Inflammation of Myofibroblasts and Loss of Elastic Recoil in Severe Asthma

描述(由申请人提供)： 初步数据显示，重度易加重哮喘与轻度哮喘的不同之处在于特定于远端肺的异常。我们假设，远端呼吸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导致严重哮喘的临床、生理和放射异常(图18)。为了评估这些临床、生理和病理生物学改变(以及它们对大剂量全身类固醇激素的反应)，我们提出了三个目标。在目标1中，我们将继续阐述易加重的严重哮喘的生理和结构变化。这一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、后座力丧失和塌陷)、在TLC和FRC/TGV拍摄的数字合格和量化的多层螺旋CT图像观察到的呼吸道和实质的结构变化及其与炎症过程的关系。这些变化将在曲安奈德治疗后重新评估。在目标2中，我们将确定炎性细胞因子(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、MMPs)在远端和近端气道中的存在，这些因素可能与重症哮喘患者远端肺嗜酸性粒细胞/肥大细胞炎症有关。我们将评估这些因素和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，我们将阐述从近端肺和远端肺分离出的成纤维细胞的表型差异(通过从相同个体的支气管内和经支气管镜活检获得)如何有助于远端肺的炎症和修复过程的持续。作为SARP II的一部分，我们将确定CS的剂量反应是否发生了变化，这可能有助于解释肺远端炎症的持久性和疾病的难治性。完成这些目标应该有助于更好地理解小气道/肺泡的炎症和损伤修复在严重哮喘发生中的作用。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.