PDE4 as a target in preterm labour

Abstract

Cyclic nucleotide phosphodiesterases (PDE) are the enzymes catalyzing the hydrolysis and inactivation of the second messengers, cAMP and cGMP. Eleven PDE families are described to date, and selective inhibitors of some PDEs families are currently used in clinic for treating cardiovascular disorders, erectile dysfunction, and pulmonary hypertension. Isoforms of the PDE4 family are involved in smooth muscle contraction and inflammation. PDE4 selective inhibitors are currently in clinical trials for the treatment of diseases related to inflammatory disorders. Because of their myorelaxant properties, we first examined their expression in human myometrium and uncover an increased expression of one specific isoform, PDE4B2, in the near-term myometrium as compared to myometrium in the nonpregnant state. Using human myometrial cells in culture, we demonstrated that PDE4B2 can be induced by its own substrate, under the control of one of the major utero-contractile agonists, PGE2, itself upregulated by the proinflammatory cytokine IL-1beta. Functionally, augmentation of global PDE4 activity decreases the ability of beta-adrenergic agonists (the most commonly used tocolytic drugs) to inhibit myometrial contraction at the end of pregnancy and during pathophysiological situations, such as persistent intrauterine inflammation which is a major cause of very preterm delivery. Currently exploring the anti-inflammatory properties of PDE4 inhibitors in gestational tissues, we recently demonstrated the ability of these drugs to block a persistent inflammatory response of the foetal membranes in Humans and to prevent inflammation-driven preterm delivery and foetal demise in mice. These data open up a new therapeutical strategy to prevent inflammation-induced preterm delivery and its sequelae in very preterm infants.

Figure 1

Schematic organization of the PDE4 family. PDE4s have a highly conserved globular catalytic domain, flanked by regulatory domains, such as the PDE4 signature domains UCR1 and UCR2 (for Upstream Conserved Regulatory domains), containing, for example, a PKA phosphorylation site. PDE4s are divided in short or long forms, defined by the absence or the presence of UCR1. Some examples of short and long forms, expressed or regulated in human myometrium are quoted. Short form products of PDE4B and PDE4D gene derived from a cAMP-sensitive intronic promoter. Long forms are usually constitutive.

Figure 2

Potentiation of the relaxant effect of β-adrenergic agonist in the presence of a PDE4 selective inhibitor in pregnant myometrium. Strips were mounted for isometric recording under 900 mg tension and after 2 h equilibration, contractile activity was assessed. Myometrial strip of either pregnant (A) or nonpregnant women (B) were preincubated with 3 × 10^-9M RP73401, a competitive selective PDE4 inhibitor (open circles) or saline (closed circles), 30 min prior the construction of the concentration-response to salbutamol. Results are expressed in percentage of maximal contraction at the end of the equilibration period. Strips from the same patients were subjected in parallel to treatments. Data are expressed as the mean ± SEM for strips isolated from myometrium of five different pregnant women and three different nonpregnant women. (Adapted from [8]).

Figure 3

Inflammation-induced preterm delivery is prevented by rolipram. Delivered and undelivered dams were numbered 48 h after intrauterine injection of LPS or saline (A) and number of live pups per dams were recorded (B). The Fisher exact test was applied for comparison of preterm delivery rate in each group. ***p < 0.001 versus saline-vehicle group. For comparison of the number of live per dam, statistical difference between groups was assessed by two-way ANOVA, followed by Student's t test, two tailed for unpaired samples.^†††p < 0.001, versus the saline-vehicle group. (Adapted from [12]).

Figure 4

Summary of the effects of the PDE4 inhibition in gestational tissues in the case of intra-uterine inflammation. Intrauterine inflammation leads to massive production of cytokines and chemokines, mainly by the fetal membranes, the chorio-decidua. Cytokines and chemokines start a feedforward mechanism and the production of uterotonic agonists and metalloproteases in the chorio-decidua. These agents further digest the fetal membranes, contract the myometrium, and soften the cervix, causing preterm labor. Moreover, inflammation of the amniotic cavity may target the developing brain and lungs of the fetus. We showed that PDE4 inhibition may directly in the human myometrium and indirectly by decreasing production of cytokines in the fetal membranes diminish uterine contraction and delay preterm delivery. Furthermore, by decreasing intrauterine inflammation, PDE4 inhibitors may favor a normal development of the fetal brain and lungs.