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.
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