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.

肥胖是一种哮喘共病，与病情加重和更好的医疗保健有关。 2型辅助T细胞(Th2)相关生物标志物的增加不能解释的机制的利用 与特应性哮喘相关的呼吸道炎症。除了肺部免疫反应的改变 (Th1/Th17)肥胖哮喘患者也受到低级别、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。也会导致全身炎症 是一氧化氮合酶(NOS)被精氨酸(Arg)代谢物不对称二甲基精氨酸解偶联 (ADMA)。Arg/ADMA比值低与体重指数增加和由此导致的较低相关 呼出部分一氧化氮(FeNO)。一氧化氮合酶解偶联导致一氧化氮生物利用度降低 在超氧阴离子的产生中，因此有助于整个氧化环境。这样做的目的是 研究是为了表征膳食补充剂硝酸盐(NO3-)和亚硝酸盐(NO2-)(NOx)和 共轭亚油酸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他们的 与包括心血管疾病和代谢紊乱在内的疾病病理有关的益处。最近 我们进行的初步研究表明，从 NOx+CLA在健康受试者中的补充浓度约为内源性基础水平的3倍。重要的是 这些水平在临床前动物模型中产生全身影响的剂量范围内。这种情况会发生 因为硝基烯烃脂肪酸通过翻译后修饰介导抗炎信号作用 关键的转录调节蛋白和酶。这些效应已经在NO2-ClA中得到了演示 在动物和细胞培养模型中，已证明使用一种合成同系物硝基油酸是安全的 在FDA批准的第一阶段临床试验中。由于个体膳食成分NO3-、NO2-和CLA都是 与代谢综合征症状的风险降低有关，而NO2-CLA是炎症的调节因子， 推测NO3-+NO2-(NOx)+CLA对肥胖哮喘患者的治疗效果会有所改善。 FeNO和减少呼吸道高反应性和炎症。这一假设将通过以下方式检验 追求两个具体目标：目标1：改善气道.NO的生物利用度和气道高反应性 NOx+CLA处理。目的2：确定NOx+CLA是否能减少全身和呼吸道炎症 导致肥胖的哮喘表型。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和氧化应激标记物以及哮喘的临床标记物 包括呼吸道高反应性和哮喘控制试验。使用NOx+CLA获得积极的临床结果 饮食补充提供了一种补充和综合的健康干预以及一种新的 针对肥胖哮喘病理的治疗策略。