Redox-Derived Pulmonary Anti-Inflammatory Mediators

氧化还原衍生的肺部抗炎介质

• 批准号: 8452097
• 负责人: Bruce Alan Freeman
• 金额: $ 42.36万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-06-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8452097
• 关键词: Address; Amino Acids; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Aspirin; Asthma; Bronchoalveolar Lavage; Cell model; Cells; Characteristics; Chemicals; Chronic; Clinical; Clinical Research; Cysteine; Data; Development; Disease; Environmental Risk Factor; Epithelial Cells; Event; Fatty Acids; Fishes; Foundations; Future; Gene Expression; Generations; High Pressure Liquid Chromatography; Homologous Gene; Indomethacin; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Infiltrate; Irrigation; Ketones; Learning; Ligands; Link; Lipids; Lipoxygenase; Liquid substance; Lung; Mass Spectrum Analysis; Mediating; Mediator of activation protein; Metabolic; Metabolism; Modeling; Molecular; Molecular Target; Mus; Nitrates; Nitric Oxide Synthase; Nuclear; Organism; Oxidases; Oxidation-Reduction; Oxygenases; Patients; Pattern; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Physicians; Post-Translational Protein Processing; Prevalence; Production; Prostaglandin-Endoperoxide Synthase; Protein Array; Proteins; Publishing; Reaction; Regulation; Research; Research Personnel; Resolution; Rodent Model; Sampling; Scientist; Signal Pathway; Signal Transduction; Signaling Protein; Solid; Specimen; Sputum; Sulfhydryl Compounds; Testing; Therapeutic; Transcription Regulatory Protein; Unsaturated Fatty Acids; Work; adduct; airway epithelium; airway inflammation; asthmatic airway; asthmatic patient; base; clinically relevant; cost; cyclooxygenase 2; defined contribution; design; drug discovery; experience; fatty acid oxidation; health care delivery; in vivo; insight; interest; keto fatty acid; macrophage; nitration; novel; novel therapeutic intervention; public health relevance; receptor; response; skills; stem; transcription factor

DESCRIPTION (provided by applicant): The proposed research plan will be pursued by a basic and physician scientist team interested in the development and testing of new drug strategies to treat airway inflammation and asthma. Preliminary data reveal that nitro (RNO2) and a,¿-unsaturated keto (R=O) electrophilic fatty acid oxidation products (EFOX) are produced by inflammatory-activated macrophages and are present at increased concentrations in the airway lining fluids obtained by bronchoalveolar lavage of asthmatic patients. EFOXs are found in predominantly protein-adducted states (explaining why these species were just recently discovered), and are viewed as components of the adaptive response of organisms to inflammation. The investigators have observed that EFOX signal via both receptor-dependent mechanisms (as potent PPAR? ligands) and via electrophile-responsive transcription factor-regulated mechanisms. We intend to characterize the patterns and mechanisms of EFOX production during conditions relevant to airway inflammation in a) cultured airway epithelial cells and inflammatory cells, b) a murine model of asthma and c) sputum and lavage samples obtained from asthmatic patients. This endeavor will employ an unbiased HPLC-mass spectrometry-based "electrophile fishing" strategy. After learning more about the structural characteristics, concentrations and molecular targets of specific EFOXs in airway inflammation, we will evaluate the therapeutic potential of EFOXs in a murine model of asthma by in vivo administration of structurally identical synthetic compounds. The research strategy was designed to test the hypothesis that electrophilic nitro and keto derivatives of unsaturated fatty acids are formed by the oxidative inflammatory milieu of asthmatic airways and mediate anti-inflammatory cell signaling responses. This endeavor is of significance because it a) lends critical insight into fundamental molecular and cellular mechanisms leading to the generation of a new class of inflammatory-regulating species in asthma and b) tests a promising new endogenous mediator-based therapeutic approach for treating asthma patients that is amenable for rapid deployment as a clinical therapeutic strategy.

描述（由申请人提供）：拟议的研究计划将由一个对开发和测试治疗气道炎症和哮喘的新药策略感兴趣的基础和内科科学家团队进行。初步数据显示，硝基（RNO2）和a，不饱和酮（R=O）亲电脂肪酸氧化产物（EFOX）是由炎症激活的巨噬细胞产生的，并且在哮喘患者支气管肺泡灌洗获得的气道衬里液中浓度升高。EFOXs主要处于蛋白质内合状态（解释了为什么这些物种是最近才被发现的），并被视为生物体对炎症适应性反应的组成部分。研究人员观察到EFOX信号通过受体依赖机制(如有效的PPAR？配体)和通过亲电反应转录因子调节机制。我们打算在a)培养的气道上皮细胞和炎症细胞，b)哮喘小鼠模型和c)哮喘患者的痰和灌洗液样本中表征与气道炎症相关的条件下EFOX产生的模式和机制。这项工作将采用一种无偏倚的基于hplc -质谱的“亲电试剂捕捞”策略。在进一步了解特定EFOXs在气道炎症中的结构特征、浓度和分子靶点后，我们将通过在体内给药结构相同的合成化合物来评估EFOXs在小鼠哮喘模型中的治疗潜力。该研究策略旨在验证不饱和脂肪酸的亲电硝基和酮衍生物是由哮喘气道的氧化炎症环境形成并介导抗炎细胞信号反应的假设。这一努力具有重要意义，因为它a)提供了对基本分子和细胞机制的关键见解，从而产生了哮喘中一类新的炎症调节物种；b)测试了一种有前途的基于内源性介质的治疗方法，用于治疗哮喘患者，可以快速部署为临床治疗策略。