Phosphodiesterase 3 and 4 Inhibition: Facing a Bright Future in Asthma Control

A recent status on asthmaticus multiple case report by Beute demonstrated the beneficial effects of phosphodiesterase III (PDE3) and phosphodiesterase IV (PDE4) inhibition. This chapter reviews the possible underlying mechanisms, beside the known effect, for the beneficial effects of a mixed PDE3/4 inhibitor in allergic airway inflammation. Structural cells of the lung and immune system express PDE3 and 4. PDE3 and 4 inhibition have a number of consequences related to physical function and cytokine production. The most direct effect of PDE3 inhibition being relaxation of smooth muscle cells results in bronchodilation. However, PDE3 inhibition appears to go further than a mere inhibitory activity in bronchial smooth muscle. It also affects structural cells, and more importantly, it creates an improved barrier function in endothelial cells. PDE3 and 4 inhibition therefore strengthens the immune barrier; but in addition, it modifies the cells of the immune system itself, as these also express PDE3 and 4 activity, thus changing their function. All aspects of asthma-related pathophysiology seem to be affected by PDE3 and 4 inhibition. Clinical use of a mixed PDE3/4 inhibitor in respiratory diseases is currently limited to a few studies, including life-threatening asthma in which mixed PDE3/4 inhibition has a beneficial effect.