A phosphodiesterase 4 inhibitor, roflumilast N-oxide, inhibits human lung fibroblast functions in vitro
Federica SabatiniLoredana PetecchiaSilvia BoeroMichela SilvestriJürgen KlarHermann TenorRolf BeumeArmin HatzelmannGiovanni A. Rossi
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Roflumilast
Phosphodiesterase inhibitor
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Phosphodiesterase inhibitor
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Objective To investigate the expression of collagen ge ne in different passages of human fibroblasts cultured in vitro and the reactivity of fibroblasts to epithelial growth factor (EGF). Method Fib roblasts from human normal skin were taken for successive cell culture. RT-PCR and 3H-TdR were performed. Result The expressions o f collagen Ⅰ and Ⅲ mRNAs, and content of 3H-TdR decreased gradually as t he passages of cultured human fibroblasts increased. EGF promotes the proliferat ion of P 10 cultured fibroblast instead of the P 60 cultured fibroblas t. Conclusion The present results might provide partial exper imental data for establishing human fibroblast senescent model in vitro.
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Chronic obstructive pulmonary disease (COPD) is a worldwide health problem resulting in significant morbidity and mortality; however, it could not be understood totally so far. Treatment options for the disease are quite limited and there is an urgent need for new treatment strategies. Among new therapeutic agents that are under development, a group of significant importance is phosphodiesterase-4 (PDE-4) inhibitors shown to have antiinflammatory actions. Phosphodiesterases are the enzymes responsible from the breakdown and inactivation of cyclic adenosine monophosphate (cAMP) which is an intracellular second messenger molecule. They are present in several structural and inflammatory cells, in these cells the inactivation of cAMP results in a proinflammatory cascade. So, in COPD which goes together with chronic inflammation, prevention of cAMP inactivation via phosphodiesterase enzyme inhibition made phosphodiesterase enzymes potential targets. Main phosphodiesterase playing a part in COPD is PDE-4 which is predominantly present in inflammatory cells and airway smooth muscle cells. The studies therefore focused on inhibitors selective to PDE-4 subtype. The two selective PDE-4 inhibitors that are at Phase III clinical trial stage are cilomilast and roflumilast. The studies have demonstrated that antiinflammatory effects of cilomilast and roflumilast positively contribute to the respiratory function, frequency of exacerbations and quality of life of COPD patients. Despite we need new studies to evaluate the influence of these agents on the natural course of COPD as well as their long-term safety; we can certainly comment that cilomilast and roflumilast are promising hope in COPD treatment by their clinical and antiinflammatory effects.
Roflumilast
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Roflumilast
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PDE4B was previously shown to be a dominant PDE4 subtype of neutrophils. However, its physiological role in the neutrophil function has not been evaluated. In this study, the inhibitory effects of a phosphodiesterase 4B (PDE4B)- selective inhibitor (compound A) and subtype non-selective PDE4 inhibitors (roflumilast and cilomilast) were evaluated in human peripheral blood cells. Compound A, roflumilast and cilomilast in a similar manner inhibited TNF-α production by LPS-stimulated human mononuclear cells. However, the inhibitory effect of compound A on IL-8 or LTB4-induced chemotactic response of neutrophils was modest even at the highest concentration (10 μmol L(-1)), whereas roflumilast and cilomilast inhibited IL-8 or LTB4-induced neutrophil chemotaxis. Our results suggest that PDE4B does not play an important role during the chemotactic response of human neutrophils.
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Phosphodiesterase inhibitor
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Cyclic nucleotide phosphodiesterase
Phosphodiesterase inhibitor
Proteinase inhibitor
Inhibitor protein
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Effect of Roflumilast in airways disorders via dual inhibition of phosphodiesterase and Ca2+-channel
The bronchodilator effects of Roflumilast "a selective phosphodiesterase type-4 (PDE4)" inhibitor studied in this experimental protocol. The spiral strips of isolated guinea-pig tracheal chains mounted in organ bath and maintained in Krebs solution ventilated with carbogen at 32 °C and in Ca++ restricted krebs solution. PDE inhibitory activity was evaluated by recording dose response curves using inhibitory effect of isoprenaline on CCh induced contractions. For confirmation of PDE inhibition the intracellular cAMP levels were also estimated. Roflumilast resulted a sharp inhibition in contractile responses of carbachol (CCh, 1 µM) and K+ (80 mM) and the results were almost similar to verapamil. In Ca++ restricted Krebs solution, a rightward shift in the Ca++ response curves observed in the tracheal chain strips which were pretreated with Roflumilast (0.001-0.003 mg/mL) and the maximum response was suppressed, similarly as with verapamil. PDE inhibitory effect of Roflumilast evaluated by recording dose-dependent (0.03-0.1 mg/mL) responses, the isoprenaline-induced inhibitory dose response curves shifted leftward similar to papaverine (PDE inhibitor). Pretreatment with Roflumilast exhibited elevated intracellular cAMP levels in tracheal strips. Findings of the experiment conclude bronchodilatory influence of Roflumilast via PDE and Ca++ channel inhibition. Results of current experiment offers comprehensive mechanistic background of Roflumilast in future as therapeutic bronchodilator for hyperactive bronchial airway diseases.
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