Mechanisms that Direct Airway Remodeling in Obese Asthma

肥胖哮喘中引导气道重塑的机制

• 批准号: 10093686
• 负责人: Jennifer L. Ingram
• 金额: $ 16.1万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-18 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10093686
• 关键词: Abdomen; Address; Adipocytes; Adipose tissue; Adult; Adult Respiratory Distress Syndrome; Adult asthma; Airway Resistance; Allergens; Allergic; Anti-Inflammatory Agents; Asthma; Biological; Cardiovascular system; Castration; Cell physiology; Cellular Structures; Chronic; Cluster Analysis; Coupled; Data; Development; Europe; Exhibits; Extracellular Matrix; Extrinsic asthma; Fatty acid glycerol esters; Female; Fibroblasts; Fibrosis; Foundations; Funding; Gender; Glucocorticoids; Glucose Intolerance; Goals; Growth Factor; Healthcare; Hepatic; Histologic; Hormones; House Dust Mite Allergens; Human; Immune response; Incubated; Inflammation Mediators; Inflammatory; Investigation; Kidney; Knowledge; Leptin; Lung; Mechanics; Metabolic; Modeling; Mus; Obesity; Organ; Outcome; PPAR gamma; Pathogenesis; Pathogenicity; Pathologic; Pathology; Patients; Pharmaceutical Preparations; Phenotype; Prevalence; Process; Production; Quality of life; Research; Resources; Respiratory physiology; Risk; Risk Factors; Role; Sample Size; Serum; Severities; Sex Differences; Signal Transduction; Strategic Planning; Structure; TGFB1 gene; Testing; Thinness; Tissues; United States National Institutes of Health; Visceral; Visceral fat; Women' s Health; adipokines; adiponectin; adult obesity; airway inflammation; airway obstruction; airway remodeling; allergic airway disease; asthma exacerbation; asthmatic; asthmatic patient; biological sex; comorbidity; disorder prevention; eosinophilic inflammation; experience; experimental study; improved; in vivo; interstitial; male; mouse model; novel; novel therapeutics; obesity treatment; preclinical study; response; sex; therapeutic target

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.

项目概要 哮喘在成年女性中比男性更常见。此外，美国近 40% 的患者患有哮喘。 肥胖的成年女性哮喘患者的哮喘严重程度增加，但病情减轻。 与男性和瘦型哮喘患者相比，肥胖患者对标准药物的反应性相关。 炎症和代谢变化导致哮喘病理学变化。 肥胖患者的代谢变化，包括瘦素（一种促炎介质）水平升高 由脂肪组织分泌，通过直接作用于结构细胞来增强哮喘的致病过程 气道重塑描述了哮喘的气道结构变化，包括气道纤维化，这可以 导致女性肥胖哮喘气道重塑的机制。 我们的初步数据显示，气道纤维化在以下人群中显着升高。 肥胖女性过敏性哮喘患者与男性肥胖过敏性哮喘患者的比较。 增强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，雄性小鼠受到保护。 与女性相比，慢性瘦素和过敏原暴露对气道病理的综合影响。 我们进一步发现，肥胖女性过敏性哮喘患者的脂肪组织分泌更多的瘦素和 促纤维化生长因子高于男性，这些变化导致气道炎症 过敏性哮喘中的纤维化通过需要 PPARg 抑制的机制进行。我们将通过以下方式检验这一假设。 在小鼠模型中确认生物性别对病理气道和脂肪反应的贡献 慢性肥胖和过敏性气道疾病（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气道成纤维细胞反应和肺功能的影响 （目标 2）。本提案中描述的研究将我们最初的 R01 中提出的研究扩展到具体的领域。 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 NIH 女性健康研究战略计划的目标：发现基础生物学 女性和男性之间的差异，并调查性别和性别对疾病预防的影响， 成功完成这些目标将增加我们的理解。 指导女性肥胖哮喘病理学的独特细胞和代谢机制。

项目成果

A Hint from Wnt: Squamous Cell Differentiation in the Airways.

• DOI: 10.1165/rcmb.2023-0065ed
• 发表时间: 2023-06
• 期刊: American journal of respiratory cell and molecular biology
• 影响因子: 6.4

Targeted HAS2 Expression Lessens Airway Responsiveness in Chronic Murine Allergic Airway Disease.

靶向 HAS2 表达可降低慢性小鼠过敏性气道疾病的气道反应性。

• DOI: 10.1165/rcmb.2017-0095oc
• 发表时间: 2017
• 期刊: American journal of respiratory cell and molecular biology
• 影响因子: 6.4
• 作者: Walker,JuliaKL;Theriot,BarbaraS;Ghio,Michael;Trempus,CarolS;Wong,JordanE;McQuade,VictoriaL;Liang,Jiurong;Jiang,Dianhua;Noble,PaulW;Garantziotis,Stavros;Kraft,Monica;Ingram,JenniferL
• 通讯作者: Ingram,JenniferL

Short-term cardiovascular events after bariatric surgery in patients with metabolic syndrome.

代谢综合征患者减肥手术后的短期心血管事件。

• DOI: 10.1016/j.soard.2023.07.009
• 发表时间: 2024
• 期刊: Surgery for obesity and related diseases : official journal of the American Society for Bariatric Surgery
• 作者: Chumakova-Orin,Maryna;Ingram,JenniferL;Que,LorettaG;Pagidipati,Neha;Gordee,Alexander;Kuchibhatla,Maragatha;Seymour,KeriA
• 通讯作者: Seymour,KeriA

Effects of Oxidative Stress on Airway Epithelium Permeability in Asthma and Potential Implications for Patients with Comorbid Obesity.

• DOI: 10.2147/jaa.s402340
• 发表时间: 2023
• 期刊: Journal of asthma and allergy
• 影响因子: 3.2

Allergic Asthma Responses Are Dependent on Macrophage Ontogeny.

过敏性哮喘反应取决于巨噬细胞个体发育。

• DOI: 10.1101/2023.02.16.528861
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Tighe,RobertM;Birukova,Anastasiya;Malakhau,Yuryi;Kobayashi,Yoshihiko;Vose,AaronT;Chandramohan,Vidya;Cyphert-Daly,JaimeM;Cumming,RIan;Kirshner,HeleneFradin;Tata,PurushothamaR;Ingram,JenniferL;Gunn,MichaelD;Que,LorettaG;Yu
• 通讯作者: Yu