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）：哮喘通常具有在生命早期发生的过敏基础。相比之下，许多肥胖哮喘患者患有迟发性非特应性（LONA）哮喘，这是其肥胖状态所特有的。此外，这种 LONA 表型通常对传统类固醇治疗没有反应。这使得这些受试者除了大幅减重之外几乎没有其他治疗选择，而减重很少能实现。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推测，LONA 肥胖性哮喘的气道高反应性发生在那些在肥胖特征性肺容量减少的支气管挑战后特别容易经历小气道闭合的个体中。我们的计算模型研究进一步表明，闭合增加可以通过这些人的气道比平均水平更顺应和/或更厚来解释，导致他们在肥胖的情况下出现哮喘症状，因为体重过重导致肺容量长期减少。我们的目我们还将确定提升肺的功效 呼气末正压 (PEEP) 的容量作为哮喘发作后解决的一种手段（即作为救援治疗），并首先降低哮喘发作的可能性（即作为控制治疗）。同样，肺阻抗和氮气冲刷将用作反映 PEEP 对肺功能影响的关键结果指标。在美国，哮喘发病率的上升与肥胖人数的增加有关，这大大增加了肥胖流行造成的巨大公共卫生负担。通过定义容量增加在肥胖哮喘中的效用和功效，我们预计能够为目前几乎没有治疗选择的大量患者群体的治疗方式带来重大改变。