Modulation of matrix metalloproteinase production from human lung fibroblasts by type 4 phosphodiesterase inhibitors.
Over-expression of matrix metalloproteinases by lung fibroblasts has been blamed for much of the tissue destruction associated with airway inflammation. Because cyclic AMP is known to regulate fibroblast proliferation, as well as cytokine and extracellular matrix protein production, the current study was designed to evaluate the ability of three selective phosphodiesterase (PDE) type 4 inhibitors, rolipram, cilomilast and CI-1044, to inhibit extracellular matrix degradation. Using zymography and ELISA, we found that pro-MMP-2 release was enhanced following 24 h treatment of human lung fibroblast (MRC-5) with TGF-beta1 (10 ng/ml) or TNF-alpha (10 ng/ml), whereas PMA (0.02 microM) had no effect. One hour of pre-incubation with PDE4 inhibitors (10 microM) induced an inhibition of TNF-alpha-stimulated pro-MMP-2 release. Zymography and immunoblotting revealed that fibroblasts cultured with PMA or TNF-alpha released increased amounts of pro-MMP-1, whereas TGF-beta1 had no effect. Incubation with CI-1044 or cilomilast significantly prevented the TNF-alpha increase in pro-MMP-1. These results suggest that PDE4 inhibitors are effective in inhibiting the pro-MMP-2 and pro-MMP-1 secretion induced by TNF-alpha and might underline a potential therapeutic benefit of selective PDE4 inhibitors in lung diseases associated with abnormal tissue remodelling.
Martin-Chouly
Corinne A E
CA
INSERM U456, Université de Rennes 1, 2 avenue du Pr Léon Bernard, 35043 Rennes, France. corinne.chouly@rennes.inserm.fr
Astier
Alexandra
A
Jacob
Claire
C
Pruniaux
Marie-Pierre
MP
Bertrand
Claude
C
Lagente
Vincent
V
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D001381:Azepines / Q000494:pharmacology*; D015153:Blotting, Western; D001993:Bronchodilator Agents / Q000494:pharmacology; D002264:Carboxylic Acids; D002460:Cell Line; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D003509:Cyclohexanecarboxylic Acids; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D007527:Isoenzymes; D008168:Lung / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D045726:Metalloproteases / Q000096:biosynthesis*; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology*; D009570:Nitriles; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020889:Rolipram / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D001381:Azepines; D001993:Bronchodilator Agents; D002264:Carboxylic Acids; D003509:Cyclohexanecarboxylic Acids; D007527:Isoenzymes; D009570:Nitriles; D010726:Phosphodiesterase Inhibitors; D012333:RNA, Messenger; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D009536:Niacinamide; C433247:Cilomilast; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D045726:Metalloproteases; D020778:Matrix Metalloproteinase 2; D020781:Matrix Metalloproteinase 1; D020889:Rolipram; D013755:Tetradecanoylphorbol Acetate; C418118:CI 1044