Phosphodiesterases inhibitors and airway disease

Abstract

Phosphodiesterases exist as 11 families in a variety of inflammatory and structural cells.They hydrolyse intracellular cyclic adenosine monophosphate(cAMP)and cyclic guanosine monophosphate (cGMP)into inactive state.So PDE inhibitors allow the elevation of cAMP and cGMP which lead to a variety of cellular effects including airway smooth muscle relaxation and inhibition of cellular inflanlmation or of immune responses.PDE4 inhibitors specifically prevent the hydrolysis of cAMP.Selective PDE4 inhibitors have broad spectrum anti-inflammatory effects such as inhibition of cell trafficking,cytokine and chemokine release from inflammatory cells.The new type PDE4 inhibitors,Cilomilast and Roflumilast,have reached clinical trial stage and were demonstrated to have beneficial effects in asthma and chronic obstructive pulmonary disease(COPD).The side effects of these PDE4 inhibitors may limit their clinical using doses.Development of inhibitors of other PDE classes,combined with PDE4 inhibition,may be another way forward.PDE5,PDE3 and PDE7 are other cAMP specific inactivators of cAMP.PDE5 inhibitor may have beneficial effects on hypoxic pulmonary hypertension and vascular remodelling.PDE7 is involved in T cell activation and a dual PDE4-PDE7 inhibitor may be more effective in asthma and COPD.A dual PDE3-PDE4 inhibitor compound may provide more bronchodilator and bronchoprotective effect compared with PDE4 inhibitors only. Key words: Cyclic adenosine monophosphate; Cyclic guanosine monophosphate; Chronic obstructive pulmonary disease; Bronchial asthma