Prevention of Inflammation-Associated Preterm Birth by Knockdown of the Endothelin-1-Matrix Metalloproteinase-1 Pathway

Wang, Wei; Yen, Hao-Ting; Chen, Chih‐Hung; Jasani, Nitesh; Soni, Rimabahen; Koscica, Karen L.; Reznik, Sandra E.

doi:10.2119/molmed.2010.00030

Cited by 15 publications

(11 citation statements)

References 31 publications

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“…We sought to determine if the CRTH2 agonist Pyl A had the same tocolytic and feto‐protective effect as 15dPGJ 2 in delaying preterm labour in LPS‐treated mice. A dose–response effect was demonstrated with LPS (serotype 0111:B4) since varying potencies can be seen between serotypes and within batches . Administration of 20 μg LPS led to reliable preterm delivery with the least variation between mice (Fig.…”

Section: Resultsmentioning

confidence: 95%

The CRTH2 agonist Pyl A prevents lipopolysaccharide‐induced fetal death but induces preterm labour

et al. 2013

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SummaryWe have previously demonstrated that the anti-inflammatory prostaglandin 15-deoxy-D 12,14-prostaglandin J 2 (15dPGJ 2 ) delays inflammationinduced preterm labour in the mouse and improves pup survival through the inhibition of nuclear factor-jB (NF-jB) by a mechanism yet to be elucidated. 15dPGJ 2 is an agonist of the second prostaglandin D 2 receptor, chemoattractant receptor homologous to the T helper 2 cell (CRTH2). In human T helper cells CRTH2 agonists induce the production of the antiinflammatory interleukins IL-10 and IL-4. We hypothesized that CRTH2 is involved in the protective effect of 15dPGJ 2 in inflammation-induced preterm labour in the murine model. We therefore studied the effects of a specific small molecule CRTH2 agonist on preterm labour and pup survival. An intrauterine injection of lipopolysaccharide (LPS) was administered to CD1 mice at embryonic day 16, AE CRTH2 agonist/vehicle controls. Mice were killed at 4.5 hr to assess fetal wellbeing and to harvest myometrium and pup brain for analysis of NF-jB, and T helper type 1/2 interleukins. To examine the effects of the CRTH2 agonist on LPSinduced preterm labour, mice were allowed to labour spontaneously. Direct effects of the CRTH2 agonist on uterine contractility were examined ex vivo on contracting myometrial strips. The CRTH2 agonist increased fetal survival from 20 to 100% in LPS-treated mice, and inhibited circular muscle contractility ex vivo. However, it augmented LPS-induced labour and significantly increased myometrial NF-jB, IL-1b, KC-GRO, interferon-c and tumour necrosis factor-a. This suggests that the action of 15dPGJ 2 is not via CRTH2 and therefore small molecule CRTH2 agonists are not likely to be beneficial for the prevention of inflammation-induced preterm labour.

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Section: Resultsmentioning

confidence: 95%

The CRTH2 agonist Pyl A prevents lipopolysaccharide‐induced fetal death but induces preterm labour

et al. 2013

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“…The levels of ET-1 and ECE-1 were increased in gestational tissue, and treatment with an ECE-1 inhibitor, ET-1 receptor A antagonist, or ECE-1 RNA interference could prevent preterm delivery in mice [10]. Those authors also reported that upregulation of MMP-1, which is increased during human labor, was inhibited by ECE-1 RNA interference in the mouse model [9]. ET-1 has been reported to be synthesized in the human amnion [11,12], and its concentration in amniotic fluid is approximately 10-to 100-fold higher than that observed in plasma [7].…”

Section: Introductionmentioning

confidence: 93%

“…The level of ET-1 is increased in the amniotic fluid of the forebag, the compartment between the fetal head and the cervix, during labor [7] and increases myometrial smooth muscle tone [8]. Recently, it was reported that the ECE-1/ET-1 pathway plays a critical role in preterm delivery in a mouse model [9,10]. The levels of ET-1 and ECE-1 were increased in gestational tissue, and treatment with an ECE-1 inhibitor, ET-1 receptor A antagonist, or ECE-1 RNA interference could prevent preterm delivery in mice [10].…”

Section: Introductionmentioning

confidence: 99%

Altered Expression of Enzymes Regulating the Activity of Endothelin-1 in the Lower Segment of the Human Amnion During Labor1

Kotani

Iwase

Tsuda

et al. 2013

Biology of Reproduction

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The level of endothelin (ET)-1, a uterotonin, increases in amniotic fluid during labor. The known metallopeptidases include ET-converting enzyme (ECE), which converts inactive precursor to potent ET-1, and neutral endopeptidase (NEP), which inactivates ET-1. These enzymes are present in fetal membranes, and the aims of this study were to establish the protein expression of the enzymes within the amnion of human fetal membranes. Expressions were compared between amnions obtained before and after term labor using a Western blot analysis and enzyme-linked immunosorbent assay, respectively. The localization of these enzymes was determined using immunohistochemistry. The protein expression of the enzymes and output of bioactive ET-1 in human amnion epithelial cells (HAECs) and mesenchymal cells (HAMCs) were investigated with and without proinflammatory cytokines, oxytocin, and prostaglandin treatment. The effects of sphingosine-1-phosphate (S1P), a bioactive lipid, were also examined. The protein expression of ECE-1 was significantly increased (P < 0.01), whereas that of NEP was significantly decreased, followed by increased ET-1 (P < 0.01), in the amnion obtained after labor (P < 0.01). HAECs and HAMCs primarily expressed ECE-1 and NEP, respectively. The protein expression of ECE-1 was significantly induced (P < 0.01). However, the NEP levels were significantly reduced (P < 0.05) by treatment with TNFalpha and IL1beta followed by the 7.5-fold and 6.5-fold increase of ET-1 (P < 0.01), respectively, in the HAECs. ET-1 was increased 2-fold by S1P (P < 0.01). These results suggest that the altered expression of enzymes regulating the activity of ET-1 during parturition is controlled by inflammatory cytokines.

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“…Finally, endothelin 1, an extremely potent vasoconstrictor peptide (Yanagisawa et al, ) produced by endothelin‐converting enzyme 1 (Rubanyi and Polokoff, ), induces contractile responses in human myometrium (Kaya et al, ). Silencing the endothelin 1 signaling by RNA interference knockdown of endothelin‐converting enzyme 1 prevents the onset of preterm birth and the up‐regulation of MMP1 (Wang et al, ).…”

Section: Regulation Of the Mmp System By Inflammatory Cytokines Hormmentioning

confidence: 99%

“…For example, preterm birth, defined as delivery occurring before the 37th week of gestation, is the most‐significant contributor to neonatal morbidity and mortality. Preterm birth occurs in 12% of all pregnancies, and accounts for more than 50% of long‐term morbidity (Manase et al, ) and 60–80% of perinatal mortality, which is second only to congenital anomalies (Wang et al, ). Preterm birth is thought to be triggered by multiple mechanisms, especially by premature rupture of membranes (PPROM) (Parry and Strauss, ), which can result from the dysregulated activitity of MMPs on the ECM.…”

Section: Introductionmentioning

confidence: 99%

Roles and regulation of the matrix metalloproteinase system in parturition

Geng

Huang

Jiang

2016

Molecular Reproduction Devel

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SUMMARYSignificant tissue destruction, repair, and remodeling are involved in parturition, which involves fetal membrane rupture, cervical ripening, and uterine contraction and its subsequent involution. Extracellular matrix degradation and remodeling by proteolytic enzymes, such as matrix metalloproteinases (MMPs), are required for the final steps of parturition. MMPs participate in physiological degradation and remodeling through their proteolytic activities on specific substrates, and are balanced by the action of their inhibitors. Disruption to this balance can result in pathological stress that ends with preterm or post-term birth or pre-eclampsia. In this review, we examine the roles and regulation of the MMP system in physiological and pathological labor, and propose a model that illustrates the mechanisms by which the MMP system contributes to these processes.Mol. Reprod. Dev. 83: 276À286,

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Prevention of Inflammation-Associated Preterm Birth by Knockdown of the Endothelin-1-Matrix Metalloproteinase-1 Pathway

Cited by 15 publications

References 31 publications

The CRTH2 agonist Pyl A prevents lipopolysaccharide‐induced fetal death but induces preterm labour

The CRTH2 agonist Pyl A prevents lipopolysaccharide‐induced fetal death but induces preterm labour

Altered Expression of Enzymes Regulating the Activity of Endothelin-1 in the Lower Segment of the Human Amnion During Labor1

Roles and regulation of the matrix metalloproteinase system in parturition

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