Non-Allergic Late-Onset Asthma of Obesity: Pathophysiology and Therapy

肥胖引起的非过敏性迟发型哮喘：病理生理学和治疗

• 批准号: 9243305
• 负责人: Jason HT Bates
• 金额: $ 57.8万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-15 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9243305
• 关键词: Acute; Adipose tissue; Airway Resistance; Allergic; Animals; Area; Asthma; Body Weight decreased; Bronchial Spasm; Characteristics; Chest wall structure; Chronic; Computer Simulation; Custom; Data; Disease; Environmental air flow; Functional Residual Capacity; Functional disorder; Goals; Heterogeneity; Incidence; Individual; Lead; Left; Life; Link; Lung; Measures; Nature; Nitrogen; Non obese; Obesity; Outcome Measure; Pathogenesis; Patients; Periodicity; Peripheral; Phenotype; Physiological; Play; Positive-Pressure Respiration; Public Health; Research; Respiratory physiology; Risk; Risk Factors; Role; Steroid therapy; Steroids; Study models; Surrogate Markers; Symptoms; Techniques; Testing; Therapeutic; Thick; Time; Total Lung Capacity; Weight; X-Ray Computed Tomography; airway hyperresponsiveness; asthmatic; electric impedance; experience; lung imaging; lung volume; methacholine; novel therapeutics; pandemic disease; patient population; public health relevance; response; therapy development

 DESCRIPTION (provided by applicant): Asthma typically has an allergic basis that develops early in life. By contrast, many obese asthmatics have late-onset, non-atopic (LONA) asthma that is specific to their obese state. Furthermore, this LONA phenotype is frequently unresponsive to conventional steroid therapy. This leaves these subjects with few treatment options other than major weight loss, which is rarely achieved. There is thus a critical need to develop alternative approaches to asthma therapy in obese patients. Our preliminary data lead us to hypothesize that the airways hyperresponsiveness of LONA obese asthma occurs in those individuals who are particularly prone to experience closure of their small airways following bronchial challenge at the reduced lung volumes characteristic of obesity. Our computational modeling studies further show that increased closure can be explained by these individuals having airways that are more compliant and/or thicker than average, causing them to experience the symptoms of asthma in the setting of obesity when lung volume becomes chronically reduced as a result of excess weight. Our goal is to test this hypothesis in LONA asthmatics by assessing airway wall compliance as reflected in lung impedance measured with the forced oscillation technique, ventilation heterogeneity measured by nitrogen washout, and airway compliance and wall thickness determined by comparing CT images taken at total lung capacity and at functional residual capacity. We will also establish the efficacy of elevating lung volume with positive end-expiratory pressure (PEEP) as a means of resolving an asthma attack once it starts (i.e. as a rescue therapy), and for reducing the likelihood of having an asthma attack in the first place (i.e. as a controller therapy). Again, lung impedance and nitrogen washout will be used as the key outcome measures reflective of the effects that PEEP has on lung function. The increasing incidence of asthma in the US has been linked to increasing obesity, adding significantly to the already huge public health burden created by the obesity pandemic. By defining the utility and efficacy of volume elevation in obese asthma we anticipate being able to bring about an important change in the way therapies are administered to a large patient population that currently has few treatment options.

 描述（由申请人提供）：哮喘通常有过敏的基础，在生命早期发展。相比之下，许多肥胖哮喘患者患有迟发性非特应性（LONA）哮喘，这是他们肥胖状态所特有的。此外，这种LONA表型通常对常规类固醇治疗无反应。这使得这些受试者除了很少实现的主要体重减轻外几乎没有治疗选择。因此，迫切需要开发肥胖患者哮喘治疗的替代方法。我们的初步数据使我们假设LONA肥胖性哮喘的气道高反应性发生在那些特别容易在肥胖特征性肺体积减少的支气管激发后经历小气道关闭的个体中。我们的计算建模研究进一步表明，增加的闭合可以通过这些个体具有比平均值更顺应和/或更厚的气道来解释，导致他们在肥胖的情况下经历哮喘的症状，当肺体积由于超重而慢性减少时。我们的目标是通过评估气道壁顺应性来验证LONA哮喘患者的这一假设，气道壁顺应性反映在用强迫振荡技术测量的肺阻抗、用氮气冲洗测量的通气异质性以及通过比较在总肺容量和功能残气量下拍摄的CT图像确定的气道顺应性和壁厚度。我们还将确定提升肺部的功效 使用呼气末正压（PEEP）作为缓解哮喘发作的一种手段（即作为抢救治疗），并首先降低哮喘发作的可能性（即作为控制治疗）。同样，肺阻抗和氮洗脱将被用作反映PEEP对肺功能影响的关键结局指标。美国哮喘发病率的增加与肥胖的增加有关，这大大增加了肥胖流行病造成的巨大公共卫生负担。通过定义容量升高在肥胖性哮喘中的效用和功效，我们预期能够在对目前几乎没有治疗选择的大量患者群体进行治疗的方式上带来重要的改变。