Prostaglandin E2

Ki = 9.1, 4.9, 0.33, 0.79 nM for EP1, EP2, EP3, and EP4 receptors respectively [1]

Prostaglandin E2 (PGE2) is lipid-derived autacoid which is the main effector prostanoid produced in the zebrafish, and it works by binding and activating the PGE2 receptor. PGE2 receptor is a orphan G protein-coupled receptor.

In vitro: PGE2 can stimulate the gastric nonparietal secretion [3] and has been shown to regulate the function of many cell types including dendritic cells, macrophages, T and B lymphocytes leading to both pro- and anti-inflammatory effects [2].

In vivo: PGE2 regulates many physiological systems including the gastrointestinal and immune systems. In the gastrointestinal tract, PGE2 plays a protective role in maintaining the integrity of the gastric mucosa. PGE2 has also been shown to play a role in the maintenance of blood pressure, particularly in the setting of salt overload [2].

Clinical trial: PGE2 has cytoprotective properties, which prevents mucosal damage of the gastrointestinal tract and also accelerates the healing of existent duodenal ulcers [3]. PGE2 is the active ingredient of dinoprostone, which is a medicine used in labour for softening the cervix and causing uterine contraction.

References:
[1] Abramovitz M1, Adam M, Boie Y, Carrière M, Denis D, Godbout C, Lamontagne S, Rochette C, Sawyer N, Tremblay NM, Belley M, Gallant M, Dufresne C, Gareau Y, Ruel R, Juteau H, Labelle M, Ouimet N, Metters KM.  The utilization of recombinant prostanoid receptors to determine the affinities and selectivities of prostaglandins and related analogs. Biochim Biophys Acta. 2000 Jan 17;1483(2):285-93.
[2] Hata AN, Breyer RM.  Pharmacology and signaling of prostaglandin receptors: multiple roles in inflammation and immune modulation. Pharmacol Ther. 2004 Aug;103(2):147-66.
[3] Johansson C, Kollberg B.  Clinical trials with prostaglandin E2. Prostaglandins. 1981;21 Suppl:161-4.

Prostaglandin E2 Upregulated Trigeminal Ganglionic Sodium Channel 1.7 Involving Temporomandibular Joint Inflammatory Pain in Rats.[Pubmed:28349234]

Inflammation. 2017 Jun;40(3):1102-1109.

Prostaglandin E2 (PGE2) is a key proinflammatory mediator that contributes to inflammatory hyperalgesia. Voltage-gated sodium channel 1.7 (Nav1.7) plays an important role in inflammatory pain. However, the modulation of Nav1.7 in inflammatory pain remains poorly understood. We hypothesized that PGE2 might regulate Nav1.7 expression in inflammatory pain. We here showed that treatment of rat trigeminal ganglion (TG) explants with PGE2 significantly upregulated the mRNA and protein expressions of Nav1.7 through PGE2 receptor EP2. This finding was confirmed by studies on EP2-selective antagonist PF-04418948. We also demonstrated that Nav1.7 and COX-2 expressions, as well as PGE2 levels, were upregulated in the TG after induction of rats' temporomandibular joint (TMJ) inflammation. Correspondingly, hyperalgesia, as indicated by head withdrawal threshold, was observed. Moreover, TMJ inflammation-induced upregulation of Nav1.7 expression and PGE2 levels in the TG could be reversed by COX-2-selective inhibitor meloxicam given by oral gavage, and meanwhile, the hyperalgesia of inflamed TMJ was also mitigated. So we concluded that PGE2 upregulated trigeminal ganglionic Nav1.7 expression to contribute to TMJ inflammatory pain in rats. Our finding suggests that PGE2 was an important regulator of Nav1.7 in TMJ inflammatory pain, which may help increase understanding on the hyperalgesia of peripheral inflammation and develop a new strategy to address inflammatory pain.

Prostaglandin E2 reduces swine myocardial ischemia reperfusion injury via increased endothelial nitric oxide synthase and vascular endothelial growth factor expression levels.[Pubmed:28357071]

Biomed Rep. 2017 Feb;6(2):188-194.

Prostaglandin E2 (PGE2) has been demonstrated to attenuate cardiac ischemia-reperfusion (I/R) injury. However, the underlying mechanism of PGE2 in cardiac I/R injury remains unknown. Upregulated expression levels of vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS) were reported in acute myocardial infarction (AMI), and were demonstrated to diminish I/R injury. In the current study the involvement of VEGF and eNOS in the myocardial protective effect of PGE2 were investigated in a catheter-based porcine model of AMI. Twenty-two Chinese miniature pigs were randomized into sham-surgery (n=6), control (n=8) and PGE2 (n=8) groups. PGE2 (1 microg/kg) was injected from 10 min prior to left anterior descending occlusion up to 1 h after reperfusion in the PGE2 group. Subsequently, the hemodynamic parameters were evaluated. Thioflavin-S and Evans Blue double staining were performed to evaluate the extent of the myocardial reperfusion area (RA) and no-reflow area (NRA). Immunohistochemical and western blot analysis were used to evaluate protein expression levels of VEGF and eNOS. Left ventricular (LV) systolic pressure significantly improved and LV end-diastolic pressure significantly decreased in the PGE2 group when compared with the control group 2 h after occlusion and 3 h after reperfusion (P<0.05, respectively). The RA and NRA were smaller in the PGE2 group than in the control group (P<0.05, respectively). Furthermore, PGE2 treatment increased the myocardial content of VEGF and eNOS when compared with the control group (P<0.05, respectively). Thus, the results of the present study demonstrate the cardio-protective mechanisms of PGE2, which may protect the heart from I/R injury via enhancement of VEGF and eNOS expression levels.

Salivary Prostaglandin E2: Role in Tick-Induced Allergy to Red Meat.[Pubmed:28365087]

Trends Parasitol. 2017 Jul;33(7):495-498.

Tick-induced allergy to red meat is associated with anti-alpha-Gal IgE antibody levels. We propose that tick salivary Prostaglandin E2 triggers antibody class switching in mature B cells, increasing the levels of anti-alpha-Gal IgE antibodies. Immune tolerance to alpha-Gal in blood type B individuals might reduce the risk to this allergy.

Efferocytosis-induced prostaglandin E2 production impairs alveolar macrophage effector functions during Streptococcus pneumoniae infection.[Pubmed:28359217]

Innate Immun. 2017 Apr;23(3):219-227.

Alveolar macrophages (AMs) are multitasking cells that maintain lung homeostasis by clearing apoptotic cells (efferocytosis) and performing antimicrobial effector functions. Different PRRs have been described to be involved in the binding and capture of non-opsonized Streptococcus pneumoniae, such as TLR-2, mannose receptor (MR) and scavenger receptors (SRs). However, the mechanism by which the ingestion of apoptotic cells negatively influences the clearance of non-opsonized S. pneumoniae remains to be determined. In this study, we evaluated whether the Prostaglandin E2 (PGE2) produced during efferocytosis by AMs inhibits the ingestion and killing of non-opsonized S. pneumoniae. Resident AMs were pre-treated with an E prostanoid (EP) receptor antagonist, inhibitors of cyclooxygenase and protein kinase A (PKA), incubated with apoptotic Jurkat T cells, and then challenged with S. pneumoniae. Efferocytosis slightly decreased the phagocytosis of S. pneumoniae but greatly inhibited bacterial killing by AMs in a manner dependent on PGE2 production, activation of the EP2-EP4/cAMP/PKA pathway and inhibition of H2O2 production. Our data suggest that the PGE2 produced by AMs during efferocytosis inhibits H2O2 production and impairs the efficient clearance non-opsonized S. pneumoniae by EP2-EP4/cAMP/PKA pathway.

Prostaglandin E2 regulates vertebrate haematopoietic stem cell homeostasis.[Pubmed:17581586]

Nature. 2007 Jun 21;447(7147):1007-11.

Haematopoietic stem cell (HSC) homeostasis is tightly controlled by growth factors, signalling molecules and transcription factors. Definitive HSCs derived during embryogenesis in the aorta-gonad-mesonephros region subsequently colonize fetal and adult haematopoietic organs. To identify new modulators of HSC formation and homeostasis, a panel of biologically active compounds was screened for effects on stem cell induction in the zebrafish aorta-gonad-mesonephros region. Here, we show that chemicals that enhance prostaglandin (PG) E2 synthesis increased HSC numbers, and those that block prostaglandin synthesis decreased stem cell numbers. The cyclooxygenases responsible for PGE2 synthesis were required for HSC formation. A stable derivative of PGE2 improved kidney marrow recovery following irradiation injury in the adult zebrafish. In murine embryonic stem cell differentiation assays, PGE2 caused amplification of multipotent progenitors. Furthermore, ex vivo exposure to stabilized PGE2 enhanced spleen colony forming units at day 12 post transplant and increased the frequency of long-term repopulating HSCs present in murine bone marrow after limiting dilution competitive transplantation. The conserved role for PGE2 in the regulation of vertebrate HSC homeostasis indicates that modulation of the prostaglandin pathway may facilitate expansion of HSC number for therapeutic purposes.

Prostaglandin E2 is a hormone-like substance that participate in a wide range of body functions such as the contraction and relaxation of smooth muscle, the dilation and constriction of blood vessels, control of blood pressure, and modulation of inflammation.

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