MATRIX REGULATION OF FIBROPROLIFERATIVE LUNG DISEASE

慢性肺部疾病如哮喘和闭塞性细支气管炎综合征（BOS）的标志是： 炎症的持续和细胞外基质（ECM）的不适当沉积。的机制 调节这些纤维增生性气道疾病的慢性化还不完全清楚。此外，本发明还提供了一种方法， 慢性哮喘和BOS的特征在于ECM过度转换，并且共同具有不可逆的 气流受限、上皮细胞损伤、炎症、气道重塑和反应性普遍缺乏 皮质类固醇治疗我们认为ECM周转，随着持续基质降解的产生， 产品，驱动慢性炎症和纤维增生性气道重塑。特别是，我们的工作 实验室已经表明，ECM糖胺聚糖透明质酸（HA）在 肺损伤、炎症和修复。我们现在提出HA片段的持续存在导致慢性 炎症和纤维增生性肺病，如分别在哮喘和BOS中观察到的。主机 上皮细胞和巨噬细胞识别ECM降解产物是通过与 Toll样受体（TLR）。我们发现HA片段刺激巨噬细胞的炎症基因， 需要TLR2和TLR4。此外，HA在上皮细胞的细胞表面上的表达促进了上皮细胞的生长。 修复损伤，而可溶性HA片段促进炎症反应。我们将检验这个假设 基质与宿主先天免疫受体的相互作用在肺损伤的病理生物学中是重要的， 目的：（1）探讨哮喘和BOS的发病机制， 使用TLR-缺陷小鼠和基因靶向的HA和TLR调节体内炎症和纤维化， HA酶的细胞特异性缺失和转基因表达;（2）确定HA的功能作用， TLR在IL-13转基因哮喘模型中的慢性气道炎症和重塑中的作用;（3）确定 哮喘患者气道成纤维细胞产生HA的功能作用;（4）确定哮喘患者的预后 HA作为BOS预测因子的价值。 与SCCOR项目/核心的相互作用：该项目研究了透明质酸和TLR在 慢性肺病与项目1、2和3一起。项目2和3的临床样本将 分析了该项目将与所有核心进行交互。

A hallmark of chronic lung diseases such as asthma and bronchiolitis obliterans syndrome (BOS) are the persistence of inflammation and inappropriate deposition of extracellular matrix (ECM). The mechanisms that regulate the chronicity of these fibroproliferative airways diseases are incompletely understood. In addition, chronic asthma and BOS are characterized by excessive turnover of ECM, and have in common irreversible airflow limitation, epithelial cell injury, inflammation, airway remodeling and a general lack of responsiveness to corticosteroid therapy. We propose that ECM turnover, with the generation of persistent matrix degradation products, drives chronic inflammation and fibroproliferative airway remodeling. In particular, work from our laboratory has shown that the ECM glycosaminoglycan hyaluronan (HA) undergoes dynamic regulation in lung injury, inflammation and repair. We now propose that the persistence of HA fragments leads to chronic inflammation and fibroproliferative lung disease as observed in asthma and BOS, respectively. Host recognition of ECM degradation products by both epithelial cells and macrophages is through interaction with Toll-like receptors (TLRs). We found that HA fragment stimulation of inflammatory genes by macrophages requires both TLR2 and TLR4. Furthermore, HA expression on the cell surface of epithelial cells promotes repair of injury, whereas soluble HA fragments promote inflammatory responses. We will test the hypothesis that matrix interactions with host innate immune receptors is important in the pathobiology of lung injury, inflammation, and fibroproliferation in ashtma and BOS in the following aims: (1) Determine the mechanisms of HA and TLR regulation of inflammation and fibrosis in vivo using TLR-deficient mice and gene targeted and cell-specific deletion and transgenic expression of HA synthases; (2) Determine the functional role of HA and TLRs in chronic airway inflammation and remodeling in an IL-13 transgenic model of asthma; (3) Determine the functional role of HA produced by airway fibroblasts from asthmatics; and (4) Determine the prognostic value of HA as a predictor of BOS. Interactions with SCCOR Projects/Cores: This project investigates the role of hyaluronan and TLRs in chronic lung disease in conjunction with Projects 1, 2 and 3. Clinical samples from Projects 2 and 3 will be analyzed. The project will interact with all the Cores.