Inflammation of Myofibroblasts and Loss of Elastic Recoil in Severe Asthma

严重哮喘中肌成纤维细胞的炎症和弹性回缩力的丧失

• 批准号: 7919100
• 负责人: Sally E Wenzel
• 金额: $ 4.98万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-20 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7919100
• 关键词: Address; Adhesions; Adrenal Cortex Hormones; Air; Alveolar; Alveolus; Asthma; Biopsy; CD44 gene; Caliber; Cell Adhesion Molecules; Cell Survival; Cells; Clinical; Collaborations; Data; Defect; Development; Disease; Distal; Dose; Elements; Event; Family; Fibroblasts; Gelatinase B; Generations; Growth Factor; Hyaluronan; Image; Immunoglobulins; Individual; Inflammation; Inflammatory; Interleukin-13; Interleukins; Interstitial Collagenase; Irrigation; Lead; Lung; Maintenance; Matrix Metalloproteinases; Measures; Myofibroblast; Nature; Pathologic; Pattern; Phenotype; Physiological; Process; Production; Property; Proto-Oncogene Protein c-kit; Protocols documentation; Qualifying; Refractory; Research Personnel; Respiratory physiology; Serum; Site; Sputum; Stem Cell Factor; Steroid therapy; Steroids; Thick; Tissues; Triamcinolone; cell motility; cytokine; eosinophil; follower of religion Jewish; hyaluronan synthase 1; improved; injury and repair; mast cell; migration; programs; repaired; response

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.

描述（由申请人提供）： 初步数据表明，在远端肺特异性异常方面，重度急性发作倾向性哮喘与轻度哮喘不同。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，导致严重哮喘的临床、生理和放射学异常（图18）。为了评价这些临床、生理和病理变化（及其对大剂量全身性类固醇的反应），我们提出了3个目标。在目标#1中，我们将继续扩大在严重急性发作倾向性哮喘中存在的生理和结构变化。这一目的将包括比较重度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TLC和FRC/TGV拍摄的数字化合格和定量多探测器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。这些变化将在曲安西龙治疗后重新评估。在目标#2中，我们将鉴定远端和近端气道中炎性细胞因子（IL-13/TNF-α）、生长因子（TGF-15 1/2、c-kit/c-kit配体）和基质成分（透明质酸/HAS、IGSF-4、MMP）的存在，其可能导致重度哮喘中观察到的持续远端肺嗜酸性粒细胞/肥大细胞炎症。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，我们将讨论从近端肺与远端肺分离的成纤维细胞的表型差异（通过来自相同个体的支气管内和经支气管活检获得）如何有助于远端肺中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。完成这些目标将有助于更好地理解小气道/肺泡中炎症和损伤修复对严重哮喘发展的贡献。这些发现也可能改善治疗。