Background: Chronic infiltration of the airway wall with inflammatory cells characterizes both asthma and chronic bronchitis. Remodeling of the airway wall is also a feature of both diseases. Objective: We hypothesized that collagen degradation may take place during coculture of monocytes with smooth-muscle cells (SMCs) and that this degradation might be altered by agents that modify the inflammatory regimen. Methods: Monocytes (4.5 × 10⁵/mL) were cast into collagen gels containing human airway SMCs (4.5 × 10⁵/mL) and released into serum-free Dulbecco's modified Eagle's medium containing neutrophil elastase. Collagen content was quantified as total insoluble hydroxyproline on day 5. Zymography and immunoblotting were used to detect matrix metalloproteinases. Results: Monocytes cocultured with SMCs in 3-dimensional native type I collagen gels produced TNF-⍺ and IL-1β and resulted in collagen degradation (30.5 vs 17.9 mg per gel) through inducing matrix metalloproteinase 1, 2, and 9 by means of SMCs. PGE₂ was significantly increased in coculture (0.9 vs 10.5 ng/mL). Indomethacin (1 μmol/L) completely inhibited PGE₂ production but augmented collagen degradation (17.9 vs 2.3 μg per gel), and this was blocked by the addition of exogenous PGE₂. Dexamethasone also inhibited collagen degradation in coculture. Conclusion: The current study supports the concept that interactions among cells present in the airway inflammatory milieu that characterize airway disease can lead to alterations in tissue structure and suggests mechanisms by which therapeutic strategies can be designed to modify tissue remodeling. (J Allergy Clin Immunol 2001;108:989-96.)