation Exposure to Family Feedback Future Generations Genes Genomics Glutathione Glycols Guanine Human Hydrolysis Hydroxyeicosatetraenoic Acids Inflammatory Inflammatory Response Isomerism Isoprostanes Isotopes Label Lead Lesion Link Linoleic Acids Lipid Peroxidation Lipid Peroxides Lipids Lipoxygenase Liquid Chromatography Liquid substance Lung Mainstreaming Malignant Neoplasms Malignant neoplasm of pancreas Malignant neoplasm of urinary bladder Mass Spectrum Analysis Measurement Measures Mediating Messenger RNA Metabolic Activation Metabolism Methodology Methods Modeling Monitor Mutagens Nicotine Oxidation-Reduction Oxidative Stress Oxides Oxidoreductase PGF receptor PTGS2 gene Pathway interactions Peptide Hydrolases Phenotype Polyunsaturated Fatty Acids Population Production Prostaglandin D2 Prostaglandin H2 Prostaglandins Protein Isoforms Protein Secretion Proteins Proteome Proteomics Protocols documentation Pyrenes Quinones Reaction Reactive Oxygen Species Regulation Relative (related person)Reporting Research Research Design Resolution Response Elements Role Sampling Sensitivity and Specificity Serum Serum Proteins Skin Smoke Smoker Smoking Smooth Muscle Smooth Muscle Myocytes Specificity Stable Isotope Labeling Sulforaphane Techniques Testing Time Tobacco Tobacco smoke Transcript Transferase Urine adduct base cell type cigarette smoking cigarette smoking cohort cytokine detoxication enantiomer feeding gene environment interaction human subject in vivo interest ionization killings multiple reaction monitoring non-smoker novel therapeutics oxidation oxidative DNA damage oxidized lipid perhydroxyl radical peroxidation promoter prostaglandin-F synthase respiratory smooth muscle response small molecule stable isotope stem tandem mass spectrometry urinary

项目摘要

Exposure and biological response biomarkers of cigarette smoke. Exposure to tobacco smoke (mainstream and environmental) is a leading cause of death in the US. Cigarette smoke is an extremely complex mixture, which some 3800 constituents including numerous polycyclic aromatic hydrocarbons (PAHs), in both the mainstream and sidestream (environmental) smoke fractions. Cigarette smokers provide an extreme model of PAH exposure that will permit both exposure and biological response biomarkers to be developed. There is substantial evidence that PAHs are causative agents in lung, skin, and bladder cancer. Furthermore, tobacco smoke is associated with oxidative stress, pancreatic cancer, cardiovascular disease, and chronic obstructive pulmonary disease (COPD), although the specific role of PAHs is not clear. Interestingly, the cardiovascular effects of sidestream smoke are almost as great as mainstream smoke. The present proposal stems from significant advances we have made over the last six years in the quantification of protein, lipid, and DNA biomarkers using stable isotope methodology and our basic research into enzyme regulation during oxidative stress. Previous methods for he the analysis of oxidative DNA damage has been fraught with numerous methodological problems so that the current state-of-the-art involves the use of a COMET assay to measure 8-oxo-2'-deoxyguanosine (dGuo) lesions. We have recently devised a more quantitative method based on immunoaffinity stable isotope dilution liquid chromatography- tandem mass spectrometry (LC-MS/MS) that can be readily elaborated to studies of tobacco smokers. We also showed that oxidative stress could induce the formation of aldo-keto reductases (AKRs) of the 1C family. AKR1C3 is the enzyme, which we recently showed is responsible for the conversion of prostaglandin (PG) D2 to the potent bronchoconstrictor 11p-PGF2. This provides an additional potential link between oxidative stress and COPD as well as the potential for a new therapeutic strategy, which involves AKR1C3 inhibition. Finally, preliminary studies have revealed that a DNA-adduct than can only arise from lipid peroxidation is present in the urine of cigarette smokers but is completely absent in urine from non-smokers. We propose to build on these exciting new findings by developing panels of in vivo biomarkers of exposure and biological response, which we hypothesize will make it possible to distinguish a cohort of non-smokers from a cohort of disease-free tobacco smokers. The hypothesis will be tested by conducting research under the following three specific aims: Aim 1. To discover whether B[a]P and B[a]P-7,8-dione induce AKR1C/2 in NHBE cells and increase oxidative stress to form 8-oxo-dGuo and HedGuo in DNA, induce AKR1C3 in HASM cells and increase the biosynthesis of the potent bronchoconstrictor 11p-PGF2, as potential urine and EEC biological response biomarkers of PAH exposure. Aim 2: To discover secreted proteins following treatment of NHBE and HASM cells with B[a]P and its oxidative metabolites as potential serum biological response biomarkers of PAH exposure. Aim 3: To conduct predictive and refinement analyses of in vivo exposure and response biomarkers in urine together with biological response biomarkers in EBC and serum in order to distinguish non-smokers from disease-free tobacco smokers. Successful completion of the proposed research will provide a panel of biomarkers of exposure and biological response to tobacco smoke will have significant utility in future studies designed to elucidate the relationship between gene environment interactions and diseases such as cancer, cardiovasculardisease, and COPD.

香烟烟雾的暴露和生物反应生物标志物。接触烟草烟雾（主流和环境）是美国死亡的主要原因。香烟烟雾是一种极其复杂混合物，约有 3800 种成分，其中包括多种多环芳烃（多环芳烃），存在于主流和侧流（环境）烟雾组分中。吸烟者提供 PAH 暴露的极端模型将允许暴露和生物反应生物标志物发达。有大量证据表明多环芳烃是肺癌、皮肤癌和膀胱癌的致病因素。此外，烟草烟雾与氧化应激、胰腺癌、心血管疾病、和慢性阻塞性肺疾病（COPD），尽管多环芳烃的具体作用尚不清楚。有趣的是，侧流烟雾对心血管的影响几乎与主流烟雾一样大。本提案源于我们过去六年在以下领域取得的重大进展：使用稳定同位素方法定量蛋白质、脂质和 DNA 生物标志物以及我们的基础研究氧化应激期间的酶调节。以前的氧化 DNA 分析方法损害充满了许多方法论问题，因此当前最先进的方法涉及使用 COMET 测定来测量 8-oxo-2'-脱氧鸟苷 (dGuo) 损伤。我们最近有设计了一种基于免疫亲和稳定同位素稀释液相色谱的更加定量的方法- 串联质谱 (LC-MS/MS) 可轻松用于吸烟者的研究。我们还表明氧化应激可以诱导 1C 醛酮还原酶 (AKR) 的形成家庭。 AKR1C3 是一种酶，我们最近证明它负责前列腺素的转化 (PG) D2 为强效支气管收缩剂 11p-PGF2。这提供了之间的额外潜在联系氧化应激和 COPD 以及涉及 AKR1C3 的新治疗策略的潜力抑制。最后，初步研究表明 DNA 加合物只能由脂质产生吸烟者的尿液中存在过氧化作用，但不吸烟者的尿液中完全不存在过氧化作用。我们建议通过开发体内暴露生物标志物组来建立这些令人兴奋的新发现和生物反应，我们假设这将能够区分一群非吸烟者来自一群没有疾病的吸烟者。该假设将通过进行研究来检验以下三个具体目标：目的 1. 探索 B[a]P 和 B[a]P-7,8-二酮是否诱导 AKR1C/2 NHBE细胞增加氧化应激，在DNA中形成8-oxo-dGuo和HedGuo，诱导AKR1C3 HASM 细胞并增加强效支气管收缩剂 11p-PGF2 的生物合成，作为潜在的尿液和 EEC 多环芳烃暴露的生物反应生物标志物。目标 2：发现以下分泌蛋白用 B[a]P 及其氧化代谢物作为潜在的血清生物处理 NHBE 和 HASM 细胞 PAH 暴露的反应生物标志物。目标 3：进行体内预测和细化分析尿液中的暴露和反应生物标志物以及 EBC 和血清中的生物反应生物标志物为了区分非吸烟者和无病吸烟者。圆满完成了拟议的研究将提供一组关于烟草烟雾暴露和生物反应的生物标志物将在未来旨在阐明基因环境之间关系的研究中具有重要作用相互作用和疾病，如癌症、心血管疾病和慢性阻塞性肺病。