IL-13, MYOFIBROBLASTS & ELASTIC RECOIL IN SEVERE ASTHMA

IL-13，肌成纤维细胞

• 批准号: 6437135
• 负责人: Sally E Wenzel
• 金额: $ 52.17万
• 依托单位: NATIONAL JEWISH HEALTH
• 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 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6437135
• 关键词: asthma; bronchomotion; cell differentiation; computed axial tomography; disease /disorder classification; elasticity; elastin; emphysema; extracellular matrix; fibroblasts; growth factor; human subject; inflammation; interleukin 13; metalloendopeptidases; myoblasts; pathologic process; patient oriented research; respiratory airflow measurement; tissue /cell culture

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.

描述(由申请人提供)： 重症哮喘的病理生理学还知之甚少。的子集 易发生近乎致命事件的严重哮喘患者出现 增加了气道的塌陷性和弹性后坐损失 加剧了他们的严重性。我们假设这些变化是由 通过远端肺的炎症和结构变化，涉及到 成纤维细胞向肌成纤维细胞的转化。与此相关的伤害和 修复过程，涉及肥大细胞蛋白酶和金属蛋白酶(MMPs)， 单独或联合分解弹性蛋白和其他细胞外基质(ECM) 组件。ECM的分解产物反过来又反馈到 肌成纤维细胞继续生产弹性蛋白的循环 释放/激活和弹性蛋白分解。这些改变改变了肺泡实质。 附着物，减少弹性后坐，并显著恶化 哮喘的临床严重程度。在具体目标1中，我们将描述 被认为对哮喘很重要的生理参数：气流受限， 支气管高反应性，此外还有弹性反冲(通过 压力-体积曲线)。哮喘受试者将接受支气管镜检查 和经纤维支气管镜活检以评估细胞和免疫炎症 在两个肺室都有突起。肺气肿患者切除的肺将 用来作比较。高分辨率CT扫描将评估实质 不同群体之间的差异。专门的目标2将测量弹性蛋白在 受试者肺远端及其与肌成纤维细胞的关系 表型变化。这些变化将与基质金属蛋白酶和肥大细胞进行比较 酶的数量和活性，以及ECM降解产物 远端肺。在特定的目标3中，我们将建立一个体外模型 培养近、远端成纤维细胞观察体内过程 阿龙。生长因子、蛋白酶与细胞间的相互作用 将对细胞外基质进行专门评估。完成这些研究 哮喘和肺气肿应为治疗和治疗提供新的靶点 预防严重的阻塞性肺疾病。