Reduction of matrix metalloproteinase-9 activity by the selective phosphodiesterase 4 inhibitor, RP 73-401 in sensitized mice.
Matrix metalloproteinases are particularly potent in degrading basement membrane collagen and other extracellular matrix components. We have investigated the effects of a selective phosphodiesterase 4 inhibitor, RP 73-401 [N-(3, 5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-methoxybenzamide], on gelatinase (matrix metalloproteinase-2 and matrix metalloproteinase-9) activity in ovalbumin-sensitized and -challenged mice. Twenty-four hours after the last challenge, matrix metalloproteinase activity was evaluated in the bronchoalveolar lavage fluids by a zymography technique, and a significant increase in matrix metalloproteinase-9, but not matrix metalloproteinase-2, activity was noted. When administered orally (0.3-3 mg/kg) 1 h before each ovalbumin challenge, the selective phosphodiesterase 4 inhibitor, RP 73-401, significantly reduced this increased matrix metalloproteinase-9 activity in bronchoalveolar lavage fluids. Our data suggest that RP 73-401 may modulate tissue remodelling associated with lung inflammatory processes including asthma.
Belleguic
C
C
INSERM U 456, Faculté des Sciences Pharmaceutiques et Biologiques, Université de Rennes 1, 2, Avenue du Prof. Léon Bernard, 35043 cedex, Rennes, France.
Corbel
M
M
Germain
N
N
Boichot
E
E
Delaval
P
P
Lagente
V
V
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D001992:Bronchoalveolar Lavage Fluid; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000187:drug effects / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*
D001549:Benzamides; D010726:Phosphodiesterase Inhibitors; D011725:Pyridines; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; C087566:piclamilast