Severe Asthma Research Program (SARP)-Washington University

描述(申请人提供)：这项建议的总体目标是更好地了解重症哮喘患者气道重塑的分子基础、结构和生理后果，以及重塑如何随着时间的推移而变化。在这种背景下，我们建议使用多学科方法研究一组具有良好特征的成人和儿童严重哮喘受试者，其中包括最先进的呼吸道形态测量、成像和生理测量。我们将把这些发现与控制良好的哮喘组、正常对照组和患病对照组(慢性支气管炎)进行比较，以确定可以为严重哮喘提供独特生物靶点的特征。我们已经证明，重度哮喘患者的气道重塑以上皮增生、杯状细胞化生和粘蛋白产生为特征，而上皮重塑是由于上皮细胞增殖增加和细胞死亡减少所致。我们认为，与控制良好的哮喘相比，重度哮喘患者有：(1)杯状细胞化生和粘蛋白产生证明的气道重塑增加；(11)多层螺旋CT胸部扫描(MDCT)显示的气道厚度增加，导致超极化氦(^He)MRI和MDCT显示的空气滞留所显示的换气缺陷；(3)与更严重和进行性的气流阻塞相关的气道重塑。我们假设，我们在严重哮喘中观察到的杯状细胞化生和粘蛋白增加是由IL-13和EGFR依赖的机制驱动的，该机制抑制上皮细胞凋亡，并允许IL-13将呼吸道上皮分化为杯状细胞(目标I)。我们进一步假设，严重哮喘患者的这种节段性气道重塑导致远端呼吸缺陷和空气滞留(AIM II)。为了确定严重哮喘患者随后肺功能下降的潜在预测因素，我们假设MDCT气道壁面积(AWA%)反映的基线气道重塑可预测FEVi(激素/支气管扩张剂后FEVi)下降(Aim III)。识别与重塑和严重哮喘相关的潜在变量将有助于识别哪些高危个体将受益于特定的靶向治疗。该项目与SARP的共同努力将导致对重度哮喘的机制基础的新见解，进一步阐明其与轻-中度哮喘的不同之处，确定潜在的干预靶点，并将提供成像指标来客观评估新治疗的结果。 相关性：了解重症哮喘杯状细胞化生和粘蛋白产生的分子基础将为治疗提供新的靶点。了解通风缺陷和空气滞留的病理生理学机制将对热成形术等治疗产生影响，并提供通过成像无创评估新治疗方法的手段。最后，识别进行性加速肺功能下降的预测因素可能允许对高危患者进行更早的干预，从而导致随后不那么严重的哮喘。

DESCRIPTION (provided by applicant): The overall goal of this proposal is to better understand the molecular basis and structural and physiologic consequences of airway remodeling in severe asthma and how remodeling changes over time. In that context, we propose to study a well-characterized cohort of adult and pediatric subjects with severe asthma using a multidisciplinary approach that includes state-of-the-art morphometric, imaging, and physiologic measurements of airways. We will contrast these findings to those in groups with well- controlled asthma, normal controls, and diseased controls (chronic bronchitis) to identify features that can provide biologic targets unique to severe asthma. We have demonstrated that epithelial hyperplasia, goblet cell metaplasia and mucin production are features of airway remodeling in subjects with severe asthma, and that epithelial remodeling was due to increased epithelial proliferation and decreased cell death. We propose that individuals with severe asthma, in comparison to well controlled asthma, have: (I) increased airway remodeling as evidenced by goblet cell metaplasia and mucin production, (11) greater airway thickness by multidetector-row CT of the chest (MDCT) leading to ventilation defects demonstrated by hyperpolarized helium (^He) MRI and air trapping demonstrated by MDCT, and (III) airway remodeling associated with more severe and progressive airflow obstruction. We hypothesize that the goblet cell metaplasia and increased mucin we have observed in severe asthma are being driven by an IL-13- and EGFR-dependent mechanism that inhibits epithelial cell apoptosis and allows IL-13 differentiation of the airway epithelium into goblet cells (Aim I). We further hypothesize that this remodeling of segmental airways in severe asthma leads to distal ventilation defects and air trapping (Aim II). In an effort to define potential predictors of subsequent decline in lung function in severe asthma, we hypothesize that baseline airway remodeling as reflected by MDCT airway wall area (AWA%) is predictive of FEVi (post-corticosteroid/bronchodilator FEVi) decline (Aim III). The identification of potential variables associated with remodeling and severe asthma will help identify individuals at risk whom would benefit from specific targeted therapy. The concerted efforts of this project together with the SARP will lead to new insights on the mechanistic basis for severe asthma, further elucidate how it differs from mild-moderate asthma, identify potential targets for intervention, and will provide imaging metrics to objectively evaluate outcomes for new treatments. RELEVANCE: Understanding the molecular basis of goblet cell metaplasia and mucin production in severe asthma will provide new targets for therapy. Understanding the pathophysiologic mechanism of ventilation defects and air trapping will impact therapies such as thermoplasty and provide means of evaluating new treatments noninvasively with imaging. Finally, identification of predictors of progressive accelerated lung function decline may allow for earlier intervention in at-risk patients, leading to less severe asthma subsequently.