Airway epithelium is emerging as a regulator of local inflammation and immune responses. However, the cellular and molecular mechanisms responsible for the immune modulation by these cells have yet to be fully elucidated. At the cellular level, the hallmarks of airway inflammation are mucus gland hypertrophy with excess mucus production, accumulation of inflammatory mediators, inflammation in the airway walls and lumen, and breakdown and turnover of the extracellular matrix. We demonstrate that fragments of the extracellular matrix component hyaluronan induce inflammatory chemokine production in primary airway epithelial cells grown at an air-liquid interface. Furthermore, hyaluronan fragments use two distinct molecular pathways to induce IL-8 and IP-10 chemokine expression in airway epithelial cells. Hyaluronan-induced IL-8 requires the MAP kinase pathway whereas hyaluronan-induced IP-10 utilizes the NF-B pathway. The induction is specific to low molecular weight hyaluronan fragments as other glycosaminoglycans do not induce IL-8 and IP-10 in airway epithelial cells. We hypothesize that the extracellular matrix is not only a target of destruction in airway inflammation, but that it plays a critical role in perpetuating inflammation through the induction of cytokines, chemokines and modulatory enzymes in epithelial cells. Furthermore hyaluronan, by inducing IL-8 and IP-10 by distinct pathways, provides a unique target for differential regulation of key inflammatory chemokines.