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前列腺素脱氢酶与分娩发动

Prostaglandin dehydrogenase and the initiation of labor.

作者信息

Challis J R, Patel F A, Pomini F

机构信息

Department of Physiology, University of Toronto, Canada.

出版信息

J Perinat Med. 1999;27(1):26-34. doi: 10.1515/JPM.1999.003.

Abstract

In summary, these studies have suggested that prostaglandin dehydrogenase may have a central role to play in the mechanisms which determine biologically active prostaglandin concentrations within human fetal membranes and placenta at the time of labor, at term or preterm. Moreover, our studies indicate that the regulation of PGDH may by multifactorial (figure 3). In certain regions of the membranes, we suggest that PGDH expression may be influenced by levels of anti-inflammatory and pro-inflammatory cytokines. In other regions of the membranes, we suggest that PGDH may be regulated at a transcriptional level by competing activities of progesterone and cortisol. The action of progesterone could be effected through systemically-derived steroid, or by locally synthesized steroid, acting in a paracrine and/or autocrine fashion. The effects of cortisol in placenta must be due to glucocorticoid derived from the maternal or fetal compartment, since the placenta lacks the hydroxylases required for endogenous cortisol production. However, metabolism of cortisol by 11 beta-HSD-2 reduces the potency of this glucocorticoid in placental tissue. In chorion however, cortisol may be formed locally, from cortisone, in addition to its being derived from the maternal circulation and/or from the amniotic fluid. Our current studies do not allow us to delineate whether the effects of progesterone and cortisol on PGDH are exerted through the glucocorticoid receptor (GR) or progesterone receptor (PR) or both. It is possible that through pregnancy, PGDH activity is maintained by progesterone acting either through low levels of PR in membranes, or, more likely, acting through GR. At term, elevated levels of cortisol compete with and displace progesterone from GR, resulting in inhibition of PGDH transcription and activity. In this way, local withdrawal of progesterone action would be effected within human intrauterine tissues, without requiring changes in systemic, circulating progesterone concentrations. Since glucocorticoids appear also to increase expression of prostaglandin synthesizing enzymes within the amnion and chorion, directly by upregulating PGHS-2, or indirectly through the intermediary action of a paracrine effector such as CRH, their role in coordinating processes of parturition remains central. Further understanding of the regulation of PGDH may be of therapeutic importance. For example, it is possible that PGDH activity in lower segment chorion may be reduced in those patients with premature cervical softening, or may be particularly high in those patients with an unfavorable cervix, presenting with a low Bishop score and poor progression at the time of labor. If the enzyme in this region crucially determines the passage and availability of biologically active prostaglandins from amnion and chorion to underlying cervix, then pharmacologic manipulation of PGDH activity may effectively regulate PG transfer in these clinical conditions. Glucocorticoids appear to have a central role in promoting production of agents that are uterotonic to myometrial activity. It is likely that these activities explain the transient increments in uterine contractility reported in patients receiving prenatal corticosteroids to promote fetal pulmonary maturity [11]. Recognition of this physiology suggests that careful monitoring of these patients is advised, and would argue further against repeated, indiscriminate, use of glucocorticoids in patients with an inappropriate diagnosis of threatened preterm labor.

摘要

总之,这些研究表明,前列腺素脱氢酶可能在分娩时(足月或早产)决定人胎膜和胎盘中生物活性前列腺素浓度的机制中发挥核心作用。此外,我们的研究表明,PGDH的调节可能是多因素的(图3)。在胎膜的某些区域,我们认为PGDH的表达可能受抗炎和促炎细胞因子水平的影响。在胎膜的其他区域,我们认为PGDH可能在转录水平上受孕酮和皮质醇竞争活性的调节。孕酮的作用可能通过全身来源的类固醇实现,或通过局部合成的类固醇以旁分泌和/或自分泌方式发挥作用。皮质醇在胎盘中的作用必定归因于来自母体或胎儿区室的糖皮质激素,因为胎盘缺乏内源性皮质醇产生所需的羟化酶。然而,11β-HSD-2对皮质醇的代谢降低了这种糖皮质激素在胎盘组织中的效力。然而,在绒毛膜中,除了来自母体循环和/或羊水外,皮质醇还可能由可的松局部形成。我们目前的研究无法确定孕酮和皮质醇对PGDH的作用是通过糖皮质激素受体(GR)还是孕酮受体(PR)或两者来实现的。有可能在整个孕期,PGDH活性通过孕酮作用得以维持,孕酮要么通过胎膜中低水平的PR起作用,或者更有可能是通过GR起作用。在足月时,皮质醇水平升高与GR上的孕酮竞争并取代孕酮,导致PGDH转录和活性受到抑制。通过这种方式,人子宫内组织中孕酮作用的局部撤退将得以实现,而无需全身循环孕酮浓度发生变化。由于糖皮质激素似乎还通过直接上调PGHS-2或通过旁分泌效应物如CRH的中介作用间接增加羊膜和绒毛膜中前列腺素合成酶的表达,它们在协调分娩过程中的作用仍然至关重要。对PGDH调节的进一步了解可能具有治疗意义。例如,在宫颈过早软化的患者中,下段绒毛膜中的PGDH活性可能降低,或者在宫颈条件不佳、Bishop评分低且分娩时进展不佳的患者中,PGDH活性可能特别高。如果该区域的酶关键地决定了生物活性前列腺素从羊膜和绒毛膜到下方宫颈的传递和可用性,那么对PGDH活性进行药理操作可能有效地调节这些临床情况下的PG传递。糖皮质激素似乎在促进产生对子宫肌层活动有宫缩作用的物质方面发挥核心作用。很可能这些作用解释了接受产前糖皮质激素以促进胎儿肺成熟的患者中报告的子宫收缩力的短暂增加[11]。认识到这种生理学情况表明,建议对这些患者进行仔细监测,并且进一步反对在不适当诊断为先兆早产的患者中反复、不加区分地使用糖皮质激素。

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