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

项目摘要 哮喘是一种以气道高反应性（AHR）为特征的常见疾病， 炎症特征在哮喘患者中，共病肥胖与较差的哮喘控制相关， 降低治疗效果。肥胖和哮喘共病患者的炎症特征是典型的 与瘦型患者相比， 哮喘这种观察的机制尚不清楚。然而，患有共病肥胖症和 哮喘患者的气道上皮细胞中对氧磷酶2（PON 2）水平低于瘦型哮喘患者。 此外，PON 2水平受过氧化物酶体增殖物激活受体γ（PPAR-beta）调节， 多种组织该提案研究了PON 2和PPAR β的变化在促进氧代- 肥胖和哮喘共病患者的亚硝化应激使用饮食诱导肥胖的小鼠模型 和臭氧暴露作为吸入性氧化应激的模型，该提案将解决三个问题。第一、 肥胖状态下Pon 2的表达与氧亚硝化应激的关系如何？这 这个问题将通过使用高脂肪，高糖饮食来诱导肥胖和急性臭氧暴露来回答， 外源性氧化损伤Pon 2表达、氧亚硝化应激的标志物和气道生理学将 在瘦小鼠和肥胖小鼠中进行评估，以确定Pon 2水平和气道炎症之间是否存在关联。 氧亚硝化胁迫将这些发现与相同条件下的Pon 2-/-小鼠进行比较，以分离出 PON 2的影响为了分离肺上皮在此过程中的确切作用，培养人气道 将上皮细胞暴露于臭氧并评估氧代亚硝化应激。第二，Pon 2 表达变化影响慢性暴露于氧化应激后气道纤维化的发展？ 这个问题将通过给小鼠喂食高脂肪、高糖或对照饮食来解决，然后长期 将它们暴露在臭氧中6周。在六周结束时，将测量气道生理学和肺组织 将评估纤维化的发展。第三，过氧化物酶体增殖物激活体激活是否消除了肥胖对 PON 2表达、AHR和氧亚硝化应激标志物？这个问题将通过治疗小鼠来解决 与过氧化物酶体增殖物激活物受体激动剂吡格列酮，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、PON 2水平和氧代亚硝化应激。

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.