Cyclic nucleotide phosphodiesterase-4 inhibitors: a promising therapeutic approach to premature birth?

Abstract

Pharmacological interventions in preterm labour attempt to target various protagonists involved in the signalling pathway leading to myometrial contractions. None of these interventions has clearly demonstrated any real clinical benefit, and some are associated with severe maternal and fetal side effects. The original study now reported has disclosed a new potential target, myometrial phosphodiesterase-4 (PDE4), for tocolysis. The PDE4 family specifically hydrolyses cAMP, a major intracellular second messenger implicated in the mechanisms governing smooth muscle motility. One particular isoform, PDE4B2, is overexpressed in the human myometrium at the end of pregnancy, and we observed a change of the myorelaxant properties of selective PDE4 inhibitors at this time. Signalling factors involved in labour at term or in infection-induced preterm labour, such as PGE 2 or IL-1β, are also able to induce PDE4B2 expression by way of a cAMP-dependent pathway. This feedback loop explains, at least in part, the process of desensitisation to relaxant agents that occurs at the end of pregnancy. In addition, PDE4 inhibitors block the production of LPS-induced inflammatory cytokines by myometrial explants. Thus, a combination of myorelaxant and anti-inflammatory properties make the PDE4 inhibitors particularly attractive as a target for the prevention of threatened infection-induced preterm delivery and its consequences for the premature infant.