Mechanisms that Direct Airway Remodeling in Obese Asthma

项目摘要 哮喘在成年女性中比男性更普遍。此外，美国近40%的哮喘患者 肥胖。成年女性肥胖哮喘患者的哮喘严重程度增加， 与男性和瘦型哮喘患者相比，肥胖与 炎症和代谢变化导致哮喘病理学。具体而言，系统 肥胖患者的代谢变化，包括促炎介质瘦素水平升高 由脂肪组织分泌，通过直接作用于哮喘的结构细胞， 气道。气道重塑描述了哮喘的气道结构变化，包括气道纤维化， 导致永久性气道阻塞。女性肥胖性哮喘气道重塑的机制 尤其不为人所知。我们的初步数据显示，气道纤维化显著升高， 女性肥胖过敏性哮喘患者与男性肥胖过敏性哮喘患者相比。此外，Leptin 增加慢性过敏原诱导的气道纤维化，小气道阻力和嗜酸性粒细胞炎症， 雌性小鼠与雄性小鼠相比。我们的总体假设是，在肥胖性哮喘中，男性受到保护， 与女性相比，慢性瘦素和过敏原暴露对气道病理学的联合作用。 我们进一步假设肥胖女性过敏性哮喘患者的脂肪组织分泌增加的瘦素， 促纤维化生长因子比男性多，这些变化有助于气道炎症 和过敏性哮喘中的纤维化通过需要PPARg抑制的机制。我们将通过以下方式检验这一假设： 证实了生物性别对小鼠模型中病理性气道和脂肪反应的作用， 慢性肥胖和过敏性气道疾病（目的1），并通过测试性别特异性影响内脏脂肪 组织源性分泌因子对肥胖哮喘患者气道成纤维细胞反应和肺功能的影响 (Aim 2）。本提案中描述的研究将扩展我们最初R 01中建议的研究， 解决肥胖性哮喘的性别特异性差异，他们将解决战略中列出的两个目标 2019-2023年跨NIH妇女健康研究战略计划的目标：发现基本的生物学 男女之间的差异，并调查性别和性别对疾病预防的影响， 介绍、管理和成果。成功地完成这些目标将增加我们的理解 独特的细胞和代谢机制指导女性肥胖哮喘的病理生物学。

Project Summary Asthma is more prevalent in adult females than males. In addition, nearly 40% of patients with asthma in the US are obese. Adult female obese asthma patients experience increased asthma severity with diminished responsiveness to standard medications compared to male and lean asthma patients. Obesity is associated with inflammatory and metabolic changes that contribute to asthma pathobiology. Specifically, systemic metabolic changes in the obese patient, including increased levels of leptin, a pro-inflammatory mediator secreted by adipose tissue, augments pathogenic processes in asthma by acting directly on structural cells in the airway. Airway remodeling describes airway structural changes in asthma, including airway fibrosis, that can result in permanent airway obstruction. The mechanisms directing airway remodeling in female obese asthma are particularly poorly understood. Our preliminary data show that airway fibrosis is significantly elevated in obese female patients with allergic asthma compared to male obese allergic asthma patients. Furthermore, leptin augments chronic allergen-induced airway fibrosis, small airways resistance and eosinophilic inflammation in female mice compared to male mice. Our overarching hypothesis is that, in obese asthma, males are protected from the combined effects of chronic leptin and allergen exposure on airway pathology compared to females. We further hypothesize that adipose tissue in obese female allergic asthmatics secretes increased leptin and pro-fibrotic growth factors than their male counterparts and that these changes contribute to airway inflammation and fibrosis in allergic asthma through a mechanism requiring PPARg inhibition. We will test this hypothesis by confirming the contribution of biological sex to pathologic airway and adipose responses in a mouse model of chronic obesity and allergic airways disease (Aim 1), and by testing the sex-specific influence of visceral adipose tissue-derived secreted factors on airway fibroblast cellular responses and lung function in human obese asthma (Aim 2). The studies described in this proposal will extend the studies proposed in our original R01 to specifically address sex-specific differences in obese asthma and they will address two objectives listed in the strategic goals of the 2019-2023 Trans-NIH Strategic Plan for Women’s Health Research: to discover basic biological differences between females and males and investigate the influence of sex and gender on disease prevention, presentation, management and outcomes. Successful completion of these Aims will increase our understanding of the unique cellular and metabolic mechanisms directing the pathobiology of female obese asthma.