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

 描述(申请人提供)：哮喘通常有一个过敏的基础，在生命的早期发展。相比之下，许多肥胖哮喘患者患有晚发性非特应性(LONA)哮喘，这是他们肥胖状态特有的。此外，这种LONA表型通常对传统的类固醇治疗无效。这使得这些受试者除了大幅减肥之外几乎没有其他治疗选择，而这是很少实现的。因此，迫切需要开发替代方法来治疗肥胖患者的哮喘。我们的初步数据使我们假设，LONA肥胖性哮喘的呼吸道高反应性发生在那些特别容易经历他们的小呼吸道关闭的人，在肥胖的特征是肺体积减少后，他们的支气管挑战。我们的计算模型研究进一步表明，闭合率增加的原因是这些人的呼吸道比平均水平更顺应性和/或更厚，导致他们在肥胖的情况下经历哮喘症状，当肺体积因超重而慢性减少时。我们的目标是在LONA哮喘患者中验证这一假设，方法是评估通过强迫振荡技术测量的肺阻抗反映的气道壁顺应性，通过氮气冲洗测量的通风异质性，以及通过比较在总肺活量和功能剩余容量下拍摄的CT图像确定的气道顺应性和管壁厚度。我们还将确立升肺的功效。 呼气末正压(PEEP)作为哮喘发作后缓解的一种手段(即作为一种抢救疗法)，以及首先降低哮喘发作的可能性(即作为一种控制疗法)。再次，肺阻抗和氮气洗出将被用作反映PEEP对肺功能影响的关键结果指标。美国哮喘发病率的增加与肥胖症的增加有关，大大增加了肥胖症大流行已经造成的巨大公共健康负担。通过定义容量增加在肥胖性哮喘中的效用和有效性，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要的变化。

 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.