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：
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
项目类别：
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

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.

肥胖是与加重率提高和更高的医疗保健相关的哮喘合并症通过2型辅助T细胞（TH2）相关的生物标志物增加的机制利用与特应性哮喘有关的气道炎症。除了肺中的免疫反应改变（Th1/th17）肥胖哮喘患者也受到低级，慢性，全身性炎症的困扰促炎性趋化因子和细胞因子的脂肪细胞分泌。也导致系统性炎症是通过精氨酸（ARG）代谢物，非对称二甲基精氨酸的一氧化氮合酶（NOS）的解偶联（ADMA）。低ARG/ADMA比与体重增加的增加相关，结果较低分数呼出的一氧化氮（Feno）。 NOS解偶联会导致一氧化氮生物利用度低，并增加在超氧化阴离子的产生中，从而有助于整体氧化环境。这个目的研究是为了表征饮食补充剂硝酸盐（NO3-）和亚硝酸盐（NO2-）（NOX）和肥胖哮喘患者气道高反应性和炎症的共轭亚油酸（CLA）。使用NOX或CLA（单独）补充的流行病学和临床研究已报告其与包括心血管疾病和代谢性疾病在内的疾病病理学有关的好处。最近我们进行的试点研究表明，来自电池脂肪酸的形成健康受试者中的NOX + CLA补充浓度约为3倍，内源性基础水平。重要的是，这些水平在剂量范围内，在临床前动物模型中发挥全身作用。发生这种情况因为硝基烷酸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。这些效果已通过NO2-CLA证明在动物和细胞培养模型和安全性中，已使用合成同源硝基酸证明了在FDA批准的第1阶段临床试验中。由于个人饮食成分No3-，No2-和CLA都是与降低代谢综合征症状的风险相关，而NO2-CLA是炎症的调节剂，假设用NO3- + NO2-（NOX） + CLA治疗的肥胖哮喘患者将改善 Feno和气道高反应性和炎症。该假设将通过追求两个具体目标：目标1：改善气道。 NOX + CLA处理。目标2：确定NOX + CLA是否减少了全身性和气道炎症有助于肥胖的哮喘表型。 Feno和亚硝基血红蛋白，炎症细胞因子和将测量趋化因子，NO2-CLA和氧化应激的标记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的阳性临床结果饮食补充提供了互补和综合的健康干预措施以及一种新颖靶向肥胖哮喘病理学的治疗策略。