nan Mitchell

THE MOLECULAR MECHANISMS OF TERM AND PRETERM LABOR : RECENT PROGRESS AND CLINICAL IMPLICATIONS

Current tocolytic protocols rely largely on the use of beta-mimetics to induce myometrial quiescence and delay delivery. Unfortunately, the rapid transplacental passage and poor receptor specificity of the commonly used beta-mimetics results in widespread activation of intrauterine and extrauterine beta 1 and beta 2 receptors. The use of beta-mimetics is associated with a range of well-recognized and potentially dangerous side effects for mother and fetus. The value of continued use of beta-agonists after obtaining uterine quiescence also has been the subject of recent debate. In this article we have attempted to explore the biochemical and molecular rationale for the use of alternative therapeutic modalities in the treatment and prevention of PTL. In the light of the current view that the term preterm labor covers a considerable diversity of causes, we propose that a range of treatment regimes should be chosen on the basis of the diagnosis and classification of the patient according to the their particular condition. Although the measurement of several biochemical parameters have been suggested to be of use in predicting PTL, we believe that a panel of diagnostic indicators (e.g., free or total CRH, IL-6, extracellular matrix proteases, fetal fibronectin) is more likely to provide useful diagnostic information on which appropriate treatment modalities can be selected (Table 1). Because of the complex and interactive nature of the mechanisms operating within the intrauterine environment to regulate myometrial activation and uterotonin production, we speculate that a combination of tocolytics, anti-inflammatory agents, uterotonic antagonists, and receptor blockers is likely to be more effective than a monotherapeutic approach, which focuses on only one facet of the process of uterine activation for pharmacologic intervention. For example, the use of antibiotics, PGHS inhibitors, and/or beta-mimetics might be an appropriate first line of treatment for infection-associated PTL in extreme prematurity. If it is successful, this treatment might be followed by longer term use of a progestagen and/or NO donor to maintain myometrial quiescence until closer to term. Alternatively, use of progesterone or oxytocin antagonists may be effective in augmenting the actions of beta-mimetics while reducing their side effects, whereas other combinations may be useful as long-term prophylactics in women with a high risk of developing PTL. Improvements continue in our diagnostic ability to correctly identify the different causes of preterm labor. We anticipate that careful selection of differing combinations of therapeutic options will result in significant reductions in the morbidity, mortality, and healthcare costs associated with preterm birth.

Key enzymes of prostaglandin biosynthesis and metabolism. Coordinate regulation of expression by cytokines in gestational tissues: a review

Preterm labor is frequently associated with ascending intrauterine infection, accompanied by leukocytes infiltration and enhanced local production of cytokines and other inflammatory mediators. The resulting amplification of the inflammatory response, and of prostanoid production in particular, is postulated to be a principal mechanism of infection-driven preterm labor. In this review the effects of pro- and anti-inflammatory cytokines are discussed with respect to the expression of enzymes involved in three key steps of prostanoid biosynthesis and metabolism: liberation of arachidonic acid (AA), conversion of AA to bioactive prostanoids, and prostanoid catabolism. We suggest that by exerting coordinate actions on all three key steps, through multiple molecular mechanisms, inflammatory cytokines acutely up-regulate prostanoid production in intrauterine tissues.

Serum activin A, inhibin A, and follistatin concentrations in preeclampsia or small for gestational age pregnancies

OBJECTIVE To determine whether maternal serum activin A, inhibin A, and follistatin concentrations in idiopathic small for gestational age (SGA) pregnancies are similar to those in normal pregnancies or elevated as in preeclampsia. METHODS Maternal serum activin A, inhibin A, and follistatin concentrations were determined in 1) nulliparous women with idiopathic SGA (birth weight <10th percentile; n = 18), preeclampsia (systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg plus proteinuria ≥2+or >0.3 g/24h; n = 22), and normotensive controls, matched for gestational age at sampling (n = 22), and 2) a longitudinal series of samples collected at five intervals throughout pregnancy from nulliparous women with idiopathic SGA (n = 19), preeclampsia (n = 22), preeclampsia plus SGA (n = 15), or who had uncomplicated pregnancies (n = 20). RESULTS Serum concentrations of activin A and inhibin A were similar in idiopathic SGA pregnancies to controls. In preeclampsia, activin A and inhibin A levels were markedly increased compared with controls or women with idiopathic SGA (P < .001), particularly in those with early‐onset disease. Follistatin concentrations were only modestly (<twofold) elevated in preeclampsia (P < .001). In the longitudinal study, serum activin A or inhibin A concentrations were increased in women who later developed preeclampsia, whereas in women with idiopathic SGA pregnancy, a small overall increase in activin A levels was observed. CONCLUSIONS In contrast to women with preeclampsia, normotensive women with SGA pregnancies do not have markedly elevated circulating levels of activin A and inhibin A. These data support the hypothesis that increased serum activin A concentrations in preeclampsia may be a manifestation of maternal disease rather than just a marker of abnormal placentation.

Placental cytokines and preeclampsia.

Preeclampsia is a serious and life-threatening pregnancy complication. Reduced uteroplacental perfusion and oxygen tension, impaired trophoblast differentiation and invasion, and altered placental production of immunomodulators and growth factors are all considered to be important aspects in the aetiology of the condition. The placenta expresses a variety of pro and anti-inflammatory cytokines, adipokines and cytokine-like angiogenic growth factors, production of which is altered in preeclampsia, driven (at least in part) by hypoxia. Altered levels of cytokines have been measured in the circulation of women with preeclampsia, although for reasons that are not always apparent much of the data are disturbingly inconsistent. While the placenta undoubtedly makes an important contribution to plasma cytokine levels, production by maternal peripheral blood mononuclear cells (PBMCs) and other tissues is also likely to be significant, although to what extent remains undetermined. Increased placental expression of soluble receptors occurs with preeclampsia, resulting in elevated circulating concentrations which confer impaired angiogenesis, deficient placental vascularisation, increased placental apoptosis and endothelial dysfunction. The extent to which these changes reflect a response to the disorder, as opposed to being a causative factor in the development of maternal disease, is a matter of some debate. Nevertheless, convincing evidence is now accruing that autocrine/paracrine interactions between placental cytokines/growth factors and the maternal endothelium play a central role in the pathogenesis of preeclampsia.

Does leptin exhibit cytokine-like properties in tissues of pregnancy?

PROBLEM: To determine whether leptin exhibits cytokine‐like properties in gestational tissues in light of its homologies with the class I family of cytokines.u2028 METHOD OF STUDY: WISH and JEG3 cells, and amnion and choriodecidua explants, were treated inflammatory modulators (interleukin‐1β [IL‐1β], tumor necrosis factor‐α [TNF‐α] and bacterial lipopolysaccharide [LPS]) and leptin production was measured by immunoassay. Other agents known to regulate adipocyte leptin production were also tested for comparative purposes. In addition, WISH cells, JAR cells and placental explants were treated with leptin to assess its effects on production of IL‐8, IL‐6 and prostaglandin E2 (PGE2).u2028 RESULTS: Leptin production by all cells and tissues studied was unaffected by treatment with IL‐1β (2.5 ng/mL), TNF‐α (25 ng/mL) and LPS (2.5 μg/mL). Dexamethasone stimulated leptin production over two‐fold by WISH and JEG3 cells, whereas insulin also stimulated a two‐fold increase in leptin production in JEG3 cells. IL‐6 production by JAR cells and placental explants was stimulated (two‐ to three‐fold) by leptin (300 ng/mL). PGE2 production was unaffected.u2028 CONCLUSIONS: Leptin derived from gestational tissues is unlikely to play a role in inflammatory reactions within the placenta, but may regulate placental cytokine production. The physiological significance of amnion‐derived leptin remains to be established.

Expression of prostaglandin H synthase-1 and -2 in murine intrauterine and gestational tissues from mid pregnancy until term.

These studies were undertaken to evaluate the changes in mRNA expression of prostaglandin H synthase (PGHS)-1 and -2 in murine gestational tissues during the latter half of pregnancy. Gestational tissues (decidual caps, membranes surrounding the fetus, and placentae), uterus, and cervix were collected from pregnant mice at days 12, 14, 16, 18, and 19 (am and pm) of gestation (n = 4), and total RNA was isolated and evaluated for PGHS-1 and PGHS-2 expression by northern blot analysis. Expression was normalized to GAPDH. There were no significant increases in PGHS-2 mRNA expression in any of the tissues studied through gestation. In contrast, expression of PGHS-1 mRNA increased significantly at term in the uterus and fetal membranes. In the placenta, mRNA for PGHS-1 was elevated at day 18 and remained elevated over the remainder of the study. These findings suggest that, in the mouse, increased production of PGs by uterine and intrauterine tissues during pregnancy is associated with up-regulation of PGHS-1 and not PGHS-2.

Cytokines, Hypoxia, and Preeclampsia:

Cytokines, Hypoxia, and Preeclampsia J effrey A. Keelan, PhD, and Murray D. Mitchell, DSc I lmnune mediators are intimately involved in many aspects of pregnancy-from implantation and placentation, to cervical ripening and uterine activation. Indeed, pregnancyspecific immunomodulation is a prerequisite for successful initiation, maintenance, and completion of pregnancy. An inappropriate or over-exuberant immune reaction, on the other hand, is associated with the major pregnancy pathologies, including recurrent miscarriage, preeclampsia, gestational diabetes, and preteml labor. The placenta expresses a variety of molecules typically associated with itmnunomodulation and inflammatory activation, including many cytokines, which act on both immune and non-immune eens via specific receptors to carry out a variety of functions. 1 Cytokines are now known to exert pleiotropie actions in a range of tissues and een types, both inmmne and non-itmnune, physiologic and pathophysiologic. Within the placenta, cytokines appear to be principally involved in modulating four fundamental processes: (1) matemal-placental immune dialogue; (2) trophoblast invasion and differentiation; (3) placental growth, proliferation, and apoptosis; and (4) placental metabolic and endocrine homeostasis. 1 Establishment of placental itmnune privilege around the time of implantation, for example, involves coordinated actions of cytokines such as interleukin (IL)-l, IL-ll, leukemia inhibitory factor (LIF) , colony-stimulating factor-l (CSF-l), and interferon-gamma (IFN-)) at the fetomatemal interface. 2 The pro-inflammatory cytokines IL-l, LIF, and activin promo te trophoblast ditlerentiation towards an invasive phenotype, whereas transforming growth factor-beta (TGF-[3) exerts generally inhibitory functions in the placenta, most notably on trophoblast proliferation, invasion, and ditlerentiation. Another immunosuppressive cytokine, IL-la, also inhibits invasion, through decreased placental matrix metalloproteinase (MMP) release.3 Tumor necrosis factor-alpha (TNF-a), IFN-), and placental-TGF-[3 (also known as MIC-l/PL74) are also inducers of trophoblast apoptosis.4 Finally, TNF-a IL-l[3, IL-6, and TGF-[3 have all been documented as having etlects on production of placetltal homlones (human chorionic gonadotropin [hCG] and progesterone), suggesting roles in maintaining normal endocrine function. 1 In addition to their intraplacental actions, cytokines produced by the placenta enter the matemal circulation and interact with matemal endothelial and hematopoietic eens. TNF-a, which is produced by fetoplacental macrophages and trophoblasts (most notably invasive extravillous trophoblast exerts potent etlects on endothelial and platelet function, promoting enhanced coagulation, microvascular leakage, vasoconstriction, endothe-