MATRIX REGULATION OF FIBROPROLIFERATIVE LUNG DISEASE

哮喘和闭塞性毛细支气管炎综合征(BOS)等慢性肺部疾病的一个特征是 炎症持续和细胞外基质(ECM)不适当沉积。这些机制可以 对这些慢性纤维增生性呼吸道疾病的调控尚不完全清楚。此外, 慢性哮喘和BOS的特点是细胞外基质过度周转，且具有共同的不可逆性 气流受限、上皮细胞损伤、炎症、气道重塑和普遍缺乏反应性 进行皮质类固醇治疗。我们提出了ECM的周转，伴随着持久基质降解的产生 产品，推动慢性炎症和纤维增生性呼吸道重塑。特别是，来自我们的工作 实验室研究表明，细胞外基质中的糖胺聚糖透明质酸(HA)在体内受到动态调节。 肺损伤、炎症和修复。我们现在提出，HA片段的持久性导致慢性 炎症和纤维增生性肺疾病分别在哮喘和BOS中观察到。寄主 上皮细胞和巨噬细胞对ECM降解产物的识别是通过与 Toll样受体(TLRs)。我们发现HA片段对巨噬细胞刺激炎症基因的作用 需要TLR2和TLR4。此外，上皮细胞表面HA的表达促进了 修复损伤，而可溶性HA片段促进炎症反应。我们将检验这一假设 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很重要， 炎症和纤维增生在ASTMA和BOS中的作用如下：(1)确定其机制 利用TLR缺陷小鼠体内HA和TLR对炎症和纤维化的调节以及基因靶向和 细胞特异性的HA合酶的缺失和转基因表达；(2)确定HA和 IL-13转基因哮喘模型中TLRs在慢性呼吸道炎症和重构中的作用；(3)确定 哮喘患者呼吸道成纤维细胞产生的透明质酸的功能作用；以及(4)决定预后 透明质酸作为BOS预测指标的价值 与SCCOR项目/核心的互动：该项目调查透明质酸和TLRs在 慢性肺部疾病与项目1、2和3相结合。项目2和3的临床样本将是 分析过了。该项目将与所有核心进行互动。

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.