权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

The Effects of Nitrate/Nitrite and Conjugated Linoleic Acid Supplementation on the Obese Asthmatic Pathology

硝酸盐/亚硝酸盐和共轭亚油酸补充剂对肥胖哮喘病理的影响

基本信息

批准号：
9297207
负责人：
Stacy Lynn Gelhaus
金额：
$ 23.31万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-15 至 2018-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9297207
关键词：
Address Adipocytes Adult American diet Animal Model Animals Anti-Inflammatory Agents Anti-inflammatory Area Under Curve Arginine Asthma Biological Availability Biological Markers Body Composition Body mass index Breathing Bronchodilator Agents CD4 Positive T Lymphocytes Cardiovascular Diseases Cardiovascular Physiology Cell Culture Techniques Chronic Clinical Clinical Markers Clinical Research Comorbidity Conjugated Linoleic Acids Dairy Products Diastolic blood pressure Diet Dietary Supplementation Disease Dose Drug Compounding Environment Enzymes Epithelial Exhalation Extrinsic asthma FDA approved Fatty Acids Forced expiratory volume function Helper-Inducer T-Lymphocyte Homologous Gene Human Human Volunteers Immune response Impairment Individual Infarction Inflammation Inflammatory Injury Integrative Medicine Intervention Investigational Drugs Label Leptin Link Lung Measures Meat Mediating Mediator of activation protein Metabolic Metabolic Diseases Metabolic syndrome Metabolism Mitochondria Modeling NOS2A gene Nitrates Nitric Oxide Nitric Oxide Synthase Nitrites Nitrogen Oxides Obesity Oleic Acids Oral Outcome Overweight Oxidative Stress Pathology Pathway interactions Phase I Clinical Trials Phenotype Pilot Projects Plasma Post-Translational Protein Processing Production Property Proteins Publishing Pulmonary Function Test/Forced Expiratory Volume 1 Quality of life Questionnaires Reaction Reporting Respiratory Signs and Symptoms Respiratory physiology Risk Ruminants Safety Scheme Severities Signal Transduction Steroids Structure Superoxides Supplementation Symptoms Testing Transcription Regulatory Protein Transferase Unsaturated Fatty Acids Urine Vital capacity adipokines airway hyperresponsiveness airway inflammation asthmatic chemokine cytokine dietary constituent dietary supplements epidemiology study health care service utilization improved inflammatory marker insulin sensitivity methacholine nitration nitroalkene nitrogen dioxide radical nitrosative stress nitrosyl hemoglobin novel strategies novel therapeutics pi bond pre-clinical response safety study

项目摘要

Obesity is an asthma comorbidity associated with increased exacerbation rates and greater healthcare utilization by mechanisms that are not explained by increases in Type 2 helper T cell (Th2)-related biomarkers of airway inflammation associated with atopic asthma. In addition to an altered immune response in the lung (Th1/Th17) obese asthmatics are also plagued by the low-grade, chronic, systemic inflammation attributed to adipocyte secretion of pro-inflammatory chemokines and cytokines. Also contributing to systemic inflammation is the uncoupling of nitric oxide synthase (NOS) by the arginine (Arg) metabolite, asymmetric dimethyl arginine (ADMA). Low Arg/ADMA ratios are correlated with increasing body mass index and the resulting lower fractional exhaled nitric oxide (FeNO). NOS uncoupling leads to low nitric oxide bioavailability and an increase in superoxide anion production, thus contributing to the overall oxidative environment. The objective of this study is to characterize the effects of the dietary supplements nitrate (NO3-) and nitrite (NO2-) (NOx) and conjugated linoleic acid (cLA) on airway hyperresponsiveness and inflammation in obese asthmatics. Epidemiological and clinical studies using NOx or cLA (individually) supplementations have reported on their benefits in relation to disease pathologies including cardiovascular disease and metabolic disorder. A recent pilot study we conducted demonstrated the formation of the electrophilic fatty acid, nitro-cLA (NO2-cLA) from NOx + cLA supplementation in healthy subjects at concentrations ~3X endogenous basal levels. Importantly, these levels are within a dose range that exerts systemic effects in preclinical animal models. This occurs because nitroalkene fatty acids mediate anti-inflammatory signaling actions via post translational modification of key transcriptional regulatory proteins and enzymes. These effects have been demonstrated with NO2-cLA in animal and cell culture models and safety has been demonstrated using a synthetic homolog nitro-oleic acid in FDA-approved phase 1 clinical trials. Since the individual dietary constituents NO3-, NO2-, and cLA are all associated with decreased risk of metabolic syndrome symptoms and NO2-cLA is a modulator of inflammation, it is hypothesized that obese asthmatics treated with NO3- + NO2- (NOx) + cLA will manifest improved FeNO and reduced airway hyperresponsiveness and inflammation. This hypothesis will be tested by pursuing two Specific Aims: Aim 1: Improve airway .NO bioavailability and airway hyperresponsiveness with NOx + cLA treatment. Aim 2: Determine if NOx + cLA reduce the systemic and airway inflammation that contributes to the obese asthmatic phenotype. FeNO and nitrosyl hemoglobin, inflammatory cytokines and chemokines, NO2-cLA, and markers of oxidative stress will be measured as well as clinical markers of asthma including airway hyperresponsiveness and the asthma control test. Positive clinical outcomes using NOx + cLA dietary supplementation provides a complementary and integrative health intervention as well as a novel therapeutic strategy for targeting the obese asthmatic pathology.

肥胖是一种哮喘合并症，与恶化率增加和更好的医疗保健相关 2 型辅助 T 细胞 (Th2) 相关生物标志物的增加无法解释的机制的利用与特应性哮喘相关的气道炎症。除了肺部免疫反应的改变 (Th1/Th17) 肥胖哮喘患者还受到低度、慢性、全身性炎症的困扰，这些炎症归因于脂肪细胞分泌促炎趋化因子和细胞因子。也会导致全身炎症是一氧化氮合酶 (NOS) 与精氨酸 (Arg) 代谢物不对称二甲基精氨酸的解偶联（阿玛）。低 Arg/ADMA 比率与体重指数的增加以及由此产生的较低体重指数相关。呼出一氧化氮 (FeNO) 分数。 NOS 解偶联导致一氧化氮生物利用度降低并增加参与超氧阴离子的产生，从而有助于整体氧化环境。此举的目的研究的目的是表征膳食补充剂硝酸盐 (NO3-) 和亚硝酸盐 (NO2-) (NOx) 的影响共轭亚油酸（cLA）对肥胖哮喘患者气道高反应性和炎症的影响。使用 NOx 或 cLA（单独）补充剂的流行病学和临床研究报告了其效果与疾病病理相关的益处，包括心血管疾病和代谢紊乱。最近的一个我们进行的初步研究证明了亲电子脂肪酸硝基-cLA (NO2-cLA) 的形成健康受试者中 NOx + cLA 的补充浓度约为内源性基础水平的 3 倍。重要的是，这些水平处于在临床前动物模型中产生全身效应的剂量范围内。出现这种情况因为硝基烯烃脂肪酸通过翻译后修饰介导抗炎信号传导作用关键转录调节蛋白和酶。这些效果已通过 NO2-cLA 得到证实在动物和细胞培养模型中，使用合成同系物硝基油酸已证明其安全性 FDA批准的1期临床试验。由于各个膳食成分 NO3-、NO2- 和 cLA 都是与代谢综合征症状风险降低相关，NO2-cLA 是炎症调节剂，据推测，用 NO3- + NO2- (NOx) + cLA 治疗的肥胖哮喘患者将表现出改善 FeNO 并减少气道高反应性和炎症。这个假设将被检验追求两个具体目标：目标 1：改善气道。NO 生物利用度和气道高反应性 NOx + cLA 处理。目标 2：确定 NOx + cLA 是否可以减轻全身和气道炎症导致肥胖哮喘表型。 FeNO 和亚硝酰血红蛋白、炎症细胞因子和将测量趋化因子、NO2-cLA、氧化应激标志物以及哮喘临床标志物包括气道高反应性和哮喘控制测试。使用 NOx + cLA 取得积极的临床结果膳食补充剂提供了一种补充性和综合性的健康干预措施，也是一种新颖的方法针对肥胖哮喘病理的治疗策略。