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: 10533862
• 负责人: Matthew McCravy
• 金额: $ 8.07万
• 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/10533862
• 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; Epithelial Cells; 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 of activation protein; Modeling; Mus; Nitrates; Nitrites; Non obese; Nuclear; Obese Mice; Obesity; Oxidative Stress; Ozone; PPAR alpha; PPAR gamma; Paraoxonase-2; Pathway interactions; Patients; Phenotype; 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; obesity-associated asthma; 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 哮喘是一种以气道高反应性（AHR）和异源为特征的常见疾病 炎症概况。在患有哮喘的患者中，合并症肥胖与哮喘控制较差有关 降低治疗效率。合并性肥胖症和哮喘患者的炎症特征是典型的 与瘦患者相比 哮喘。该观察的机制尚不清楚。但是，肥胖症患者和 与哮喘患者相比，哮喘的气道上皮中的副氧酮酶2（PON2）较低。 此外，PON2水平由过氧化物体增殖物激活受体伽马（PPAR）在 多次。该提案检查PON2和PPAR在有助于氧气中的变化的作用 合并性肥胖和哮喘患者的硝酸应激。使用饮食诱发肥胖的鼠模型 臭氧暴露是遗传氧化物压力的模型，该提案将解决三个问题。第一的， 在肥胖状况下，PON2表达与氧硝化应激之间的关系是什么？这 通过使用高脂肪，高糖饮食来诱导肥胖和急性臭氧暴露，将回答问题 外源氧化侮辱。 PON2表达，氧气硝化应激和气道生理学的标志物将 在精益和肥胖的小鼠中进行评估，以确定PON2水平与气道之间是否存在关联 氧气硝化应激。这些发现将在相同条件下与PON2 - / - 小鼠进行比较，以分离 PON2的效果。为了隔离肺上皮在此过程中的精确作用，培养的人气道 上皮细胞将暴露于臭氧并评估氧气硝化应激。第二，PON2如何 表达变化会影响长期暴露于氧化物应激源后气道纤维化的发展？ 这个问题将通过喂养高脂肪，高糖或对照饮食，然后长期解决这个问题 将它们暴露于臭氧6周。在六周结束时，将测量气道生理学并进行肺组织 将评估纤维化的发展。第三，PPAR激活消除了肥胖对 PON2表达，AHR和氧硝化应激的标志物？这个问题将通过治疗老鼠解决 使用PPAR激动剂，吡格列酮，并重复高脂肪，高糖饮食和急性臭氧暴露 从我们的第一个问题。然后将评估气道生理学，PON2水平和氧硝化应激。