Application Of Prostaglandin E2 Research Articles

Prostaglandin E2 depolarises sensory axons in vitro in an ANO1 and Nav1.8 dependent manner

Prostaglandin E2 (PGE2) is a major contributor to inflammatory pain hyperalgesia, however, the extent to which it modulates the activity of nociceptive axons is incompletely understood. We developed and characterized a microfluidic cell culture model to investigate sensitisation of the axons of dorsal root ganglia neurons. We show that application of PGE2 to fluidically isolated axons leads to sensitisation of their responses to depolarising stimuli. Interestingly the application of PGE2 to the DRG axons elicited a direct and persistent spiking activity propagated to the soma. Both the persistent activity and the membrane depolarisation in the axons are abolished by the EP4 receptor inhibitor and a blocker of cAMP synthesis. Further investigated into the mechanisms of the spiking activity showed that the PGE2 evoked depolarisation was inhibited by Nav1.8 sodium channel blockers but was refractory to the application of TTX or zatebradine. Interestingly, the depolarisation of axons was blocked by blocking ANO1 channels with T16Ainh-A01. We further show that PGE2-elicited axonal responses are altered by the changes in chloride gradient within the axons following treatment with bumetanide a Na-K-2Cl cotransporter NKCC1 inhibitor, but not by VU01240551 an inhibitor of potassium-chloride transporter KCC2. Our data demonstrate a novel role for PGE2/EP4/cAMP pathway which culminates in a sustained depolarisation of sensory axons mediated by a chloride current through ANO1 channels. Therefore, using a microfluidic culture model, we provide evidence for a potential dual function of PGE2 in inflammatory pain: it sensitises depolarisation-evoked responses in nociceptive axons and directly triggers action potentials by activating ANO1 and Nav1.8 channels.

Liposome Loaded Prostaglandin E2 (PGE2) for Muscle Regeneration

Prostaglandin E2 (PGE2) is an FDA approved lipid signaling molecule for range of disorders. Also, it has a significant therapeutic potential for tissue repair and regeneration. However, to date there are no applications of PGE2 specifically designed for the muscle repair and regeneration. Liposome systems offer several advantages for PGE2 delivery, improved drug stability, reduced side effects, and tissue-specific targeting. Our hypothesis is that encapsulating PGE2 in liposome system will significantly enhance its bioavailability and maintain an effective therapeutic level. The research was designed to optimize PGE2 concentration in muscle cells, study its effect on cells differentiation, use the optimized PGE2 concentration for liposome-loading and testing the delivery system in-vitro and in-vivo using muscle injury models. We further investigated the molecular mechanism and signaling pathways triggered by the intracellular elevation of PGE2 in muscle cells. Optimization results revealed that nM concentration of PGE2 was beneficial while μM concentrations were detrimental. All our studies reported here were conducted with 50nM PGE2. 50nM PGE2 significantly enhances proliferation and myogenic differentiation as indicated by increased fusion index ( p=0.02) compared to a control. Scanning Electron Microscopy (SEM) images confirmed the lipid bi-layer formation with core-shell structure of 3μm liposomes containing PGE2. In-vitro studies on the C2C12 muscles cells showed that PGE2-liposome system significantly increased the intracellular concentration of PGE2 compared to a PGE2-vehicle (DMSO) control ( p=0.019), confirming the effcacy of this delivery system. Additionally, 50nM PGE2 significantly regulated myogenic signaling pathways and genes associated with calcium homeostasis, mitochondrial biogenesis, cellular hypertrophy, and oxidative stress. These findings support the notion that PGE2 induces the acceleration of myogenic differentiation which is supported by our initial signaling pathway analysis. Our in-vitro muscle damage model indicated that 50nM PGE2 can significantly attenuate the muscle damage and regenerate myotubes within 48 hours compared to 4 days in normal control. In conclusion, the findings suggest that liposome-PGE2 delivery system can positively influence myogenic differentiation, muscle properties, and cellular signaling pathways, offering promise for improving the delivery of PGE2 to injured skeletal muscles to assist in their regeneration process. This work was directly supported by NIH-National Institutes of Aging P01AG039355 (MB) and the George W. and Hazel M. Jay and Evanston Research Endowments (MB). Authors were supported by NIH Grants: National Institutes of Aging (NINDS) 2-R01NS105621; NIA-R01AG056504, NIA-2R01AG060341, National Institutes of Diabetes, Digestive, and Kidney Diseases Kidney (NIDDK)-1R01DK119066 to MB, and National Institutes of Neurological Disorders and Stroke (NINDS) 2-R01NS105621 to MB. Also, NIH/NIDC 1R01DE031872-01 (VV). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Prostaglandin E2 involvement in the reproduction of small abalone, Haliotis diversicolor

Prostaglandin E2 (PGE2) has been reported to be involved in reproduction as one of the most abundant and widely distributed prostaglandins in invertebrates. Regulating gonad development and gamete production in mollusks can greatly assist artificial breeding, which is believed to promote the commercial benefits of various mollusk species. In the present study, the contents of PGE2 in the gonads of abalone at different developmental stages (maturing stage, ripe stage, and spawning stage) and reproduction states (before and after spawning) were measured. A higher PGE2 level was found in the gonads of abalones at the ripe stage than other stages, and the highest PGE2 level was detected in the ovaries of female H. diversicolor in the UV-stimulated group. Then the effects of PGE2 injection on the spawning efficiency were explored, and the gamete emission rates of female and male abalone were significantly increased after PGE2 injection. Through qRT-PCR and in situ hybridization assay, higher expression levels and wide distribution of phospholipase A2 (PLA2), cyclooxygenase 2 (COX2), prostaglandin E synthases (PGES2), and prostaglandin E2 receptor 4 (EP4) in the gonads of H. diversicolor were observed after spawning. It is speculated that PGE2 may promote the reproductive cycle in both male and female H. diversicolor, although the regulation mechanism of PGE2 in female and male abalone might be different. The results will be useful for the application of PGE2 in the abalone aquaculture practices to increase the reproduction efficiency in future.

The sustained PGE2 release matrix improves neovascularization and skeletal muscle regeneration in a hindlimb ischemia model

BackgroundThe promising therapeutic strategy for the treatment of peripheral artery disease (PAD) is to restore blood supply and promote regeneration of skeletal muscle regeneration. Increasing evidence revealed that prostaglandin E2 (PGE2), a lipid signaling molecule, has significant therapeutic potential for tissue repair and regeneration. Though PGE2 has been well reported in tissue regeneration, the application of PGE2 is hampered by its short half-life in vivo and the lack of a viable system for sustained release of PGE2.ResultsIn this study, we designed and synthesized a new PGE2 release matrix by chemically bonding PGE2 to collagen. Our results revealed that the PGE2 matrix effectively extends the half-life of PGE2 in vitro and in vivo. Moreover, the PGE2 matrix markedly improved neovascularization by increasing angiogenesis, as confirmed by bioluminescence imaging (BLI). Furthermore, the PGE2 matrix exhibits superior therapeutic efficacy in the hindlimb ischemia model through the activation of MyoD1-mediated muscle stem cells, which is consistent with accelerated structural recovery of skeletal muscle, as evidenced by histological analysis.ConclusionsOur findings highlight the chemical bonding strategy of chemical bonding PGE2 to collagen for sustained release and may facilitate the development of PGE2-based therapies to significantly improve tissue regeneration.Graphical

Receptor-mediated activation of CFTR via prostaglandin signaling pathways in the airway.

Cystic fibrosis (CF) is a genetic disease caused by mutations of the gene encoding a cAMP-activated Cl- channel, the cystic fibrosis transmembrane conductance regulator (CFTR). CFTR modulator therapies consist of small-molecule drugs that rescue mutant CFTR. Regimens of single or combinations of CFTR modulators still rely on endogenous levels of cAMP to regulate CFTR activity. We investigated CFTR activation by the natural mediator prostaglandin E2 (PGE2) and lubiprostone (a Food and Drug Administration-approved drug known to target prostaglandin receptors) and tested the hypothesis that receptor-mediated CFTR activators can be used in combination with currently available CFTR modulators to increase function of mutant CFTR. Primary-cultured airway epithelia were assayed in Ussing chambers. Experimental CFTR activators and established CFTR modulators were applied for 24 h and/or acutely and analyzed for their effect on CFTR activity as measured by changes in short-circuit current (ISC). In non-CF airway epithelia, acute application of lubiprostone and PGE2 activated CFTR to the levels comparable to forskolin (Fsk). Pretreatment (24 h) with antagonists to prostaglandin receptors EP2 and EP4 abolished the ability of lubiprostone to acutely activate CFTR. In F508del homozygous airway epithelia pretreated with the triple combination of elexacaftor, tezacaftor, and ivacaftor (ELEXA/TEZ/IVA; i.e., Trikafta), acute application of lubiprostone was able to maximally activate CFTR. Prolonged (24 h) cotreatment of F508del homozygous epithelia with ELEXA/TEZ/IVA and lubiprostone increased acute CFTR activation by ∼60% compared with the treatment with ELEXA/TEZ/IVA alone. This work establishes the feasibility of targeting prostaglandin receptors to activate CFTR on the airway epithelia and demonstrates that cotreatment with lubiprostone can further restore modulator-rescued CFTR.

Comparison of intracervical and intravaginal prostaglandin E2 for induction of labor in term pregnancies with unfavorable cervix: Randomized controlled trial

ObjectiveThe aim of this study was to compare intracervical (IC) and intravaginal (IV) application of prostaglandin E2 (PGE2) for labor induction in term pregnancies with unfavorable cervix. Study designThis prospective randomized trial included 212 pregnant women with term pregnancy and unfavorable cervix randomly assigned for labor induction with either IC (0.5 mg) or IV (2 mg) PGE2 formulation. Main outcome measured was time interval from labor induction to delivery. Difference in mode of delivery and adverse perinatal outcomes between two studied groups was also investigated. Significance was set at p < 0.05. ResultsStudied groups did not significantly differ regarding main characteristics such as age, parity, body mass index or Bishop score. Women in IV group compared to those in IC group had shorter induction to delivery time interval (p < 0.001) and induction to active phase time interval (p = 0.001), higher prevalence of vaginal delivery within 24 h of labor induction (63,3% vs 40,6%, p = 0.002) and higher prevalence of successful induction of labor (95,9% vs. 86,5%, p = 0.020). The analysis did not reveal significant difference in mode of delivery between groups (p = 0.453) or other adverse perinatal outcomes. ConclusionIV application of PGE2 compared to IC application is more efficacious and comparably safe for labor induction in term pregnancies with unfavorable cervix and should be the method of choice for labor induction.

The Role of mPGES-1 in Promoting Granulation Tissue Angiogenesis Through Regulatory T-cell Accumulation.

Microsomal prostaglandin E synthase-1 (mPGES-1) is an enzyme, which catalyzes the final step of prostaglandin E2 (PGE2) synthesis. PGE2 in involved in wound-induced angiogenesis. Regulatory T cells (Tregs) regulate not only immune tolerance but also tissue repair and angiogenesis. We examined whether the mPGES-1/PGE2 axis contributes to wound-induced angiogenesis and granulation tissue formation through Treg accumulation. The dorsal subcutaneous tissues of male mPGES-1-deficient (mPGES-1-/-) and C57BL/6 wild-type (WT) mice were implanted with polyurethane sponge disks. Angiogenesis was estimated by determining the wet weight of sponge tissues and the expression of proangiogenic factors including CD31, vascular endothelial growth factor (VEGF), and transforming growth factor β (TGF-β) in granulation tissues. Angiogenesis was suppressed in mPGES-1-/- mice compared with WT mice, which was associated with attenuated forkhead box P3 (Foxp3) expression and Foxp3+ Treg accumulation. The number of cells double-positive for Foxp3/TGFβ and Foxp3/VEGF were lower in mPGES-1-/- mice than in WT mice. Neutralizing Tregs with antibodies (Abs) against CD25 or folate receptor 4 (FR4) inhibited the Foxp3+ Treg angiogenesis and accumulation in WT mice, but not in mPGES-1-/- mice. The topical application of PGE2 into the implanted sponge enhanced angiogenesis and accumulation of Tregs expressing TGFβ and VEGF in WT and mPGES-1-/- mice. Tregs producing TGFβ and VEGF accumulate in wounds and contribute to angiogenesis through mPGES-1-derived PGE2 mPGES-1 induction may control angiogenesis in skin wounds by recruiting Tregs.

Prostaglandin E2 Dilates Intracerebral Arterioles When Applied to Capillaries: Implications for Small Vessel Diseases.

Prostaglandin E2 (PGE2) has been widely proposed to mediate neurovascular coupling by dilating brain parenchymal arterioles through activation of prostanoid EP4 receptors. However, our previous report that direct application of PGE2 induces an EP1-mediated constriction strongly argues against its direct action on arterioles during neurovascular coupling, the mechanisms sustaining functional hyperemia. Recent advances have highlighted the role of capillaries in sensing neuronal activity and propagating vasodilatory signals to the upstream penetrating parenchymal arteriole. Here, we examined the effect of capillary stimulation with PGE2 on upstream arteriolar diameter using an ex vivo capillary-parenchymal arteriole preparation and in vivo cerebral blood flow measurements with two-photon laser-scanning microscopy. We found that PGE2 caused upstream arteriolar dilation when applied onto capillaries with an EC50 of 70 nM. The response was inhibited by EP1 receptor antagonist and was greatly reduced, but not abolished, by blocking the strong inward-rectifier K+ channel. We further observed a blunted dilatory response to capillary stimulation with PGE2 in a genetic mouse model of cerebral small vessel disease with impaired functional hyperemia. This evidence casts previous findings in a different light, indicating that capillaries are the locus of PGE2 action to induce upstream arteriolar dilation in the control of brain blood flow, thereby providing a paradigm-shifting view that nonetheless remains coherent with the broad contours of a substantial body of existing literature.

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.

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.

Role of prostaglandin E2 in tissue repair and regeneration.

Tissue regeneration following injury from disease or medical treatment still represents a challenge in regeneration medicine. Prostaglandin E2 (PGE2), which involves diverse physiological processes via E-type prostanoid (EP) receptor family, favors the regeneration of various organ systems following injury for its capabilities such as activation of endogenous stem cells, immune regulation, and angiogenesis. Understanding how PGE2 modulates tissue regeneration and then exploring how to elevate the regenerative efficiency of PGE2 will provide key insights into the tissue repair and regeneration processes by PGE2. In this review, we summarized the application of PGE2 to guide the regeneration of different tissues, including skin, heart, liver, kidney, intestine, bone, skeletal muscle, and hematopoietic stem cell regeneration. Moreover, we introduced PGE2-based therapeutic strategies to accelerate the recovery of impaired tissue or organs, including 15-hydroxyprostaglandin dehydrogenase (15-PGDH) inhibitors boosting endogenous PGE2 levels and biomaterial scaffolds to control PGE2 release.

Role of the COX2-PGE2 axis in S. pneumoniae-induced exacerbation of experimental fibrosis.

Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease (ILD) associated with high morbidity and mortality. Patients with ILD frequently develop an acute exacerbation of their disease, which may be triggered by viral and/or bacterial infections. Prostaglandin E2 (PGE2) is an eicosanoid released in a cyclooxygenase-2 (COX2)-dependent manner and is considered to contribute to regulation of lung fibrosis. However, its role in infection-induced exacerbation of lung fibrosis is poorly defined. We found significantly increased levels of PGE2 in lung tissue of patients with ILD. Increased levels of PGE2 were also found in lung tissue of mice with AdTGF-β1-induced lung fibrosis and even more so in Streptococcus pneumoniae exacerbated lung fibrosis. Type II alveolar epithelial cells (AT II cells) and alveolar macrophages (AM) contributed to PGE2 release during exacerbating fibrosis. Application of parecoxib to inhibit PGE2 synthesis ameliorated lung fibrosis, whereas intratracheal application of PGE2 worsened lung fibrosis in mice. Both interventions had no effect on S. pneumoniae-exacerbated lung fibrosis. Together, we found that the COX2-PGE2 axis has dual roles in fibrosis that may offset each other: PGE2 helps resolve infection/attenuate inflammation in fibrosis exacerbation but accentuates TGF-β/AT II cell-mediated fibrosis. These data support the efficacy of COX/PGE2 interventions in the setting of non-exacerbating lung fibrosis.

Prostaglandin signals from adult germ stem cells delay somatic aging of Caenorhabditis elegans.

A moderate reduction of body temperature can induce a remarkable lifespan extension. Here we examine the link between cold temperature, germ line fitness and organismal longevity. We show that low temperature reduces age-associated exhaustion of germ stem cells (GSCs) in Caenorhabditis elegans, a process modulated by thermosensory neurons. Notably, robust self-renewal of adult GSCs delays reproductive aging and is required for extended lifespan at cold temperatures. These cells release prostaglandin E2 (PGE2) to induce cbs-1 expression in the intestine, increasing somatic production of hydrogen sulfide (H2S), a gaseous signaling molecule that prolongs lifespan. Whereas loss of adult GSCs reduces intestinal cbs-1 expression and cold-induced longevity, application of exogenous PGE2 rescues these phenotypes. Importantly, tissue-specific intestinal overexpression of cbs-1 mimics cold-temperature conditions and extends longevity even at warm temperatures. Thus, our results indicate that GSCs communicate with somatic tissues to coordinate extended reproductive capacity with longevity.

Prostaglandin E2 depresses GABA release onto parvocellular neuroendocrine neurones in the paraventricular nucleus of the hypothalamus via presynaptic receptors.

Inflammation-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis and the ensuing release of anti-inflammatory glucocorticoids are critical for the fine-tuning of the inflammatory response. This immune-induced neuroendocrine response is in large part mediated by prostaglandin E2 (PGE2 ), the central actions of which ultimately translate into the excitation of parvocellular neuroendocrine cells (PNCs) in the hypothalamic paraventricular nucleus. However, the neuronal mechanisms by which PGE2 excites PNCs remain incompletely understood. In the present study, we report that PGE2 potently depresses GABAergic inhibitory synaptic transmission onto PNCs. Using whole-cell patch clamp recordings obtained from PNCs in ex vivo hypothalamic slices from rats, we found that bath application of PGE2 (0.01-100μmolL-1 ) concentration-dependently decreased the amplitude of evoked inhibitory postsynaptic currents (eIPSCs) with maximum effects at 10μmolL-1 . The PGE2 -mediated depression of eIPSCs had a rapid onset and was long-lasting, and also was accompanied by an increase in paired pulse ratio. In addition, PGE2 decreased the frequency but not the amplitude of both spontaneous IPSCs and miniature IPSCs. These results collectively indicate that PGE2 acts at a presynaptic locus to decrease the probability of GABA release. Using pharmacological approaches, we also demonstrated that the EP3 subtype of the PGE2 receptor mediated the actions of PGE2 on GABA synapses. Taken together, our results show that PGE2 , via actions of presynaptic EP3 receptors, potently depresses GABA release onto PNCs, providing a plausible mechanism for the disinhibition of HPA axis output during inflammation.

Pathophysiological role of prostaglandin E2-induced up-regulation of the EP2 receptor in motor neuron-like NSC-34 cells and lumbar motor neurons in ALS model mice

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by selective degeneration of motor neurons. The primary triggers for motor neuronal death are still unknown, but inflammation is considered to be an important factor contributing to the pathophysiology of ALS both clinically and in ALS models. Prostaglandin E2 (PGE2) and its corresponding four E-prostanoid receptors play a pivotal role in the degeneration of motor neurons in human and transgenic models of ALS. It has also been shown that PGE2-EP2 signaling in glial cells (astrocytes or microglia) promotes motor neuronal death in G93A mice. The present study was designed to investigate the levels of expression of EP receptors in the spinal motor neurons of ALS model mice and to examine whether PGE2 alters the expression of EP receptors in differentiated NSC-34 cells, a motor neuron-like cell line. Immunohistochemical staining demonstrated that EP2 and EP3 immunoreactivity was localized in NeuN-positive large cells showing the typical morphology of motor neurons in mice. Semi-quantitative analysis showed that the immunoreactivity of EP2 in motor neurons was significantly increased in the early symptomatic stage in ALS model mice. In contrast, the level of EP3 expression remained constant, irrespective of age. In differentiated NSC-34 cells, bath application of PGE2 resulted in a concentration-dependent decrease of MTT reduction. Although PGE2 had no effect on cell survival at concentrations of less than 10 μM, pretreatment with 10 μM PGE2 significantly up-regulated EP2 and concomitantly potentiated cell death induced by 30 μM PGE2. These results suggest that PGE2 is an important effector for induction of the EP2 subtype in differentiated NSC-34 cells, and that not only EP2 up-regulation in glial cells but also EP2 up-regulation in motor neurons plays a pivotal role in the vulnerability of motor neurons in ALS model mice.

Obligatory Role of EP1 Receptors in the Increase in Cerebral Blood Flow Produced by Hypercapnia in the Mice.

Hypercapnia induces potent vasodilation in the cerebral circulation. Although it has long been known that prostanoids participate in the cerebrovascular effects of hypercapnia, the role of prostaglandin E2 (PGE2) and PGE2 receptors have not been fully investigated. In this study, we sought to determine whether cyclooxygenase-1 (COX-1)-derived PGE2 and EP1 receptors are involved in the cerebrovascular response induced by hypercapnia. Cerebral blood flow (CBF) was recorded by laser-Doppler flowmetry in the somatosenasory cortex of anesthetized male EP1-/- mice and wild type (WT) littermates. In WT mice, neocortical application of the EP1 receptor antagonist SC-51089 attenuated the increase in CBF elicited by systemic hypercapnia (pCO2 = 50–60 mmHg). SC-51089 also attenuated the increase in CBF produced by neocortical treatment of arachidonic acid or PGE2. These CBF responses were also attenuated in EP1-/- mice. In WT mice, the COX-1 inhibitor SC-560, but not the COX-2 inhibitor NS-398, attenuated the hypercapnic CBF increase. Neocortical application of exogenous PGE2 restored the attenuation in resting CBF and the hypercapnic response induced by SC-560. In contrast, exogenous PGE2 failed to rescue the attenuation both in WT mice induced by SC-51089 and EP1-/- mice, attesting to the obligatory role of EP1 receptors in the response. These findings indicate that the hypercapnic vasodilatation depends on COX-1-derived PGE2 acting on EP1 receptors and highlight the critical role that COX-1-derived PGE2 and EP1 receptors play in the hypercapnic regulation of the cerebral circulation.

Therapeutic effects of human gingiva-derived mesenchymal stromal cells on murine contact hypersensitivity via prostaglandin E2-EP3 signaling.

BackgroundThe immunomodulatory and anti-inflammatory functions of human gingiva-derived mesenchymal stromal cells (GMSCs) have been demonstrated in contact hypersensitivity (CHS) models; however, their therapeutic effect during the late phase of CHS has been poor.MethodsThe murine CHS model was induced by applying oxazolone to the ears of mice. Mesenchymal stromal cells were applied via two methods (intravenous or local injection) at three time points: 1 day before sensitization, 1 day before challenge, or 1 h after challenge. Prostaglandin E2 (PGE2) and sulprostone were administered subcutaneously 1 h after challenge.ResultsThe application of GMSCs, bone marrow mesenchymal stem cells, and adipose-derived stem cells all effectively suppressed CHS; however, GMSC treatment exhibited the greatest efficacy. Local injection of GMSCs led to a more marked attenuation of CHS compared with intravenous injection, especially during the late phase of CHS, and this manifested as decreased infiltration of inflammatory cells, suppression of the levels of various proinflammatory cytokines, reconstruction of the disrupted Th1/Th2 balance, and upregulation of regulatory T cells in the allergen contact areas. Pretreatment with indomethacin significantly abrogated the GMSC-mediated immunosuppressive effects, while PGE2 application reversed the effects of indomethacin pretreatment of GMSCs. Moreover, GMSC administration promoted the expression of EP3, a prostaglandin E receptor, and the application of sulprostone, an agonist of EP3, significantly attenuated CHS to a similar degree as that of GMSC administration.ConclusionsGMSCs have reproducible and powerful immunomodulatory functions. Local injection of GMSCs is the superior mode for therapeutic application. PGE2–EP3 signaling plays an important role in the immunomodulatory functions of GMSCs in murine CHS.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-016-0361-9) contains supplementary material, which is available to authorized users.

Modulation of afferent nerve activity by prostaglandin E2 upon urinary bladder distension in rats.

What is the central question of this study? It has been widely assumed that Cfibres innervating the bladder are mainly excited in overactive bladder syndrome. However, it remains unclear whether Aδ fibres are also activated in pathological conditions. What is the main finding and its importance? We found that a certain population of Aδ fibres, which become active specifically at a bladder pressure of more than 15cmH2 O in normal conditions, showed increased excitability in conditions of prostaglandin E2 -induced overactive bladder. This result suggests that a certain population of Aδ fibres, together with Cfibres, triggers pathophysiological activity. In overactive bladder syndrome, afferent Cfibres innervating the bladder show an increased activity level. However, it remains unclear whether all Cfibres are highly activated and whether Aδ fibres, the other type of bladder afferent fibre, are also involved in pathological conditions. To address these questions, we analysed the relationship between bladder pressure and single-unit firing patterns of afferent nerves in the left L6 dorsal roots in living rats. The recorded fibres were classified as Aδ fibres or Cfibres based on the response to 0.3μm tetrodotoxin. Certain populations of both Aδ fibres and Cfibres were activated at bladder pressures below 15cmH2 O (classified as low-threshold fibres), indicating their potential contribution to detection of normal bladder filling. Intravesical administration of prostaglandinE2 (PGE2 ) induced hyperexcitation in approximately half of such Cfibres, whereas the activity patterns of low-threshold Aδ fibres were unchanged. All fibres, regardless of type, which were almost silent in control conditions (classified as high-threshold fibres), were activated by application of PGE2 . Notably, the firing patterns of Aδ fibres, rather than Cfibres, were highly time locked to PGE2 -induced micro-oscillation of bladder pressure. These modulatory effects of PGE2 on Aδ fibres and Cfibres might trigger pathophysiological activity together in overactive bladder syndrome.

Effects of topical adrenergic agents on prostaglandin E2-induced aqueous flare and intraocular pressure elevation in pigmented rabbits.

To evaluate the effects of signals through adrenergic receptors on the changes in the aqueous flare and intraocular pressure (IOP) induced by topical prostaglandin E2 (PGE2) in pigmented rabbits. Adrenergic agents were applied topically to pigmented Dutch rabbits, and PGE2 was then applied to induce an increase in the aqueous flare and IOP. The degree of aqueous flare was measured with a laser flare meter, and the IOP was measured with a rebound tonometer. Measurements were made every 30 min after the PGE2 had been applied for 2 h and at 4.0 and 4.5 h. Repeated measure analysis of variance and Dunnett's post hoc tests were used for the statistical analyses. The topical application of PGE-2 increased the aqueous flare for more than 4.5 h. The topical instillation of 1.0 % apraclonidine significantly inhibited the increase in the PGE2-induced aqueous flare by 75.1 %, of 0.1 % brimonidine by 57.2 %, of 0.04 % dipivefrin by 57.4 %, and a combination of 0.1 % brimonidine and 5 % phenylephrine by 78.9 %. Topical 5.0 % phenylephrine and 0.05 % isoproterenol had little effect on the aqueous flare elevation induced by PGE2. The IOP increased 0.5 h after the topical application of PGE-2. Topical 1.0 % apraclonidine, 0.1 % brimonidine, 0.1 % dipivefrin, and the combination of 0.1 % brimonidine and 5.0 % phenylephrine significantly inhibited the PGE2-induced IOP elevation. However, topical 5.0 % phenylephrine and 0.05 % isoproterenol did not significantly inhibit the IOP elevation caused by PGE2. Signaling by the α2 receptor inhibits both the PGE2-induced flare and IOP elevation caused by topical PGE2 application.

Differential sensitization of silent nociceptors to low pH stimulation by prostaglandin E2 in human volunteers.

Inflammatory mediators activate and sensitize nociceptors. Tissue acidosis with low pH of 5.5 often accompanies inflammation and could enhance inflammatory pain and sensitization. Action potentials from single mechano-responsive (CM) and mechano-insensitive (CMi) C-nociceptors of cutaneous fascicles of the peroneal nerve in healthy volunteers were recorded by microneurography. Low pH solutions with and without prostaglandin E2 (PGE2) were injected twice (with an interval of approximately 5 min) into two spots of the receptive fields of C-fibres. Heat thresholds of the C-fibres were obtained before and after each injection. Injections of the low pH solutions immediately induced phasic responses in CM nociceptors, whereas CMi fibres responded after a delay of several seconds with a sustained response. More CMi fibres than CM fibres showed ongoing discharge after low pH injection, but the duration and intensity of the responses to the first low pH injection did not differ between them. Upon repetition, duration and intensity of the pH responses increased more than twofold in CMi fibres only. Furthermore, combined application of pH and PGE2 sensitized the response in CMi fibres only. In contrast, heat activation thresholds were sensitized by the combination of low pH and PGE2 in both fibre classes. Our results confirm nociceptor class independent heat sensitization by PGE2 which is probably mediated by transient receptor potential vanilloid 1 phosphorylation. However, prolonged and increased pain responses in humans upon low pH/PGE2 stimulation appear to be primarily dependent on CMi fibres, whereas CM nociceptors appear crucial for phasic responses.