The Role of PON2 in the Development of Non-Allergic Asthma in Obesity

PON2 在肥胖引起的非过敏性哮喘发展中的作用

• 批准号: 10734050
• 负责人: Matthew McCravy
• 金额: $ 8.53万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10734050
• 关键词: 3-nitrotyrosine; Acute; Address; Affect; Agonist; Airway Disease; Airway Fibrosis; Asthma; Bronchoalveolar Lavage Fluid; Cell Count; Chronic; Collagen; Collagen Type IV; Coronary artery; Data; Deposition; Development; Diet; Disease; Epithelial Cells; Epithelium; Exhalation; Exhibits; Exposure to; Fatty acid glycerol esters; Fibrosis; Fructose; Glutathione Disulfide; Homeostasis; Human; Individual; Inflammatory; Inhalation; Isoprostanes; Left; Link; Lipid Peroxidation; Lung; Measures; Mediator; Modeling; Mus; Nitrates; Nitrites; Non obese; Nuclear; Obese Mice; Obesity; Oxidative Stress; Ozone; PPAR gamma; Paraoxonase-2; Pathway interactions; Patients; Phenotype; Physical condensation; Physiology; Pioglitazone; Predisposition; Process; Quality of life; Reactive Oxygen Species; Research Proposals; Reverse Transcriptase Polymerase Chain Reaction; Rodent; Role; Signal Transduction; Signaling Molecule; Stress; Structure of parenchyma of lung; Symptoms; Therapeutic; Thinness; Tissues; Treatment Efficacy; Trichrome stain; Ventilator; air filter; airway epithelium; airway hyperresponsiveness; airway inflammation; antioxidant enzyme; asthmatic; asthmatic patient; cell type; comorbidity; cytokine; diet-induced obesity; dietary control; eosinophilic inflammation; experience; feeding; gastrointestinal epithelium; improved outcome; interest; knock-down; mouse model; nitrosative stress; obese patients; oxidant stress; ozone exposure; profiles in patients; response; rosiglitazone; stressor; sugar

Project Abstract Asthma is a common disease characterized by airway hyperresponsiveness (AHR) and a heterogenous inflammatory profile. In patients with asthma, comorbid obesity is associated with worse asthma control and decreased efficacy of therapy. The inflammatory profile in patients with comorbid obesity and asthma is typified by less eosinophilic inflammation and more oxidative and nitrosative (oxo-nitrosative) stress than lean patients with asthma. The mechanism of this observation is not known. However, patients with comorbid obesity and asthma have lower levels of paraoxonase 2 (PON2) in their airway epithelium than lean patients with asthma. Furthermore, PON2 levels are modulated by peroxisome proliferator-activated receptor gamma (PPAR) in multiple tissues. This proposal examines the role of changes in PON2 and PPAR in contributing to oxo- nitrosative stress in patients with comorbid obesity and asthma. Using a murine model of diet induced obesity and ozone exposure as a model of inhaled oxidative stress, this proposal will address three questions. First, what is the relationship between Pon2 expression and oxo-nitrosative stress under the condition of obesity? This question will be answered by using a high fat, high sugar diet to induce obesity and an acute ozone exposure as an exogenous oxidative insult. Pon2 expression, markers of oxo-nitrosative stress, and airway physiology will be assessed in lean and obese mice to determine if there is an association between Pon2 levels and airway oxo-nitrosative stress. These findings will be compared to Pon2-/- mice under the same conditions to isolate the effect of PON2. To isolate the precise role of the pulmonary epithelium in this process, cultured human airway epithelial cells will be exposed to ozone and assessed for oxo-nitrosative stress. Second, how does Pon2 expression changes affect the development of airway fibrosis after chronic exposure to an oxidative stressor? This question will be addressed by feeding mice either a high fat, high sugar or a control diet and then chronically exposing them to ozone for 6 weeks. At the end of six weeks, airway physiology will be measured and lung tissue will be assessed for the development of fibrosis. Third, does PPAR activation abrogate the effect of obesity on PON2 expression, AHR and markers of oxo-nitrosative stress? This question will be addressed by treating mice with the PPAR agonist, pioglitazone, and repeating the high fat, high sugar diet and acute ozone exposures from our first question. Airway physiology, PON2 levels and oxo-nitrosative stress will then be assessed.

项目摘要

项目成果

Experience With Trauma-Induced ARDS: A Retrospective Study of US Wartime Casualties 2003-2015.

创伤引起的 ARDS 经验：2003-2015 年美国战时伤亡情况回顾性研究。

• DOI: 10.55460/mtvh-oncm
• 发表时间: 2022
• 期刊: Journal of special operations medicine : a peer reviewed journal for SOF medical professionals
• 作者: Nam,JasonJ;McCravy,MatthewS;Haines,KristaL;Thomas,SarahB;Aden,JamesK;Johnston,LukeR;Mason,PhillipE;Gurney,JenniferM;Sams,ValerieG
• 通讯作者: Sams,ValerieG