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.