Inflammation of Myofibroblasts and Loss of Elastic Recoil in Severe Asthma

描述（由申请人提供）： 初步数据表明，重度易发作性哮喘与轻度哮喘的不同之处在于远端肺部特有的异常。我们假设远端气道和肺泡的结构细胞具有独特的特性，有助于炎症的产生和维持，并预测该区域的某种修复模式会导致严重哮喘的临床、生理和放射学异常（图18）。为了评估这些临床、生理和病理变化（及其对高剂量全身类固醇的反应），我们提出了 3 个目标。在目标#1中，我们将继续扩展重度哮喘易加重发作中存在的生理和结构变化。该目标将包括比较严重哮喘特有的生理异常（过度充气/空气滞留、反冲力丧失和塌陷）、通过在 TLC 和 FRC/TGV 拍摄的数字合格和量化多排 CT 图像观察到的气道和实质结构变化及其与炎症过程的关系。在曲安西龙治疗后，将重新评估这些变化。在目标#2中，我们将确定远端和近端气道中是否存在炎性细胞因子（IL-13/TNF-a）、生长因子（TGF-IS1/2、c-kit/c-kit配体）和基质元素（透明质酸/HAS、IGSF-4、MMP），这可能导致严重哮喘中出现的持续性远端肺嗜酸性粒细胞/肥大细胞炎症。我们将评估这些因素以及相关炎症与该区域发生的修复过程的关系，以及通过 CT 测量的生理变化和结构变化。最后，在目标#3中，我们将讨论从近端肺和远端肺分离的成纤维细胞（通过同一个体的支气管内和经支气管活检获得）的表型差异如何促进远端肺炎症和修复过程的持续存在。作为 SARP II 的一部分，我们将确定对 CS 的剂量反应是否发生变化，这可能有助于解释远端肺部炎症的持续性和疾病的难治性。完成这些目标应该有助于更好地了解小气道/肺泡炎症和损伤修复对严重哮喘发展的影响。这些发现也可能改善治疗。

DESCRIPTION (provided by applicant): Preliminary data suggest severe exacerbation-prone asthma differs from milder asthma in abnormalities specific to the distal lung. We hypothesize that structural cells of the distal airways and alveoli have unique properties that contribute to the generation and maintenance of inflammation and predict a certain pattern of repair in this region leading to the clinical, physiologic and radiologic abnormalities of severe asthma (Figure 18). In order to evaluate these clinical, physiologic and pathobiologic changes (and their response to high dose systemic steroids) we propose 3 aims. In Aim #1, we will continue to expand on the physiologic and structural changes present in severe exacerbation prone asthma. This aim will include comparisons between the physiologic abnormalities specific to severe asthma (hyperinflation/air-trapping, loss of recoil and collapse), the structural changes in the airways and parenchyma observed by digitally qualified and quantified multidetector CT images taken at TLC and FRC/TGV and their relation to inflammatory processes. These changes will then be re-evaluated following the triamcinolone treatment. In Aim #2 we will identify the presence of inflammatory cytokines (IL-13/TNF-a), growth factors (TGF-IS1/2, c-kit/c-kit ligand) and matrix elements (hyaluronan/HAS, IGSF-4, MMPs) in the distal and proximal airway which could contribute to the persistent distal lung eosinophil/mast cell inflammation seen in severe asthma. We will evaluate the relationship of these factors and the associated inflammation to the repair processes occurring in this region and as well as physiologic changes and structural changes measured by CT. Finally, in Aim #3 we will address how phenotypic differences in fibroblasts isolated from the proximal vs. the distal lung (as obtained by endo- and transbronchial biopsies from the same individuals) could contribute to the perpetuation of the inflammatory and repair process in the distal lung. As part of SARP II, we will determine whether there is a shift in the dose response to CS that may help to explain both the persistence of the inflammation in the distal lung and the refractory nature of the disease. Completing these aims should lead to an improved understanding of the contribution of inflammation and injury repair in the small airways/alveoli to the development of severe asthma. These findings may improve therapy as well.