Inhibition of tracheal smooth muscle cell proliferation by phosphodiesterase inhibitors

Abstract

Agents that increase intracellular cyclic 3',5'-adenosine monophosphate (cAMP), such as forskolin, prostaglandin (PG)E2, salbutamol and 8-bromo-cAMP, have been shownto inhibit the proliferation of airway smooth-muscle (ASM) cells in vitro. However, it has not yet been determined whether selective inhibitors of phosphodiesterase (PDE) isoenzymes III and IV that catalyze cAMPto 5'-adenosine monophosphate have the ability to inhibit ASM cell proliferation. To evaluate the effectsof PDE inhibitors on ASM cell proliferation, ASM cells isolated from bovine tracheae were cultured in the presence of fetal bovine serum (FBS), with or without a non-selective PDE inhibitor (theophylline), a selective PDE III inhibitor (cilostazol), and a selective PDE IV inhibitor (rolipram). The number of ASM cells cultured with 5% FBS was significantly reduced by the presence of theophylline at 10− 3 and 3 × 10− 4 mol/L, cilostazol at 10− 5, 10− 6 and 10− 7 mol/L, and rolipram at 10− 4 and 10− 5 mol/L. The release of lactic dehydrogenase from ASM cells cultured with any concentration of these agents was not significantly different from that with medium alone. Inhibitors of PDE III and IV were demonstrated to have an inhibitory effect on ASM cell proliferation induced by FBS. Our results suggest the value of the further development of PDE inhibitors for the treatment of hyperplasia of ASM cells characteristic of airway remodeling, in addition to bronchospasm and airway inflammation, in bronchial asthma.