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 都很肥胖。成年女性肥胖哮喘患者哮喘严重程度增加，但病情减轻 与男性和瘦型哮喘患者相比，对标准药物的反应性。肥胖症与 炎症和代谢变化导致哮喘的病理生物学。具体地说，系统性的 肥胖患者的代谢变化，包括促炎介质瘦素水平的升高 由脂肪组织分泌，通过直接作用于哮喘的结构细胞而增强哮喘的发病过程 呼吸道。气道重塑描述了哮喘患者的气道结构变化，包括气道纤维化，这种改变可以 导致永久性呼吸道阻塞。女性肥胖性哮喘气道重塑的机制研究 尤其令人费解的是。我们的初步数据显示，呼吸道纤维化在 肥胖女性过敏性哮喘患者与男性肥胖过敏性哮喘患者比较。此外，瘦素 增加慢性变应原诱导的气道纤维化、小气道阻力和嗜酸性炎症 雌性小鼠与雄性小鼠进行比较。我们的主要假设是，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呼吸道病理的综合影响。 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和 与男性相比，促纤维化生长因子的作用更强，这些变化导致了呼吸道炎症 通过一种需要PPARg抑制的机制来治疗过敏性哮喘。我们将通过以下方式验证这一假设 确认生物性别对病理性呼吸道和脂肪反应的贡献 慢性肥胖症和过敏性呼吸道疾病(目标1)，并通过测试内脏脂肪对性别的影响 组织源性分泌因子对肥胖哮喘患者气道成纤维细胞细胞反应和肺功能的影响 (目标2)。本建议中描述的研究将把我们最初的R01中建议的研究扩展到具体的 解决肥胖哮喘的性别差异，他们将解决战略中列出的两个目标 2019-2023年跨美国国立卫生研究院妇女健康研究战略计划的目标：发现基础生物学 性别差异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 指导女性肥胖性哮喘病理生物学的独特细胞和代谢机制。

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.