MATRIX REGULATION OF FIBROPROLIFERATIVE LUNG DISEASE

Duke University, Durham NC

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Abstract

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