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*Lung Diseases

Vol. 301, Issue 1, 258-265, April 2002

The Selective Phosphodiesterase 4 Inhibitor RP 73-401 Reduced Matrix Metalloproteinase 9 Activity and Transforming Growth Factor-beta Release During Acute Lung Injury in Mice: The Role of the Balance Between Tumor Necrosis Factor-alpha and Interleukin-10

Marianne Corbel, Noëlla Germain, Jérôme Lanchou, Sophie Molet, Patricia M. R. e Silva, Marco A. Martins, Elisabeth Boichot and Vincent Lagente

Institut National de la Santé et de la Recherche Medicale U 456, Faculté des Sciences Pharmaceutiques et Biologiques, Université de Rennes 1, Rennes, France (M.C., N.G., J.L., S.M., E.B., V.L.); and Departamento de Fisiologia e Farmacodinâmica, Instituto Oswaldo Cruz/FIOCRUZ, Rio de Janeiro, Brazil (P.M.R.e.S., M.A.M.)

Matrix metalloproteinases (MMPs) and transforming growth factor (TGF)-beta 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-beta 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)-alpha and TGF-beta 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-alpha release but not in TGF-beta production. In the second model, RP 73-401 inhibited BAL neutrophils but not MMP-9 activity and TGF-beta production that were induced by intranasal TNF-alpha . We demonstrated that RP 73-401 might modulate the expression of airway remodeling-associated mediators such as MMP-9 and TGF-beta and that this effect seemed to be at least partially mediated by the balance between TNF-alpha and IL-10.

0022-3565/02/3011-0258$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics


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