IL-13, MYOFIBROBLASTS & ELASTIC RECOIL IN SEVERE ASTHMA

描述（由申请人提供）： 严重哮喘的病理生理机制知之甚少。的子集 易发生接近致命事件的重度哮喘患者 增加了气道的可膨胀性和弹性回缩的损失 导致其严重性。我们假设这些变化是由 通过远端肺的炎症和结构变化， 成纤维细胞向肌成纤维细胞的转化。相关的伤害和 修复过程，涉及肥大细胞蛋白酶和金属蛋白酶（MMP）， 单独或组合切割弹性蛋白和其它细胞外基质（ECM） 件. ECM的分解产物反过来又反馈到 肌成纤维细胞继续弹性蛋白的生产周期，MMP 释放/活化和弹性蛋白分解。这些变化改变了肺泡实质 附件，减少弹性回缩和显着恶化 哮喘的临床严重程度。在具体目标1中，我们将描述 在哮喘中被认为是重要的生理参数：气流限制， 支气管高反应性，此外，弹性回缩（通过 压力-体积曲线）。哮喘受试者将接受支气管内 并经支气管活检以评估细胞和免疫炎症 在两个肺腔室中的过程。肺气肿病人的肺切除后， 用于比较。高分辨率CT扫描将评估脑实质 群体之间的差异。具体目标2将测量弹性蛋白在 受试者组的远端肺以及与肌成纤维细胞的关系 表型变化将这些变化与MMP和肥大细胞进行比较 蛋白酶的量和活性，以及ECM降解产物， 远端肺在具体目标3中，我们将开发一种体外模型， 通过培养近端和远端成纤维细胞观察体内过程 肺。生长因子、蛋白酶和 将具体评价细胞外基质。完成这些研究 在哮喘和肺气肿中的应用应该为治疗提供新的目标， 预防严重阻塞性肺病。

DESCRIPTION (provided by applicant): The pathophysiology of severe asthma is poorly understood. A subset of patients with severe asthma, who are predisposed to near fatal events appears to have increases in airway collapsibility and loss of elastic recoil contributing to their severity. We hypothesize that these changes are driven by inflammatory and structural changes in the distal lung which involve the transformation of fibroblasts to myofibroblasts. The associated injury and repair process, involving mast cell proteases and metalloproteinases (MMP), alone or in combination, cleaves elastin and other extracellular matrix (ECM) components. The breakdown products of ECM, in turn, feed back on the myofibroblasts continuing the cycle of elastin production, MMP release/activation and elastin breakdown. These changes alter the alveolar-parenchymal attachments, decreasing elastic recoil and markedly worsening the clinical severity of the asthma. In Specific Aim 1 we will characterize physiologic parameters felt to be important in asthma: airflow limitation, bronchial hyperreactivity, and, in addition, elastic recoil (measured by pressure-volume curves). The asthmatic subjects will undergo endobronchial and transbronchial biopsy to evaluate the cellular and immune inflammatory process in both lung compartments. Resected lung from emphysema patients will be used for comparison. High resolution CT scans will evaluate parenchymal differences among the groups. Specific Aim 2 will measure elastin in the distal lung of the subject groups and the relationship to myofibroblast phenotypic changes. These changes will be compared to MMP and mast cell protease amounts and activity, as well as ECM degradation products in the distal lung. In Specific Aim 3, we will develop an in vitro model of the observed in vivo processes by culturing fibroblasts from proximal and distal lung. Cellular interactions between growth factors, proteases and extracellular matrix will be specifically evaluated. Completing these studies in both asthma and emphysema should offer new targets for the treatment and prevention of severe obstructive lung diseases.