Nitrated Fatty Acids, Novel Anti-inflammatory Mediators in Allergic Airway Diseas

硝化脂肪酸，过敏性气道疾病中的新型抗炎介质

基本信息

批准号：
8051830
负责人：
RAJU C REDDY
金额：
$ 32.28万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-01 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8051830
关键词：
Ablation Agonist Air Allergens Allergic Animal Model Anti-Inflammatory Agents Anti-inflammatory Asthma Attenuated Biological Bronchoalveolar Lavage Fluid Chemicals Combined Modality Therapy Cyclic AMP Cyclic GMP Data Development Disease Epithelial Cells Fatty Acids Feedback Gene Silencing Genetic Genetically Engineered Mouse Health Human In Vitro Inflammation Inflammation Mediators Inflammatory Injection of therapeutic agent Interleukin-17 Interleukin-4 Investigation Knock-out Lead Ligands Liquid substance Lung Lung Inflammation Lung diseases Measures Mediating Modeling Mucins Mucous body substance Mus New Agents Nitrates Nitric Oxide Nitric Oxide Synthase Nuclear Nuclear Receptors Peroxisome Proliferator-Activated Receptors Physiological Plasma Play Process Production Protein Isoforms Public Health Reaction Research Role Serum Severities Side Signal Pathway Staging TNF gene Testing Unsaturated Fatty Acids Urine Validation airway hyperresponsiveness allergic airway disease allergic response cell type chemokine cockroach allergen compound 30 cytokine in vivo inhibitor/antagonist novel novel strategies novel therapeutics overexpression public health relevance response transcription factor

项目摘要

DESCRIPTION (provided by applicant): Asthma is a highly prevalent airway disease that is a major public health problem for which available treatment options are inadequate. Endogenous nitrated fatty acids (NFAs), thought to be produced from NO, have recently been identified as important bioactive compounds present in human plasma. Although investigation of their biological activities is at an early stage, evidence is accumulating that they are potent anti-inflammatory molecules. Our preliminary data show that administration of exogenous NFAs can significantly attenuate pathophysiologic manifestations in a murine model of allergic airway disease, whereas inhibiting endogenous NFA synthesis exacerbates allergic responses. NFAs activate the nuclear transcription factor peroxisome proliferator-activated receptor-? (PPAR-?) in some cell types, and we have found that allergic responses are exacerbated when PPAR-? is genetically eliminated but are attenuated by overexpression of PPAR-? in airway epithelial cells in vivo. Accordingly, we propose to test the hypothesis that activation of airway epithelial cell PPAR-? by nitrated fatty acids significantly suppresses the effects of allergic airway disease, including inflammation and mucus production. Our Specific Aims are: 1) to determine the extent to which NFAs modulate PPAR-? activity in the lung and the severity of murine allergic airway disease, for which we will use mice constitutively lacking all three isoforms of nitric oxide synthase (triple NOS knockout) and therefore expected to lack NFAs; 2) to determine whether PPAR-? activation in airway epithelial cells mediates NFAs' ability to inhibit effects of allergen challenge in murine allergic airway disease, for which we will utilize mice with PPAR-? either knocked out or overexpressed selectively in airway epithelial cells; and 3) to determine whether NFAs inhibit chemokine and mucus production in cultured human airway epithelial cells and the extent to which these effects are mediated through PPAR-?-dependent and/or PPAR-?-independent mechanisms, for which we will use gene silencing and chemical inhibition to suppress PPAR-? while testing for activation of other signaling pathways. For Aims 1 and 2 we will utilize an established murine model of allergic airway disease induced by cockroach allergen, while Aim 3 will be carried out in vitro using well differentiated primary human bronchial epithelial cells grown at an air-liquid interface. Validation of our hypothesis will identify and elucidate the mechanisms through which a novel endogenous substance modulates the severity of allergic airway disease and may lead to new therapeutic avenues and treatments for asthma. PUBLIC HEALTH RELEVANCE: Asthma is a serious, highly-prevalent lung disease. Our research will determine whether substances recently identified within our bodies reduce allergic airway responses. We will determine the mechanisms by which these substances act, leading to a better understanding of the processes underlying asthma and possibly to development of new approaches and agents for asthma therapy.

描述（由申请人提供）：哮喘是一种非常普遍的气道疾病，是一个主要的公共卫生问题，可用的治疗选择不足。被认为是由NO产生的内源性硝酸脂肪酸（NFA）最近被确定为人血浆中存在的重要生物活性化合物。尽管对其生物活性的研究处于早期阶段，但有证据表明它们是有效的抗炎分子。我们的初步数据表明，外源性NFA的给药可以在过敏性气道疾病的鼠模型中显着减轻病理生理表现，而抑制内源性NFA合成会加剧过敏反应。 NFA激活核转录因子过氧化物酶体增殖物激活的受体？（PPAR-？）在某些细胞类型中，我们发现当PPAR-时过敏反应会加剧吗？是否可以消除遗传学，但会因PPAR的过表达而减弱？在气道上皮细胞中。因此，我们建议测试气道上皮细胞PPAR-激活的假设？通过硝化脂肪酸，可以显着抑制过敏性气道疾病的作用，包括炎症和粘液产生。我们的具体目的是：1）确定哪种NFA调节PPAR-的程度？肺部的活性和鼠过敏性气道疾病的严重程度，为此，我们将使用小鼠组成小鼠缺乏一氧化氮合酶的所有三种同工型（Triple NOS敲除），因此预计缺乏NFA。 2）确定是否pPAR-？气道上皮细胞中的激活介导了NFAS抑制过敏原挑战在鼠过敏性气道疾病中的作用的能力，为此我们将使用PPAR-的小鼠？在气道上皮细胞中选择性地撞倒或过表达。 3）确定NFA在培养的人气道上皮细胞中是否抑制趋化因子和粘液产生，以及通过PPAR介导的这些作用的程度 - ？ - ？ - ？ - ？在测试其他信号通路的激活时。对于目标1和2，我们将使用蟑螂过敏原诱导的已建立的过敏气道疾病模型，而AIM 3将使用在空气界面上生长的良好分化的原发性人支气管上皮细胞在体外进行体外进行。对我们的假设的验证将确定并阐明新型内源物质调节过敏性气道疾病严重程度的机制，并可能导致新的治疗途径和治疗哮喘的治疗方法。公共卫生相关性：哮喘是一种严重的，高尚的肺部疾病。我们的研究将确定我们体内最近发现的物质是否会减少过敏性气道反应。我们将确定这些物质作用的机制，从而更好地理解哮喘的基础过程，以及可能开发新方法和哮喘治疗的药物。