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

• 批准号: 9180182
• 负责人: Stacy Lynn Gelhaus
• 金额: $ 19.25万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-15 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9180182
• 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; Epidemiologic Studies; Epithelial; Exhalation; Extrinsic asthma; FDA approved; Fatty Acids; Forced expiratory volume function; Helper-Inducer T-Lymphocyte; Homologous Gene; Human; Human Volunteers; Immune response; 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; NBL1 gene; NOS2A gene; Nitrates; Nitric Oxide; Nitric Oxide Synthase; Nitrites; Nitrogen Oxides; Obesity; Oleic Acids; Outcome; Overweight; Oxidative Stress; Pathology; Pathway interactions; Phase I Clinical Trials; Phenotype; Pilot Projects; Plague; 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; 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

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，与加重率增加和更多的医疗保健相关 2型辅助性T细胞（Th 2）相关生物标志物增加无法解释的机制的利用 与过敏性哮喘相关的气道炎症除了肺部免疫反应的改变 (Th1/Th 17）肥胖哮喘患者还受到归因于哮喘的低度、慢性、全身性炎症的困扰。 脂肪细胞分泌促炎趋化因子和细胞因子。也会导致全身性炎症 是精氨酸（Arg）代谢产物不对称二甲基精氨酸对一氧化氮合酶（NOS）的解偶联 （ADMA）。低Arg/ADMA比值与体重指数增加相关， 呼出气一氧化氮分数（FeNO）。NOS解偶联导致一氧化氮生物利用度低， 在超氧阴离子的生产，从而有助于整体氧化环境。的目的 研究是为了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）表征的流行病学和临床研究已经报道了其 与包括心血管疾病和代谢紊乱在内的疾病病理学相关的益处。最近的一 我们进行的初步研究表明，亲电脂肪酸，硝基-cLA（NO2-cLA）的形成， 健康受试者中浓度约为内源性基础水平3倍的NOx + cLA补充。重要的是， 这些水平在临床前动物模型中发挥全身作用的剂量范围内。发生这种情况 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 关键的转录调节蛋白和酶。这些效应已在NO2-cLA中得到证实 在动物和细胞培养模型中，使用合成同系物硝基油酸 在FDA批准的第一阶段临床试验中。由于单个膳食成分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， 假设用NO3- + NO2-（NOx）+ cLA治疗的肥胖哮喘患者将表现出改善， FeNO和降低气道高反应性和炎症。这一假设将由以下人员进行检验： 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。目的2：确定NOx + cLA是否减少全身和气道炎症， 导致了肥胖型哮喘。FeNO和亚硝基血红蛋白，炎性细胞因子和 将测量趋化因子、NO2-cLA和氧化应激标志物以及哮喘的临床标志物 包括气道高反应性和哮喘控制测试。使用NOx + cLA的积极临床结局 膳食补充剂提供了一种补充和综合的健康干预措施， 针对肥胖哮喘病理的治疗策略。