Abstract

Matrix metalloproteinases (MMPs) and transforming growth factor (TGF)-β are involved in airway remodeling associated with the inflammatory process. In this study, we investigated the effect of RP 73-401 (piclamilast), a selective phosphodiesterase-4 inhibitor, on MMP-9 activity and TGF-β production in two murine models of acute inflammation. In the first model, the lipopolysaccharide (LPS)-induced increase in neutrophils, MMP-9 activity, and tumor necrosis factor (TNF)-α and TGF-β release in bronchoalveolar lavage (BAL) was significantly reduced by RP 73-401 pretreatment. In contrast, the BAL interleukin (IL)-10 level was decreased by LPS but restored by RP 73-401. IL-10 administration in LPS-exposed mice elicited a significant reduction in BAL neutrophilia, MMP-9 activity, and TNF-α release but not in TGF-β production. In the second model, RP 73-401 inhibited BAL neutrophils but not MMP-9 activity and TGF-β production that were induced by intranasal TNF-α. We demonstrated that RP 73-401 might modulate the expression of airway remodeling-associated mediators such as MMP-9 and TGF-β and that this effect seemed to be at least partially mediated by the balance between TNF-α and IL-10.