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.

项目总结

项目成果

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

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

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

Exogenous leptin enhances markers of airway fibrosis in a mouse model of chronic allergic airways disease.

• DOI: 10.1186/s12931-022-02048-z
• 发表时间: 2022-05-24
• 期刊: Respiratory research
• 影响因子: 5.8

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