A hallmark of chronic lung diseases such as asthma and bronchiolitis obliterans syndrome (BOS) are thepersistence of inflammation and inappropriate deposition of extracellular matrix (ECM). The mechanisms thatregulate 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 irreversibleairflow limitation, epithelial cell injury, inflammation, airway remodeling and a general lack of responsivenessto corticosteroid therapy. We propose that ECM turnover, with the generation of persistent matrix degradationproducts, drives chronic inflammation and fibroproliferative airway remodeling. In particular, work from ourlaboratory has shown that the ECM glycosaminoglycan hyaluronan (HA) undergoes dynamic regulation inlung injury, inflammation and repair. We now propose that the persistence of HA fragments leads to chronicinflammation and fibroproliferative lung disease as observed in asthma and BOS, respectively. Hostrecognition of ECM degradation products by both epithelial cells and macrophages is through interaction withToll-like receptors (TLRs). We found that HA fragment stimulation of inflammatory genes by macrophagesrequires both TLR2 and TLR4. Furthermore, HA expression on the cell surface of epithelial cells promotesrepair of injury, whereas soluble HA fragments promote inflammatory responses. We will test the hypothesisthat 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 mechanismsof HA and TLR regulation of inflammation and fibrosis in vivo using TLR-deficient mice and gene targeted andcell-specific deletion and transgenic expression of HA synthases; (2) Determine the functional role of HA andTLRs in chronic airway inflammation and remodeling in an IL-13 transgenic model of asthma; (3) Determinethe functional role of HA produced by airway fibroblasts from asthmatics; and (4) Determine the prognosticvalue of HA as a predictor of BOS.Interactions with SCCOR Projects/Cores: This project investigates the role of hyaluronan and TLRs inchronic lung disease in conjunction with Projects 1, 2 and 3. Clinical samples from Projects 2 and 3 will beanalyzed. The project will interact with all the Cores.
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