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 哮喘是一种常见疾病，其特征是气道高反应性（AHR）和异质性 在哮喘患者中，合并肥胖与哮喘控制较差有关。 肥胖和哮喘共存的患者的炎症特征是治疗效果下降。 与瘦患者相比，嗜酸性粒细胞炎症较少，氧化和亚硝化（氧化亚硝化）应激较多 然而，患有肥胖症的患者的这一观察结果的机制尚不清楚。 与瘦哮喘患者相比，哮喘患者气道上皮中的对氧磷酶 2 (PON2) 水平较低。 此外，PON2 水平受过氧化物酶体增殖物激活受体 γ (PPAR) 的调节 该提案研究了 PON2 和 PPAR 的变化在促进氧化过程中的作用。 使用饮食诱导肥胖的小鼠模型研究患有肥胖和哮喘的患者的亚硝化应激。 和臭氧暴露作为吸入氧化应激的模型，该提案将解决三个问题： 肥胖条件下Pon2表达与氧化亚硝化应激有何关系？ 通过使用高脂肪、高糖饮食诱发肥胖和急性臭氧暴露可以回答这个问题 外源性氧化损伤、Pon2 表达、氧化亚硝化应激标志物和气道生理学都会影响。 在瘦小鼠和肥胖小鼠中进行评估，以确定 Pon2 水平与气道之间是否存在关联 这些发现将在相同条件下与 Pon2-/- 小鼠进行比较，以分离出 为了分离肺上皮在此过程中的精确作用，培养了人呼吸道。 上皮细胞将暴露于臭氧并评估氧化亚硝化应激 其次，Pon2 如何发挥作用。 表达变化会影响长期暴露于氧化应激源后气道纤维化的发展吗？ 这个问题可以通过给小鼠喂食高脂肪、高糖或对照饮食，然后长期喂养来解决。 将它们暴露在臭氧中六周，六周结束时，将测量气道生理学和肺组织。 第三，PPAR-激活是否会消除肥胖对纤维化的影响。 PON2 表达、AHR 和氧化亚硝化应激标志物 这个问题将通过治疗小鼠来解决？ 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 然后根据我们的第一个问题评估气道生理学、PON2 水平和氧化亚硝化应激。

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。

• 发表时间: 2022-12-16
• 作者: Nam, Jason J;McCravy, Matthew S;Haines, Krista L;Thomas, Sarah B;Aden, James K;Johnston, Luke R;Mason, Phillip E;Gurney, Jennifer M;Sams, Valerie G
• 通讯作者: Sams, Valerie G