title: 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.
abstract: 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.
authors.affiliation: Institut National de la Santé et de la Recherche Medicale U 456, Faculté des Sciences Pharmaceutiques et Biologiques, Université de Rennes 1, Rennes, France.
authors.forename: Marianne
authors.initials: M
authors.lastname: Corbel
authors.forename: Noëlla
authors.initials: N
authors.lastname: Germain
authors.forename: Jérôme
authors.initials: J
authors.lastname: Lanchou
authors.forename: Sophie
authors.initials: S
authors.lastname: Molet
authors.forename: Patricia M
authors.initials: PM
authors.lastname: R e Silva
authors.forename: Marco A
authors.initials: MA
authors.lastname: Martins
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Boichot
authors.forename: Vincent
authors.initials: V
authors.lastname: Lagente
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D015153:Blotting, Western; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004731:Endotoxins; D016753:Interleukin-10 / Q000378:metabolism*; D008070:Lipopolysaccharides; D008171:Lung Diseases / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008807:Mice, Inbred BALB C; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D001549:Benzamides; D004731:Endotoxins; D008070:Lipopolysaccharides; D061965:Matrix Metalloproteinase Inhibitors; D010726:Phosphodiesterase Inhibitors; D011480:Protease Inhibitors; D011725:Pyridines; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; C044101:endotoxin, Escherichia coli; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C087566:piclamilast