A hallmark of diseases such as idiopathic pulmonary fibrosis and chronic asthma is the excessive turnover and deposition of extracellular matrix (ECM). The mechanisms that regulate fibroproliferation and airway remodeling are incompletely understood. We hypothesize that episodes of acute worsening and deterioration are characterized by the generation of ECM degradation products. The major tenet of this proposal is that ECM turnover and the persistence of ECM fragments drives chronic inflammation and fibrosis. We have provided data that the failure to remove HA fragments from the lung following injury results in unremitting inflammation by promoting macrophage activation. The removal of HA requires the HA receptor CD44. In addition, we have provided evidence that the host recognizes HA fragments through Toll-like receptors (TLRs) on both inflammatory cells and alveolar epithelial cells. Mice deficient in both TLR2 and TLR4 (TLR2-/-/4-/-) show increased tissue injury, decreased survival and increased lung epithelial cell. The enhanced injury in TLR2-/-/4-/- mice appears to be due to impaired HA-TLR interactions on epithelial cells. In addition, we have made the novel observation that CD44 deficiency results in enhanced lung inflammation in vivo and increased macrophage activation both in vitro and in vivo, suggesting that CD44 is a negative regulator of TLR signaling. Collectively, these data have led us to hypothesize that host HA, CD44 and TLR interactions are critical components of the injury and repair response in lung inflammation, fibrosis and chronic asthma. We will test this hypothesis using gene targeted mice in the following specific aims: 1. Determine the mechanisms by which hyaluronan, CD44 and TLRs regulate lung inflammation and fibrosis in vivo using gene targeted and cell-specific deletion and transgenic overexpression of hyaluronan synthases and TLR and CD44-deficient mice. 2. Determine the functional role of hyaluronan, CD44 and TLRs in regulating chronic inflammation and airway remodeling using a lung specific IL-13 transgenic model of asthma in mice. 3. Determine the mechanisms by which CD44 negatively regulates macrophage activation and TLR signaling in vivo and in vitro. ? ? ?
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