PDE4 as a target in preterm labour

The Journal of Immunology, 2007

The aim of this study was to explore the anti-inflammatory properties of phosphodiesterase-4 (PDE4) inhibitors in vivo and their potential ability to prevent inflammation-induced preterm delivery. Indeed, intrauterine inflammation is the major etiology of very preterm delivery, the leading cause of neonatal mortality and morbidity. Intrauterine injection of Escherichia coli LPS in 15-day-pregnant mice induced an increase of PDE4 activity and PDE4B expression at the maternofetal interface, a rise of amniotic fluid levels of TNF-α, IL-1β, IL-6, and IL-10 and provoked massive preterm delivery and fetal demise. Selective PDE4 inhibition by rolipram prevented the rise in the proinflammatory cytokines. Following the nuclear translocation of the transcription factor NFκB, as a marker of cellular activation after the inflammatory challenge, showed a time-dependent sequential activation of the gestational tissues, from the uterine mesometrial to the fetal compartment, particularly in the gly...

Journal of Reproductive Immunology, 2011

The major cause of spontaneous preterm birth (sPTB) at less than 32 weeks of gestation is intrauterine inflammation as a consequence of colonisation of the gestational membranes by pathogenic microorganisms which trigger activation of the local innate immune system. This results in release of inflammatory mediators, leukocytosis (chorioamnionitis), apoptosis, membrane rupture, cervical ripening and onset of uterine contractions. Recent PCR evidence suggests that in the majority of cases of inflammation-driven preterm birth, microorganisms are present in the amniotic fluid, but these are not always cultured by standard techniques. The nature of the organism and its cell wall constituents, residence time in utero, microbial load, route of infection and extent of tissue penetration are all factors which can modulate the timing and magnitude of the inflammatory response and likelihood of progression to sPTB. Administration of anti-inflammatory drugs could be a viable therapeutic option to prevent sPTB and improve fetal outcomes in women at risk of intrauterine inflammation. Preventing fetal inflammation via administration of placentapermeable drugs could also have significant perinatal benefits in addition to those related to extension of gestational age, as a fetal inflammatory response is associated with a range of significant morbidities. A number of potential drugs are available, effective against different aspects of the inflammatory process, although the pathways actually activated in spontaneous preterm labour have yet to be confirmed. Several pharmacological candidates are discussed, together with clinical and toxicological considerations associated with administration of anti-inflammatory agents in pregnancy.

Pregnancy is characterized by a complex interplay of inflamma-tory events regulated by both the innate and acquired immune systems. Similarly, parturition can be viewed as the activation of " pro-labour " inflammatory pathways, which drive cervical ripening and myometrial activation. Premature activation of these pathways, for example, by infection, can lead to preterm labour and birth. Nuclear factor κβ is a key modulator of these pathways and functions by regulating the expression of prosta-glandins, chemokines and pro-inflammatory cytokines involved in both term and preterm labour. Future design of therapeutics that target key mediators of inflammation and immune activation would therefore be a rational approach for preventing preterm labour and immune-mediated neonatal brain damage.

Biology of Reproduction, 2019

Although progesterone (P4) supplementation is the most widely used therapy for the prevention of preterm labor (PTL), reports of its clinical efficacy have been conflicting. We have previously shown that the anti-inflammatory effects of P4 can be enhanced by increasing intracellular cAMP levels in primary human myometrial cells. Here we have examined whether adding aminophylline (Am), a non-specific phosphodiesterase (PDE) inhibitor that increases intracellular cyclic adenosine monophosphate (cAMP) levels, to P4 might improve its efficacy using in vivo and in vitro models of PTL. In a mouse model of lipopolysaccharide (LPS)-induced PTL, we found that the combination of P4 and Am delayed the onset of LPS-induced PTL, while the same dose of P4 and Am alone had no effect. Pup survival was not improved by either agent alone or in combination. Myometrial prolabor and inflammatory cytokine gene expression was reduced, but the reduction was similar in P4 and P4/Am treated mice. There was n...

BMC Pregnancy and Childbirth

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 upre...

Life Sciences, 2010

Previous results by our group showed that the in vitro uterus-relaxing potency of β 2-adrenergic receptor (β 2-AR) agonists and uterine cAMP accumulation are enhanced in case of visceral inflammation. Our aim was to study the effects of the non-selective phosphodiesterase (PDE) inhibitor theophylline and the selective PDE4 inhibitor rolipram on the uteri of intact late-pregnant female rats (on days 20 and 22 of pregnancy) and of pregnant rats treated with lipopolysaccharide (LPS) to evoke preterm labor (on day 20). Main methods: The effects of theophylline and rolipram alone and of rolipram with terbutaline were investigated in isolated organ system. Contractions were evoked with KCl. The forskolin-and terbutalinestimulated cAMP accumulations were determined by enzyme immunoassay, with or without rolipram. Key findings: The maximum uterus-relaxing effects of theophylline and rolipram decreased significantly (p b 0.05) with the progression of pregnancy in intact rats. The most pronounced effect of rolipram was detected in rats challenged with LPS on day 20. Rolipram increased the in vitro effect of terbutaline both in intact and in LPS-treated rats. In the presence of rolipram, the forskolin-and terbutaline-stimulated cAMP accumulations were higher in LPS-treated than in intact rats. Significance: The previous findings led us to conclude that the combined administration of PDE4 inhibitors with β 2-agonists is of therapeutic value for the inhibition for uterine contractions, especially in the case of genital inflammation, which often triggers preterm birth. Combination therapy in general is associated with lesser side-effects, as a consequence of lower effective doses of each drug.

Journal of Physiology and Pathophysiology

Available therapeutic interventions for managing preterm labour have not been consistently successful due to controversies related to its etiology. Multiple mechanisms, including inflammation play a significant role in the pathogenesis of preterm labour. The connective tissue extracellular matrix of the amniochorion contains collagen fibres that maintain the tensile strength of the amniochorion, resisting mechanical stress and preventing rejection of the fetal allograft. Expression of pro-inflammatory mediators in the amniochorion triggers production of prostaglandins in the uterus and enzymatic degradation of the resilient extracellular matrix of the fetal membranes by matrix metalloproteinases leading to uterine contractions and cervical remodelling resulting in preterm labour. This review appraises the pathophysiological mechanisms of pro-inflammatory mediators in spontaneous preterm labour and their associations with multi-factorial etiological pathways. The physiological pathways and biological mechanisms of uterine activity during pregnancy and parturition are also discussed. Finally, the review provides an overview of the biological basis of common therapeutic agents for treating preterm labour. In this review, keywords related to pathophysiological mechanisms of maternal proinflammatory mediators in preterm labour and clinical management were used in the literature search from the PubMed and Google Scholar databases. The snowball sampling methodology was further employed to obtain a comprehensive literature search.

Journal of Reproductive Immunology, 2008

A role for the pro-inflammatory cytokines interleukin (IL)-1␤, IL-6, IL-8 and tumor necrosis factor alpha (TNF-␣) is evident in term and preterm delivery, and this is independent of the presence of infection. All uterine tissues progress through a staged transformation near the end of pregnancy that leads from relative uterine quiescence and maintenance of pregnancy to the activation of the uterus that prepares it for the work of labour and production of stimulatory molecules that trigger the onset of labour and delivery. The uterus is activated by pro-inflammatory cytokines through stimulation of the expression and production of uterine activation proteins (UAPs). One of these actions is the stimulation of prostaglandin (PG) synthesis. Particularly important for labour is PGF 2␣ and its receptor, PTGFR. In addition, pro-inflammatory cytokines are able to increase the synthesis of matrix metalloproteinases (MMPs), vascular endothelial growth factor (VEGF) and the progesterone receptor C isoform, which leads to decreased tissue progesterone responsiveness. Some of these effects are replicated by PGF 2␣ , suggesting that it may act via its receptor to amplify the direct actions of cytokines. In turn, VEGF may enhance leukocyte recruitment to the uterus, and MMP-9 may promote activation of inactive pro-form cytokines. Pro-inflammatory cytokines also decrease the activity of 11␤-hydroxysteroid dehydrogenase, which likely increases intrauterine cortisol concentrations. In turn, cortisol may drive PG synthesis. Together these feed-forward mechanisms activate the uterus, trigger the production of uterine contractile stimulants and lead to labour and delivery.

Preterm birth occurs in 10–12% of pregnancies and is the primary cause of neonatal mortality and morbidity. Tocolytic therapies have long been the focus for the prevention of preterm labour, yet they do not significantly improve neonatal outcome. A direct causal link exists between infection-induced inflammation and preterm labour. As inflammation and infection are independent risk factors for poor neonatal outcome, recent research focus has been shifted towards exploring the potential for anti-inflammatory strategies. Nuclear factor kappa B (NFkB) is a transcription factor that controls the expression of many labour-associated genes including PTGS2 (COX2), prostaglandins (PGs) and the oxytocin receptor (OXTR) as well as key inflammatory genes. Targeting the inhibition of NFkB is therefore an attractive therapeutic approach for both the prevention of preterm labour and for reducing neonatal exposure to inflammation. While PGs are considered to be pro-labour and pro-inflammatory, the cyclopentenone PG 15-deoxy-D 12,14 PGJ 2 (15d-PGJ 2) exhibits anti-inflammatory properties via the inhibition of NFkB in human amniocytes, myocytes and peripheral blood mononuclear cells in vitro. 15d-PGJ 2 also delays inflammation-induced preterm labour in the mouse and significantly increases pup survival. This review examines the current understanding of inflammation in the context of labour and discusses how anti-inflammatory PGs may hold promise for the prevention of preterm labour and improved neonatal outcome.

Scientific reports, 2024

During labor, monocytes infiltrate massively the myometrium and differentiate into macrophages secreting high levels of reactive oxygen species and of pro-inflammatory cytokines (i.e. IL-1β), leading to myometrial contraction. Although IL-1β is clearly implicated in labor, its function and that of the inflammasome complex that cleaves the cytokine in its active form, has never been studied on steps preceding contraction. In this work, we used our model of lipopolysaccharide-induced preterm labor to highlight their role. We demonstrated that IL-1β was secreted by the human myometrium during labor or in presence of infection and was essential for myometrial efficient contractions as its blockage with an IL-1 receptor antagonist (Anakinra) or a neutralizing antibody completely inhibited the induced contractions. We evaluated the implication of the inflammasome on myometrial contractions and differentiation stages of labor onset. We showed that the effects of macrophage-released IL-1β in myometrial cell transactivation were blocked by inhibition of the inflammasome, suggesting that the inflammasome by producing IL-1β was essential in macrophage/myocyte crosstalk during labor. These findings provide novel innovative approaches in the management of preterm labor, specifically the use of an inflammasome inhibitor to block the precursor stages of labor before the acquisition of the contractile phenotype. Preterm labor (PTL) occurs before 37 weeks of gestation and its prevalence rises in industrialized countries despite advancing knowledge of related mechanisms and risks factors . With approximately 15 million of premature births, PTL remains a major obstetric challenge and represents 75% of perinatal mortality and more than half of long-term morbidity 2 . If many cases of spontaneous PTL are unexplained, a significant proportion (40 up to 70%) is linked to genital tract infection or chorioamnionitis 2,3 . Genesis of term and preterm labor is strongly correlated with the inflammatory cascade of events physiologically activated at term but also pathologically activated preterm . Labor involves a transition to a contractile phenotype characterized by differentiation stages including cytoskeleton reorganization and synchronization of myometrial cells 7 . Understanding the mechanisms of term labor may then lead to identify therapeutic targets for the management of preterm labor. It is established that the inflammatory event, implicated in labor onset, results from the massive infiltration of primed macrophages and neutrophils into the myometrium 8,9 secreting inflammatory messengers (i.e., reactive oxygen species (ROS), cytokines, prostaglandins) and inducing the expression of specific labor markers . Previous data from our team highlighted the macrophage's role in myometrial cells activation . We demonstrated that, in laboring myometrium, ROS level was increased as a result of their production by macrophages 12 . Our co-culture model of primary human macrophages and myometrial cells confirmed ROS as major intermediate messengers during labor 13 . Pro-inflammatory cytokines have also been identified in labor induction 14 . These mediators are then produced by leukocytes during term labor and at an even higher level during preterm, particularly in the presence of infection (i.e., chorioamnionitis) 11,15-17 . Among others, IL-1β has been shown to be implicated in labor onset by inducing uterine activation proteins expression 18 , progesterone metabolism 19 and oxytocin secretion and an up-regulation of its receptor . Furthermore, in case of sterile inflammation, high concentration of IL-1 β in the serum or the amniotic fluid, is correlated with PTL and in vivo administration of IL-1β on animal models induces parturition within 48 h .