Effects Of Prostaglandins Research Articles

Prostaglandin E1 attenuates AngII-induced cardiac hypertrophy via EP3 receptor activation and Netrin-1upregulation

AimsPathological cardiac hypertrophy induced by activation of the renin–angiotensin–aldosterone system (RAAS) is one of the leading causes of heart failure. However, in current clinical practice, the strategy for targeting the RAAS is not sufficient to reverse hypertrophy. Here, we investigated the effect of prostaglandin E1 (PGE1) on angiotensin II (AngII)-induced cardiac hypertrophy and potential molecular mechanisms underlying the effect. Methods and resultsAdult male C57 mice were continuously infused with AngII or saline and treated daily with PGE1 or vehicle for two weeks. Neonatal rat cardiomyocytes were cultured to detect AngII-induced hypertrophic responses. We found that PGE1 ameliorated AngII-induced cardiac hypertrophy both in vivo and in vitro. The RNA sequencing (RNA-seq) and expression pattern analysis results suggest that Netrin-1 (Ntn1) is the specific target gene of PGE1. The protective effect of PGE1 was eliminated after knockdown of Ntn1. Moreover, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that the PGE1-mediated signaling pathway changes are associated with the mitogen-activated protein kinase (MAPK) pathway. PGE1 suppressed AngII-induced activation of the MAPK signaling pathway, and such an effect was attenuated by Ntn1 knockdown. Blockade of MAPK signaling rescued the phenotype of cardiomyocytes caused by Ntn1 knockdown, indicating that MAPK signaling may act as the downstream effector of Ntn1. Furthermore, inhibition of the E-prostanoid (EP) 3 receptor, as opposed to the EP1, EP2, or EP4 receptor, in cardiomyocytes reversed the effect of PGE1, and activation of EP3 by sulprostone, a specific agonist, mimicked the effect of PGE1. ConclusionIn conclusion, PGE1 ameliorates AngII-induced cardiac hypertrophy through activation of the EP3 receptor and upregulation of Ntn1, which inhibits the downstream MAPK signaling pathway. Thus, targeting EP3, as well as the Ntn1–MAPK axis, may represent a novel approach for treating pathological cardiac hypertrophy.

Prostaglandin E2 promotes Staphylococcus aureus infection via EP4 receptor in bovine endometrium

Prostaglandin E2 (PGE2) enhances Staphylococcus aureus infection but its mechanism is not well understood. Here, we examined the effect of PGE2 on Staphylococcal Protein A (SPA) expression in bovine endometrium and determined the role of select PGE2 receptors (i.e., EP2 and EP4) in adhesion and internalization of S. aureus. S. aureus isolate SA113 was used for in vitro infection of bovine endometrial tissues and epithelial cells, with treatment conditions consisting of untreated control, SA113 treatment, SA113 + PGE2, SA113 + PGE2 + EP2 receptor antagonist (AH-6809), and SA113 + PGE2 + EP4 receptor antagonist (AH-23848). Immunofluorescence assay revealed that PGE2 could promote SPA expression in S. aureus-infected bovine endometrial tissues. PGE2 also enhanced the adhesion and internalization of S. aureus in bovine endometrial cells. The addition of EP4 antagonist, but not the EP2 antagonist, abrogated the ability of PGE2 to promote S. aureus SPA expression, adhesion, and internalization in endometrial cells. Our findings suggest that S. aureus infection in the endometrium is enhanced by PGE2 through the EP4 receptor. This result is essential for the development of new approach to treating S. aureus infection, such as the application of EP4 antagonist as an adjunct drug treatment.

Effect of vasodilator PGE1 on sciatic nerve function, VEGF level, vascular permeability and peripheral nerve in type 2 diabetic rats

Purpose: To investigate the effect of vasodilator prostaglandin E1 (PGE1) on sciatic nerve function, vascular endothelial growth factor (VEGF), vascular permeability and peripheral nerve in type 2 diabetes mellitus (T2DM) rats.
 Methods: Twenty-one rats in the study group were intraperitoneally injected with PGE1, while rats in T2DM untreated group (n = 21) were injected with an equivalent amount of normal saline. Seven rats were randomly selected from the study and the control groups every seven days for 21 days for determination of changes in sciatic nerve function, VEGF level, vascular permeability and peripheral nerves.
 Results: Sciatic nerve motor nerve conduction velocity (MNCV) was significantly higher in the study group than in T2DM untreated control group at the three time-points post-treatment (p < 0.01). The level of VEGF in the study group decreased, relative to the T2DM untreated control group on the 7th 14th and 21st days post- treatment (p < 0.05) while the water content of sciatic nerve tissue in study group was markedly decreased, relative to control value on day 21 (p < 0.05). Rats in the study group showed decreased TTT, relative to those in T2DM untreated group on days 7, 14 and 21 post-treatment (p < 0.01).
 Conclusion: PGE1 improves the sciatic nerve function of T2DM rats, reduces the level of serum VEGF and vascular permeability, and protects peripheral nerves. These findings provide a basis for the development of new T2DM drugs

Immunomodulation of T Helper Cells by Tumor Microenvironment in Oral Cancer Is Associated With CCR8 Expression and Rapid Membrane Vitamin D Signaling Pathway.

The immune system plays a key role in the protective response against oral cancer; however, the tumor microenvironment (TME) impairs this anti-cancer response by modulating T helper (Th) responses and promoting an anti-inflammatory environment. Regulatory T cells (Tregs) and Th2 effector cells (Teff) are associated with poor prognosis in oral squamous cell carcinoma (OSCC). However, the main immunomodulatory mechanisms associated with the enrichment of these subsets in OSCC remain unknown. We characterized Th-like lineages in Tregs and Teff and evaluated immunomodulatory changes induced by the TME in OSCC. Our phenotypic data revealed a higher distribution of tumour-infiltrating CCR8+ and Th2-like Treg in OSCC compared with non-malignant samples, whereas the percentages of Th1 cells were reduced in cancer. We then analyzed the direct effect of the TME by exposing T cell subsets to cancer secretomes and observed the OSCC secretome induced CCR8 expression and reduced cytokine production from both subsets. Transcriptomic analysis showed that the co-culture with OSCC secretome induced several gene changes associated with the vitamin D (VitD) signaling pathway in T cells. In addition, proteomic analysis identified the presence of several proteins associated with prostaglandin E2 (PGE2) production by rapid membrane VitD signaling and a reduced presence of the VitD binding protein. Thus, we analyzed the effect of VitD and PGE2 and observed that VitD promotes a regulatory Th2-like response with CCR8 expression whilst PGE2 also modulated CCR8 but inhibited cytokine production in combination with VitD. Finally, we evaluated the presence of CCR8 ligand in OSCC and observed increased chemokine CCL18, which was also able to upregulate CCR8 in activated Th cells. Overall, our data showed the immunomodulatory changes induced by the TME involving CCR8 expression and regulatory Th2 phenotypes, which are associated with PGE2 mediated VitD signaling pathway and CCL18 expression in OSCC.

Cyclooxygenase Inhibition Alters Proliferative, Migratory, and Invasive Properties of Human Glioblastoma Cells In Vitro.

Prostaglandin E2 (PGE2) is known to increase glioblastoma (GBM) cell proliferation and migration while cyclooxygenase (COX) inhibition decreases proliferation and migration. The present study investigated the effects of COX inhibitors and PGE2 receptor antagonists on GBM cell biology. Cells were grown with inhibitors and dose response, viable cell counting, flow cytometry, cell migration, gene expression, Western blotting, and gelatin zymography studies were performed. The stimulatory effects of PGE2 and the inhibitory effects of ibuprofen (IBP) were confirmed in GBM cells. The EP2 and EP4 receptors were identified as important mediators of the actions of PGE2 in GBM cells. The concomitant inhibition of EP2 and EP4 caused a significant decrease in cell migration which was not reverted by exogenous PGE2. In T98G cells exogenous PGE2 increased latent MMP2 gelatinolytic activity. The inhibition of COX1 or COX2 caused significant alterations in MMP2 expression and gelatinolytic activity in GBM cells. These findings provide further evidence for the importance of PGE2 signalling through the EP2 and the EP4 receptor in the control of GBM cell biology. They also support the hypothesis that a relationship exists between COX1 and MMP2 in GBM cells which merits further investigation as a novel therapeutic target for drug development.

Observation of dose dependent intravaginal Prostaglandin E2 application in free farrowing sows during parturition \u2013 a pilot study

The duration of birth is an important factor influencing the survival of piglets and the health of sows. A prolonged parturition is usually treated with oxytocin, even though several undesirable side effects are described. Therefore, the aim of this study was to evaluate the safety and efficacy of Prostaglandin E2 (PGE2) of different concentrations as an intravaginal applied gel after the birth of the fourth piglet in sows. Twelve sows were randomly allocated to one of four treatment groups: Group I (control group) application of placebo gel; Group II application of 0.5 mg; Group III application of 1.0 mg PGE2; Group IV PGE2 application of 2.0 mg PGE2. Total duration of parturition (time between first piglet and last placenta), piglet interval before and after treatment and placenta expulsion duration (time between first and last placenta) were recorded, and each piglet was scored for meconium staining and vitality. Furthermore, stillborn piglets were categorized into ante-partum and intra-partum deaths.A significant dose-dependent effect of PGE2 after the fourth piglet in a linear regression model with group I, II and III on the total duration of parturition and the placenta expulsion duration was detected. An increase of the PGE2 dosage from 0 to 1 mg significantly reduced the total duration of parturition (group I: 553.7 ± 114.2; group II:456 ± 167.9; group III: 284.7 ± 40.5; p-value: 0.02) and placenta expulsion duration (group I: 364 ± 120; group II: 289 ± 144.1; group III: 119 ± 46.13; p-value: 0.03). Although no further significant differences between the groups using ANCOVA and a linear regression model including all groups were detected, severe meconium staining in more than 10% of piglets was observed in group II and IV. Moreover, piglets of group IV showed oedematous and haemorrhagic umbilical cords, lethargy and anoxia after treatment, and intra-partum deaths were recorded.The best outcome for the sows and piglets was achieved using the 1 mg PGE2 dosage, whereas the other dosages showed more negative side effects, impairing the health and welfare of the animals. The results of this study can be used for further studies with larger sample sizes.

Mechanism of Na-K-ATPase Inhibition by PGE2 in Intestinal Epithelial Cells.

The primary means of intestinal absorption of nutrients by villus cells is via Na-dependent nutrient co-transporters located in the brush border membrane (BBM). These secondary active co-transport processes require a favorable transcellular Na gradient that is provided by Na-K-ATPase. In chronic enteritis, malabsorption of essential nutrients is partially due to inhibition of villus Na-K-ATPase activity mediated by specific immune inflammatory mediators that are known to be elevated in the inflamed mucosa. However, how Prostaglandin E2 (PGE2), a specific mediator of nutrient malabsorption in the villus BBM, may mediate the inhibition of Na-K-ATPase is not known. Therefore, this study aimed to determine the effect of PGE2 on Na-K-ATPase in villus cells and define its mechanism of action. In vitro, in IEC-18 cells, PGE2 treatment significantly reduced Na-K-ATPase activity, accompanied by a significant increase in the intracellular levels of cyclic Adenosine Monophosphate (cAMP). The treatment with cAMP analog 8-Bromo-cAMP mimicked the PGE2-mediated effect on Na-K-ATPase activity, while Rp-cAMP (PKA inhibitor) pretreatment reversed the same. The mechanism of inhibition of PGE2 was secondary to a transcriptional reduction in the Na-K-ATPase α1 and β1 subunit genes, which was reversed by the Rp-cAMP pretreatment. Thus, the PGE2-mediated activation of the PKA pathway mediates the transcriptional inhibition of Na-K-ATPase activity in vitro.

Prostaglandin E2 stimulates anion and fluid secretion triggered by lipopolysaccharide in rat vaginal epithelium

Prostaglandin E2 (PGE2) is a principal lipid mediator mediating various biological processes including immune responses and fluid secretion. As the first line of host defense against infection, vaginal epithelium plays orchestrated roles in vaginal innate immunity. However, the effect of PGE2 triggered by pro-inflammatory stimuli on vaginal epithelium remains elusive. This study aimed to investigate the regulatory role of PGE2 on vaginal epithelium after lipopolysaccharide (LPS) stimulation. RT–PCR and western blot analysis revealed that E-prostanoid (EP) receptors EP2 and EP4 were expressed in rat vagina. Basolateral application of PGE2 induced anion secretion mediated by cystic fibrosis transmembrane conductance regulator (CFTR) via EP-adenylate cyclase-cAMP signaling pathway in rat vaginal epithelial cells. The in vivo study showed that PGE2 promoted fluid secretion in rat vagina. Moreover, LPS stimulation facilitated cyclooxygenase-dependent PGE2 synthesis and vaginal fluid secretion in vivo. Conclusively, LPS stimulation triggered epithelium-derived PGE2 production in vaginal epithelium, leading to CFTR-mediated anion secretion and luminal flushing. This study provides valuable insights into the physiological role of PGE2 during vaginal bacterial infection.

A Glra3 phosphodeficient mouse mutant establishes the critical role of protein kinase A-dependent phosphorylation and inhibition of glycine receptors in spinal inflammatory hyperalgesia.

Glycinergic neurons and glycine receptors (GlyRs) exert a critical control over spinal nociception. Prostaglandin E2 (PGE2), a key inflammatory mediator produced in the spinal cord in response to peripheral inflammation, inhibits a certain subtype of GlyRs (α3GlyR) that is defined by the inclusion of α3 subunits and distinctly expressed in the lamina II of the spinal dorsal horn, ie, at the site where most nociceptive nerve fibers terminate. Previous work has shown that the hyperalgesic effect of spinal PGE2 is lost in mice lacking α3GlyRs and suggested that this phenotype results from the prevention of PGE2-evoked protein kinase A (PKA)-dependent phosphorylation and inhibition of α3GlyRs. However, direct proof for a contribution of this phosphorylation event to inflammatory hyperalgesia was still lacking. To address this knowledge gap, a phospho-deficient mouse line was generated that carries a serine to alanine point mutation at a strong consensus site for PKA-dependent phosphorylation in the long intracellular loop of the GlyR α3 subunit. These mice showed unaltered spinal expression of GlyR α3 subunits. In behavioral experiments, they showed no alterations in baseline nociception, but were protected from the hyperalgesic effects of intrathecally injected PGE2 and exhibited markedly reduced inflammatory hyperalgesia. These behavioral phenotypes closely recapitulate those found previously in GlyR α3-deficient mice. Our results thus firmly establish the crucial role of PKA-dependent phosphorylation of α3GlyRs in inflammatory hyperalgesia.

Transforming growth factor-β1 and inducible nitric oxide synthase signaling were involved in effects of prostaglandin E2 on progression of lower limb varicose veins

ObjectiveThe vital pathogenesis of varicose veins includes remodeling of the extracellular matrix and decreased vascular tone. Prostaglandin E2 (PGE2), a small molecule substance and inflammatory medium that belongs to the arachidonic acid derivatives, has the capacity to influence the expression of metalloproteinase and the vascular tone of the venous wall. The purpose of the present study was to investigate the role of PGE2 in the development of varicose veins in lower limbs. MethodsThe collected venous specimens were analyzed using hematoxylin and eosin, Masson's trichrome, and immunohistochemical staining. Transforming growth factor (TGF)-β1, PGE2, CD31, and α-smooth muscle actin antibody were used to detect the expression and distribution of these proteins. The effect of PGE2 on the proliferation, migration, and tube formation capacity of human umbilical vein endothelial cells (HUVECs) was detected in vitro. The effect of TGF-β1 on the expression of PGE2 and matrix metalloproteinases (MMPs) was assessed using Western blotting. Quantitative reverse transcription polymerase chain reaction was used to evaluate the effect of PGE2 on the expression of nitric oxide synthase (NOS) and other genes. ResultsThe expression of PGE2 and TGF-β1 in varicose veins was upregulated in the media tunica and intima tunica, and a strong positive correlation was found between PGE2 and TGF-β1 expression in both varicose veins (95% confidence interval, 0.5207-0.9582; R = 0.848; P = .0005) and normal veins (95% confidence interval, 0.2530-0.8532; R = 0.643; P = .003). PGE2 promoted the migration and tube formation ability of HUVECs. Moreover, PGE2 also upregulated the expression of MMP-1 and TGF-β1 in HUVECs and increased the mRNA level of inducible NOS. ConclusionsPGE2 can affect the remodeling of the extracellular matrix and reduce the elasticity of the vascular walls by promoting the synthesis of TGF-β1 and MMP-1. PGE2 can also reduce the tension of the great saphenous vein by promoting the expression of inducible NOS, thus aggravating the blood stasis.

Synergistic action of estradiol and PGE2 on endometrial transcriptome in vivo resembles pregnancy effects better than estradiol alone†.

Successful pregnancy establishment in mammals depends on numerous interactions between embryos and the maternal organism. Estradiol-17β (E2) is the primary embryonic signal in the pig, and its importance has been questioned recently. However, E2 is not the only molecule of embryonic origin. In pigs, prostaglandin E2 (PGE2) is abundantly synthesized and secreted by conceptuses and endometrium. The present study aimed to determine the role of PGE2 and its simultaneous action with E2 in changes in porcine endometrial transcriptome during pregnancy establishment. The effects of PGE2 and PGE2 acting with E2 were studied using an in vivo model of intrauterine hormone infusions, and were compared to the effects of E2 alone and conceptuses' presence on day 12 of pregnancy. The endometrial transcriptome was profiled using gene expression microarrays followed by statistical analyses. Downstream analyses were performed using bioinformatics tools. Differential expression of selected genes was verified by quantitative polymerase chain reaction. Microarray analysis revealed 2413 differentially expressed genes (DEGs) in the endometrium treated simultaneously with PGE2 and E2 (P<0.01). No significant effect of PGE2 administered alone on endometrial transcriptome was detected. Gene ontology annotations enriched for DEGs were related to multiple processes such as: focal adhesion, vascularization, cell migration and proliferation, glucose metabolism, tissue remodeling, and activation of immune response. Simultaneous administration of E2 and PGE2 induced more changes within endometrial transcriptome characteristic to pregnancy than infusion of E2 alone. The present findings suggest that synergistic action of estradiol-17β and PGE2 resembles the effects of pregnancy on endometrial transcriptome better than E2 alone.

Prostaglandin E1 attenuates post‑cardiac arrest myocardial dysfunction through inhibition of mitochondria‑mediated cardiomyocyte apoptosis.

Post-cardiac arrest myocardial dysfunction (PAMD) is a leading cause of death in patients undergoing resuscitation patients following cardiac arrest (CA). Although prostaglandin E1 (PGE1) is a clinical drug used to mitigate ischemia injury, its effect on PAMD remains unknown. In the present study, the protective effects of PGE1 on PAMD were evaluated in a rat model of CA and in a hypoxia-reoxygenation (H/R) in vitro model. Rats were randomly assigned to CA, CA+PGE1 or sham groups. Asphyxia for 8 min followed by cardiopulmonary resuscitation were performed in the CA and CA+PGE1 groups. PGE1 was intravenously administered at the onset of return of spontaneous circulation (ROSC). PGE1 treatment significantly increased the ejection fraction and cardiac output within 4 h following ROSC and improved the survival rate, compared with the CA group. Moreover, PGE1 inactivated GSK3β, prevented mitochondrial permeability transition pore (mPTP) opening, while reducing cytochrome c and cleaved caspase-3 expression, as well as cardiomyocyte apoptosis in the rat model. To examine the underlying mechanism, H/R H9c2 cells were treated with PGE1 at the start of reoxygenation. The changes in GSK3β activity, mPTP opening, cytochrome c and cleaved caspase-3 expression, and apoptosis of H9c2 cells were consistent with those noted in vivo. The results indicated that PGE1 attenuated PAMD by inhibiting mitochondria-mediated cardiomyocyte apoptosis.

Prostaglandin E2 and phagocytosis of inhaled particulate matter by airway macrophages in cystic fibrosis

BackgroundExposure to particulate matter (PM) air pollution is associated with adverse health outcomes in children with cystic fibrosis (CF). Airway macrophages (AM) phagocytose and retain inhaled PM in vivo, and the area of carbon in AM reflects both inhaled PM dose and phagocytic function. Since airway prostaglandin-E2 (PGE2) is increased in CF, and PGE2 suppresses AM phagocytosis, we sought evidence for PGE2-mediated suppression of AM phagocytosis of inhaled carbonaceous PM in CF. MethodsAfter informed consent, urine was obtained from 20 controls and 24 CF children. In the subgroup of older children, at least one induced sputum was done in 20 controls and 19 CF children. Urinary tetranor PGEM, the major metabolite of PGE2, and sputum PGE2 were measured by mass spectrometry. The area of carbon in AM was determined by image analysis. Exposure to PM was assessed by modelling and personal monitoring. The effect of either PGE2 or CF sputum supernatant on phagocytosis of diesel exhaust particle (DEP) by AM was assessed in vitro. Data were analysed by t-test. ResultsBoth urinary tetranor PGEM (P<0.05), and sputum PGE2 (P<0.05) were increased in CF . Despite no difference in PM exposure between groups, the area of phagocytosed carbon by AM was decreased in children with CF (P<0.01). PGE2 suppressed phagocytosis of DEP by AM from both controls and CF (P<0.0001). CF sputum supernatant suppressed phagocytosis of DEP by AM (P<0.0001) in a PGE2-dependent manner. ConclusionIncreased PGE2 in the CF airway suppresses phagocytosis of inhaled PM by AM.

ProstaglandinE2 serves a dual role in regulating the migration of dendritic cells.

Dendritic cells (DCs) are the most potent antigen-presenting cells, and are indispensable in the immune system. Prostaglandin E2 (PGE2) has been demonstrated to modulate the migration of DCs, but with inconsistent results. The present study, based on our previous research, used murine bone marrow-derived DCs to elucidate the potential regulatory mechanism of PGE2 on the migration of DCs. The results indicated that PGE2 served a dual role in regulating the migration of DCs in a dose-dependent manner. High concentrations of PGE2 inhibited cell migration, whereas low concentrations exhibited the opposite effect. Flow cytometry revealed that the expression of CC chemokine receptor type 7 on the DC surface was increased following treatment with low concentrations of PGE2 and slightly decreased by high concentrations of PGE2. The effect of PGE2 was indicated to be exerted via reorganizing the F-actin cytoskeleton using confocal micros-copy. Moreover, the regulatory effect of PGE2 on the migration of DCs was validated in vivo. Subsequent gene expression profile analyses using RNA-sequencing technology indicated that PGE2 induced alterations in the expression of multiple downstream genes and signaling pathway molecules associated with cell migration and the cytoskeleton. These findings may provide an improved understanding on the mechanism of DC migration under both pathological and physiological conditions. Moreover, the biological implications of these findings may provide a novel perspective of the immunological surveillance in the progression of different types of diseases.

The In Vitro Effect of Prostaglandin E2 and F2α on the Chemerin System in the Porcine Endometrium during Gestation.

Chemerin belongs to the group of adipocyte-derived hormones known as adipokines, which are responsible mainly for the control of energy homeostasis. Adipokine exerts its influence through three receptors: Chemokine-like receptor 1 (CMKLR1), G protein-coupled receptor 1 (GPR1), and C-C motif chemokine receptor-like 2 (CCRL2). A growing body of evidence indicates that chemerin participates in the regulation of the female reproductive system. According to the literature, the expression of chemerin and its receptors in reproductive structures depends on the local hormonal milieu. The aim of this study was to investigate the in vitro effect of prostaglandins E2 (PGE2) and F2α (PGF2α) on chemerin and chemerin receptor (chemerin system) mRNAs (qPCR) and proteins (ELISA, Western blotting) in endometrial tissue explants collected from early-pregnant gilts. Both PGE2 and PGF2α significantly influenced the expression of the chemerin gene, hormone secretion, and the expression of chemerin receptor genes and proteins. The influence of both prostaglandins on the expression of the chemerin system varied between different stages of gestation. This is the first study to describe the modulatory effect of PGE2 and PGF2α on the expression of the chemerin system in the porcine uterus during early gestation.

Caffeine prevents prostaglandin E1-induced disturbances in respiratory control in neonatal rats: implications for infants with critical congenital heart disease.

Continuous infusion of prostaglandin E1 (PGE1) is used to maintain ductus arteriosus patency in infants with critical congenital heart disease, but it can also cause central apnea suggesting an effect on respiratory neural control. In this study, we investigated whether 1) PGE1 inhibits the various phases of the acute hypoxic ventilatory response (HVR; an index of respiratory control dysfunction) and increases apnea incidence in neonatal rats; and 2) whether these changes would be reversible with caffeine pretreatment. Whole body plethysmography was used to assess the HVR and apnea incidence in neonatal rats 2 h following a single bolus intraperitoneal injection of PGE1 with and without prior caffeine treatment. Untreated rats exhibited a biphasic HVR characterized by an initial increase in minute ventilation followed by a ventilatory decline of the late phase (~5th minute) of the HVR. PGE1 had a dose-dependent effect on the HVR. Contrary to our hypothesis, the lowest dose (1 µg/kg) of PGE1 prevented the ventilatory decline of the late phase of the HVR. However, PGE1 tended to increase postsigh apnea incidence and the coefficient of variability (CV) of breathing frequency, suggesting increased respiratory instability. PGE1 also decreased brainstem microglia mRNA and increased neuronal nitric oxide synthase (nNOS) and platelet-derived growth factor-β (PDGF-β) gene expression. Caffeine pretreatment prevented these effects of PGE1, and the adenosine A2A receptor inhibitor MSX-3 had similar preventative effects. Prostaglandin appears to have deleterious effects on brainstem respiratory control regions, possibly involving a microglial-dependent mechanism. The compensatory effects of caffeine or MSX-3 treatment raises the question of whether prostaglandin may also operate on an adenosine-dependent pathway.

Prostaglandin E2 stimulates the epithelial sodium channel (ENaC) in cultured mouse cortical collecting duct cells in an autocrine manner.

Prostaglandin E2 (PGE2) is the most abundant prostanoid in the kidney, affecting a wide range of renal functions. Conflicting data have been reported regarding the effects of PGE2 on tubular water and ion transport. The amiloride-sensitive epithelial sodium channel (ENaC) is rate limiting for transepithelial sodium transport in the aldosterone-sensitive distal nephron. The aim of the present study was to explore a potential role of PGE2 in regulating ENaC in cortical collecting duct (CCD) cells. Short-circuit current (ISC) measurements were performed using the murine mCCDcl1 cell line known to express characteristic properties of CCD principal cells and to be responsive to physiological concentrations of aldosterone and vasopressin. PGE2 stimulated amiloride-sensitive ISC via basolateral prostaglandin E receptors type 4 (EP4) with an EC50 of ∼7.1 nM. The rapid stimulatory effect of PGE2 on ISC resembled that of vasopressin. A maximum response was reached within minutes, coinciding with an increased abundance of β-ENaC at the apical plasma membrane and elevated cytosolic cAMP levels. The effects of PGE2 and vasopressin were nonadditive, indicating similar signaling cascades. Exposing mCCDcl1 cells to aldosterone caused a much slower (∼2 h) increase of the amiloride-sensitive ISC. Interestingly, the rapid effect of PGE2 was preserved even after aldosterone stimulation. Furthermore, application of arachidonic acid also increased the amiloride-sensitive ISC involving basolateral EP4 receptors. Exposure to arachidonic acid resulted in elevated PGE2 in the basolateral medium in a cyclooxygenase 1 (COX-1)-dependent manner. These data suggest that in the cortical collecting duct, locally produced and secreted PGE2 can stimulate ENaC-mediated transepithelial sodium transport.

Multiple Roles of Prostaglandin E2 Receptors in Female Reproduction

Among prostaglandins, Prostaglandin E2 (PGE2) (PGE2) is considered especially important for decidualization, ovulation, implantation and pregnancy. Four major PGE2 receptor subtypes, EP1, EP2, EP3, EP4, as well as peroxisome proliferator-activated receptors (PPARs), mediate various PGE2 effects via their coupling to distinct signaling pathways. This review summarizes up-to-date literatures on the role of prostaglandin E2 receptors in female reproduction, which could provide a broad perspective to guide further research in this field. PGE2 plays an indispensable role in decidualization, ovulation, implantation and pregnancy. However, the precise mechanism of Prostaglandin E2 (EP) receptors in the female reproductive system is still limited. More investigations should be performed on the mechanism of EP receptors in the pathological states, and the possibility of EP agonists or antagonists clinically used in improving reproductive disorders.

Prostaglandin E2 confers protection against diabetic coronary atherosclerosis by stimulating M2 macrophage polarization via the activation of the CREB/BDNF/TrkB signaling pathway.

It has been documented that M2 macrophage polarization plays a suppressive role in atherosclerosis in diabetes mellitus (DM). In addition, prostaglandin E2 (PGE2) is implicated in the development of M2 macrophage polarization. Therefore, the study aimed to investigate the specific mechanism of PGE2 in M2 macrophage polarization in diabetic coronary atherosclerosis (DMAS). Initially, clinical samples were obtained and DMAS mouse model was established. The expression of BDNF was determined, and M1 and M2 macrophage polarizations were evaluated. Then, the levels of BDNF and PGE2 were modified in DMAS mice and the serum indicator, atherosclerotic plaque, lipid uptake by PBMCs, as well as M1 and M2 macrophage polarization were determined. Macrophages were isolated and the effects of PGE2 and the CREB/BDNF/TrkB signaling pathway on M2 macrophage polarization were explored. BDNF was downregulated and macrophages were differentiated into M1 in DMAS patients and mice. BDNF and PGE2 were observed to promote M2 macrophage polarization, where atherosclerotic plaque and lipid uptake by PBMCs were reduced, and DMAS was alleviated in mice. Overexpression of BDNF activated the CREB/BDNF/TrkB signaling pathway and stimulated M2 macrophage polarization in macrophages. PGE2 stimulated M2 macrophage polarization by inducing KLF4 via the activation of the CREB/BDNF/TrkB signaling pathway. This study demonstrates that PGE2 promotes M2 macrophage polarization by activating the CREB/BDNF/TrkB signaling pathway, thus alleviating DMAS.

Regulatory effect of PGE2 on microbicidal activity and inflammatory cytokines in canine leishmaniasis.

Canine leishmaniasis (CanL) is caused by the intracellular parasite Leishmania infantum. Prostaglandin E2 (PGE2 ) exerts potent regulatory effects on the immune system in experimental model Leishmania infection, but this influence has not yet been studied in CanL. In this study, PGE2 and PGE2 receptor levels and the regulatory effect of PGE2 on arginase activity, NO2 , IL-10, IL-17, IFN-γ, TNF-α and parasite load were evaluated in cultures of splenic leucocytes obtained from dogs with CanL in the presence of agonists and inhibitors. Our results showed that splenic leucocytes from dogs with CanL had lower EP2 receptor levels than those of splenic leucocytes from healthy animals. We observed that NO2 levels decreased when the cells were treated with a PGE2 receptor agonist (EP1/EP2/EP3) or COX-2 inhibitor (NS-398) and that TNF-α, IL-17 and IFN-γ cytokine levels decreased when the cells were treated with a PGE2 receptor agonist (EP2) or PGE2 itself. The parasite load in splenic leucocyte cell cultures from dogs with CanL decreased after stimulation of the cells with PGE2 . We conclude that Leishmania infection of dogs modulates PGE2 receptors and speculate that the binding of PGE2 to its receptors may activate the microbicidal capacity of cells.