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The pharmacologic actions of prostaglandin E(2) (PGE(2)) are mediated through specific E-prostanoid (EP)-1, EP-2, EP-3, and EP-4 receptors. In this study, we determined which PGE(2) receptor subtype(s) contribute to the prevention of allergen-induced bronchoconstriction.
We assessed the effects of these receptor agonists in ovalbumin (OA)-sensitize...
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Pulmonary function has been reported in mice using negative pressure-driven forced expiratory manoeuvres (NPFE) and the forced oscillation technique (FOT). However, both techniques have always been studied using separate cohorts of animals or systems. The objective of this study was to obtain NPFE and FOT measurements at baseline and following bron...
Citations
... The key enzyme, COX, catalyzes the conversion of arachidonic acid to prostaglandin H2, an unstable prostaglandin intermediate that is subsequently converted into PGE 2 via PGE 2 synthase (5). In airways, PGE 2 exerts a relaxant effect on the airway smooth muscle cells by acting on the E prostanoid 2 receptor (32,33). Early evidence showed that the loss of the epithelium or incubation with the non-selective COX inhibitor indomethacin facilitated contractile response to bethanechol in rabbit bronchi (34), which indicated the involvement of PGE 2 in epithelium-dependent smooth muscle relaxation. ...
Background:
Previous studies have suggested the involvement of epithelium in modulating the contractility of neighboring smooth muscle cells. However, the mechanism underlying epithelium-derived relaxation in airways remains largely unclear. This study aimed to investigate the mechanism underlying epithelium-dependent smooth muscle relaxation mediated by neurotransmitters.
Methods:
The contractile tension of Sprague-Dawley (SD) rat tracheal rings were measured using a mechanical recording system. Intracellular Ca2+ level was measured using a Ca2+ fluorescent probe Fluo-3 AM, and the fluorescence signal was recorded by a laser scanning confocal imaging system. The prostaglandin E2 (PGE2) content was measured using an enzyme-linked immunosorbent assay kit.
Results:
We observed that the neurotransmitter acetylcholine (ACh) restrained the electric field stimulation (EFS)-induced contraction in the intact but not epithelium-denuded rat tracheal rings. After inhibiting the muscarinic ACh receptor (mAChR) or cyclooxygenase (COX), a critical enzyme in prostaglandin synthesis, the relaxant effect of ACh was attenuated. Exogenous PGE2 showed a similar inhibitory effect on the EFS-evoked contraction of tracheal rings. Moreover, ACh triggered phospholipase C (PLC)-coupled Ca2+ release from intracellular Ca2+ stores and stimulated COX-dependent PGE2 production in primary cultured rat tracheal epithelial cells.
Conclusions:
Collectively, this study demonstrated that ACh induced rat tracheal smooth muscle relaxation by promoting PGE2 release from tracheal epithelium, which might provide valuable insights into the cross-talk among neurons, epithelial cells and neighboring smooth muscle cells in airways.
... (166) PGE2 has also been shown to limit inflammation in animal models of asthma. (179)(180)(181) ...
The clinical outcome of anaphylaxis (ANA) can be affected by several co-factors. Non-steroidal anti-inflammatory drugs (NSAIDs) are well-known co-factors of ANA acting via COX-inhibition. The NSAIDs-mediated mechanisms altering the severity of ANA are not well-defined. It is reported that patients of ASA (NSAID)-hypersensitivity show low levels of the regulatory prostaglandin E2 (PGE2). Moreover, the effectiveness of PGE2 administration in such patients suggests a critical role of PGE2 in ASA hypersensitivity. In addition, patients of ASA-tolerant and ASA-intolerant asthma show variable ANA sensitivities suggesting a role of genetic variation in susceptibility.
The aim of this thesis was to study whether and how PGE2 dysregulation predisposes to ANA and whether genetic pre-dispositions affect the PGE2 system and therefore ANA susceptibility.
First, sera from ANA patients and healthy individuals were analyzed for PGE2 levels. ANA patients were characterized by reduced PGE2 levels which inversely correlated with the severity of ANA. This disparity was confirmed by differential PGE2 levels between Balb/c and BL/6 strains, two genetic mouse strains frequently employed in allergy research. PGE2 levels in these mice were again inversely related with the severity of ANA. Results were confirmed by in vivo PGE2 stabilization using 15-hydroxyprostaglandin dehydrogenase inhibitor (15-PGDH-I). Pharmacological PGE2 stabilization ameliorated ANA severity in mice. A passive systemic ANA (PSA) model was applied to study the impact of ASA on ANA severity and the role of PGE2 in this context. ASA aggravated ANA by inhibiting COX-1/COX-2, while PGE2 reduced the aggravation through EP receptors 2, 3 and 4. To delineate the underlying mechanisms, murine and human mast cells were used to study the impact of exogenous PGE2 and EP agonists. PGE2 attenuated ANA severity by inhibiting MC activation through EP2 and EP4 receptors and interfering with MC signaling.
In summary, this thesis demonstrates that homeostatic levels of PGE2 modulate MC activation and protect against ANA severity. The impact of PGE2 on MC responses and ANA susceptibility is governed by genetic variation. Pharmacological stabilization of PGE2 may prove to be a therapeutic or preventive strategy in the management of high-risk ANA patients.
... We next explored an in vivo model where PGE 2 is known to be protective. Asthma is a disease where PGE 2 was demonstrated to be protective in humans 17,19 and in animal models 29,30 . In the OVA mouse model of allergic airway inflammation (AAI), we observed a dramatic increase in caspase-11 expression (Fig. 4a, compare lanes 1-4 to 5-8, quantified in Fig. 4b). ...
Activated caspase-1 and caspase-11 induce inflammatory cell death in a process termed pyroptosis. Here we show that Prostaglandin E2 (PGE2) inhibits caspase-11-dependent pyroptosis in murine and human macrophages. PGE2 suppreses caspase-11 expression in murine and human macrophages and in the airways of mice with allergic inflammation. Remarkably, caspase-11-deficient mice are strongly resistant to developing experimental allergic airway inflammation, where PGE2 is known to be protective. Expression of caspase-11 is elevated in the lung of wild type mice with allergic airway inflammation. Blocking PGE2 production with indomethacin enhances, whereas the prostaglandin E1 analog misoprostol inhibits lung caspase-11 expression. Finally, alveolar macrophages from asthma patients exhibit increased expression of caspase-4, a human homologue of caspase-11. Our findings identify PGE2 as a negative regulator of caspase-11-driven pyroptosis and implicate caspase-4/11 as a critical contributor to allergic airway inflammation, with implications for pathophysiology of asthma.
... The bronchodilator effect of PGE 2 has been demonstrated in healthy and asthmatic subjects (23)(24)(25). However, side effects of inhaled PGE 2 have been problematic, consisting of both cough and substernal burning (26,27). G s -coupled EP receptors on HASM are particularly attractive targets for asthma treatment, given we and others have demonstrated an ability (superior to that of b-agonists) of PGE 2 to both relax contracted HASM and inhibit mitogenstimulated HASM proliferation (14). ...
Prostaglandin E2 (PGE2) is produced in the airway during allergic lung inflammation and both promotes and inhibits features of asthma pathology. These mixed effects relate to 4 E‐prostanoid (EP) receptor subtypes (EP1, 2, 3 and 4) expressed at different levels on different resident and infiltrating airway cells. Although studies have asserted both EP2 and EP4 expression in human airway smooth muscle (HASM), a recent study asserted EP4 to be the functionally dominant EP subtype in HASM. Herein, we employ recently‐developed subtype‐selective ligands to investigate singular or combined EP2 and EP4 receptor activation in regulating HASM signaling and proliferation. The subtype specificity of ONO‐AE1‐259‐01 (EP2 agonist) and ONO‐AE1‐329 (EP4 agonist) was first demonstrated in human embryonic kidney 293 cells stably expressing different EP receptor subtypes. EP receptor knockdown and subtype‐selective antagonists demonstrated EP2 and EP4 receptor responsiveness in HASM cells to the specific ONO compounds, whereas PGE2 appeared to preferentially signal via the EP4 receptor. Both singular EP2 and EP4 receptor agonists inhibited HASM proliferation, and combined EP2 and EP4 receptor agonism exhibited positive cooperativity in both chronic Gs‐mediated signaling and inhibiting HASM proliferation. These findings suggest both EP2 and EP4 are functionally important in HASM, and their combined targeting optimally inhibits airway smooth muscle proliferation.—Michael, J. V. Gavrila, A., Nayak, A. P., Pera, T., Liberato, J. R., Polischak, S. R., Shah, S. D., Deshpande, D. A., Penn, R. B. Cooperativity of E‐prostanoid receptor subtypes in regulating signaling and growth inhibition in human airway smooth muscle. FASEB J. 33, 4780–4789 (2019). www.fasebj.org
... The majority of early studies indicate a beneficial effect 31 . While inhalation of PGE2 or its analogs ameliorates allergen-induced airway inflammation in asthmatic patients and animal models 44,45 , treatment of mice with COX inhibitors augments allergic inflammation and airway hyperresponsiveness 46,47 . Consistent with these findings, mice deficient in either COX-1 or COX-2 were found to develop a much severe disease in OVA-induced asthma models 40,42 . ...
Prostaglandins E2 (PGE2) has been shown to enhance IgE production by B cells in vitro. The physiological and pathological relevance of this phenomenon and the underlying molecular mechanism, however, remain to be elucidated. B cells from wild type and EP2-deficient mice were compared in culture for their responses to PGE2 in terms of IgE class switching and production. Ovalbumin (OVA)-induced asthma models were used to evaluate the impact of EP2-deficiency on IgE responses and the development of asthma. PGE2 promoted IgE class switching, generation of IgE+ cells and secretion of IgE by B cells stimulated with LPS+IL4. These effects were much attenuated as a consequence of EP2 deficiency. Consistent with the in vitro data, EP2-deficient mice showed a markedly suppressed IgE antibody response and developed less pronounced airway inflammation in the OVA-induced asthma model. Mechanistic studies demonstrated that PGE2, in an EP2-depedent manner, enhanced STAT6 activation induced by IL-4, thereby promoting the expression of IgE germline and post switch transcripts and the transcription of activation-induced cytidine deaminase (AID). Collectively, these data support an important regulatory role of the PGE2-EP2-STAT6 signaling pathway in IgE response and allergic diseases.
... DNP-conjugated human serum albumin (DNP-HSA), L-buthionine-S,R-sulfoximine (BSO), glutathione reduced form ethyl ester (GSH-OEt), and diamide were purchased from Sigma-Aldrich. The EP 3 agonist, sulprostone [9,10], prostaglandin E 2 (PGE 2 ), and dimethyl PGE 2 were purchased from Cayman Chemical (Ann Arbor, MI). ONO-DI-004 (an EP 1 agonist) [9][10][11], ONO-AE1-259-01 (an EP 2 agonist) [9,11], ONO-AE-248 (an EP 3 agonist) [9][10][11][12], and ONO-AE1-329 (an EP 4 agonist) [9][10][11] were kindly provided by ONO Pharmaceutical Co., Ltd. ...
... The EP 3 agonist, sulprostone [9,10], prostaglandin E 2 (PGE 2 ), and dimethyl PGE 2 were purchased from Cayman Chemical (Ann Arbor, MI). ONO-DI-004 (an EP 1 agonist) [9][10][11], ONO-AE1-259-01 (an EP 2 agonist) [9,11], ONO-AE-248 (an EP 3 agonist) [9][10][11][12], and ONO-AE1-329 (an EP 4 agonist) [9][10][11] were kindly provided by ONO Pharmaceutical Co., Ltd. (Osaka, Japan). ...
... The EP 3 agonist, sulprostone [9,10], prostaglandin E 2 (PGE 2 ), and dimethyl PGE 2 were purchased from Cayman Chemical (Ann Arbor, MI). ONO-DI-004 (an EP 1 agonist) [9][10][11], ONO-AE1-259-01 (an EP 2 agonist) [9,11], ONO-AE-248 (an EP 3 agonist) [9][10][11][12], and ONO-AE1-329 (an EP 4 agonist) [9][10][11] were kindly provided by ONO Pharmaceutical Co., Ltd. (Osaka, Japan). ...
... Multiple studies have shown that PGE 2 attenuates bronchoconstriction, increases the relaxation of airway smooth muscles and inhibits mast-cell degranulation [26]. PGE 2 activity is expressed not only by direct effect on bronchial smooth muscle relaxation but also as suppression of the inflammatory mediators releasing mainly by eosinophils and mast cells [32]. In AIA diminished level of PGE 2 was found in nasal polyps [15], peripheral blood cells [27] and bronchial fibroblasts [19]. ...
Background: Histamine is used as a direct stimulus to measure airway responsiveness. This short-acting biogenic amine acts mainly on airway smooth muscle receptors causing bronchoconstriction and is used for the airway hyperresponsiveness assessment in asthmatic patients. In aspirin-induced asthma (AIA) special regulatory role of eicosanoids is postulated. The aim of the study was to assess the influence of histamine on a wide profile of eicosanoids measured in exhaled breath condensate (EBC) in AIA patients and asthmatics tolerating aspirin well (ATA). Methods: The study population consisted of seventeen asthmatics. Ten of them were AIA patients. Eicosanoid concentrations in EBC were determined using gas chromatography/mass spectrometry or high-performance liquid chromatography/tandem mass spectrometry. Measurements were performed at baseline and following bronchial histamine challenge. Results: Bronchial reactions were precipitated by histamine in all patients and accompanied only by decrease of leukotriene (LT) C 4 and trans-LTC 4 mean level. The AIA group was characterized by higher levels of cysteinyl leukotrienes, LTC 4 , and prostaglandin (PG) E 2 in EBC at baseline, and decrease in EBC concentration of LTC 4 , trans-LTC 4 and tetranor-PGE-M following histamine challenge. In the ATA group no significant changes in eicosanoids levels after histamine were noticed. Conclusions: AIA patients present different baseline profile of EBC eicosanoids in comparison to patients with ATA. Histamine administered locally during a bronchial challenge test may influence inflammatory mediators and thus trigger indirect effects in the respiratory tract. This response for histamine differentiates two studied phenotypes of asthma; only in the AIA group histamine precipitates alterations of the eicosanoid synthesis in the lungs.
... Recently, several studies showed that the PGE 2 protective actions were mediated in large part by the EP 2 receptors [87, 88]. This protective action of PGE 2 might not only result in a direct effect on airway smooth-muscle relaxation, but also in the inhibition of many inflammatory processes [89]. These data may explain why patients with eosinophilia have normal tests of variable airway obstruction and airway responsiveness and experience chronic cough due to high PGE 2 levels [90]. ...
Eosinophilic bronchitis is a common cause of chronic cough, which like asthma is characterized by sputum eosinophilia, but unlike asthma there is no variable airflow obstruction or airway hyperresponsiveness. Several studies suggest that prostaglandins may play an important role in orchestrating interactions between different cells in several inflammatory diseases such as asthma. PGE(2) is important because of the multiplicity of its effects on immune response in respiratory diseases; however, respiratory system appears to be unique in that PGE(2) has beneficial effects. We described that the difference in airway function observed in patients with eosinophilic bronchitis and asthma could be due to differences in PGE(2) production. PGE(2) present in induced sputum supernatant from NAEB patients decreases BSMC proliferation, probably due to simultaneous stimulation of EP2 and EP4 receptors with inhibitory activity. This protective effect of PGE(2) may not only be the result of a direct action exerted on airway smooth-muscle proliferation but may also be attributable to the other anti-inflammatory actions.
... PGE 2 is a potent smooth muscle relaxant and through the EP 2 receptor can limit constriction of the airways (11). Indeed, administration of this mediator into the airways ameliorates airway hyperresponsiveness (AHR) caused by several bronchoconstrictive agents in humans and animals (12)(13)(14)(15)(16)(17) and attenuates aspirin-induced and exercise-induced bronchoconstriction (18,19). PGE 2 can induce ion secretion and thus alter the composition of the airway surface liquid, facilitating mucociliary clearance (20). ...
... In patients with allergic asthma, inhaled PGE 2 is reported to attenuate both the early-and late-phase response after exposure to Ag (12,13,15,16). PGE 2 has also been shown to limit inflammation in animal models of asthma (14,17,53). Given this, it seemed likely that the heightened inflammation observed in the COX-deficient mice reflected a loss of this protective prostanoid. ...
... Furthermore, previous work in our laboratory has indicated that PGE 2 , through the EP 3 receptor, can promote inflammation by augmenting IgE-mediated mast cell degranulation, and, in some circumstances, PGE 2 alone is sufficient to mediate this response in rodents (61,62). Much of the support for the hypothesis that PGE 2 plays a protective role in the lung, limiting inflammation, comes from studies in which exposure of mice to Ag is accompanied by inhalation of PGE 2 , its stable analog, or a PGE 2 receptor preferring antagonist and agonist (17,53,63). In vitro studies have reinforced this hypothesis, with studies such as those which have shown PGE 2 to be effective in limiting migration of eosinophils and increasing production of IL-10 by dendritic cells and naive T cells (22,63,64). ...
Elevated PGE(2) is a hallmark of most inflammatory lesions. This lipid mediator can induce the cardinal signs of inflammation, and the beneficial actions of nonsteroidal anti-inflammatory drugs are attributed to inhibition of cyclooxygenase (COX)-1 and COX-2, enzymes essential in the biosynthesis of PGE(2) from arachidonic acid. However, both clinical studies and rodent models suggest that, in the asthmatic lung, PGE(2) acts to restrain the immune response and limit physiological change secondary to inflammation. To directly address the role of PGE(2) in the lung, we examined the development of disease in mice lacking microsomal PGE(2) synthase-1 (mPGES1), which converts COX-1/COX-2-derived PGH(2) to PGE(2). We show that mPGES1 determines PGE(2) levels in the naive lung and is required for increases in PGE(2) after OVA-induced allergy. Although loss of either COX-1 or COX-2 increases the disease severity, surprisingly, mPGES1(-/-) mice show reduced inflammation. However, an increase in serum IgE is still observed in the mPGES1(-/-) mice, suggesting that loss of PGE(2) does not impair induction of a Th2 response. Furthermore, mPGES1(-/-) mice expressing a transgenic OVA-specific TCR are also protected, indicating that PGE(2) acts primarily after challenge with inhaled Ag. PGE(2) produced by the lung plays the critical role in this response, as loss of lung mPGES1 is sufficient to protect against disease. Together, this supports a model in which mPGES1-dependent PGE(2) produced by populations of cells native to the lung contributes to the effector phase of some allergic responses.
... Both pro-and anti-inflammatory roles have been proposed in allergic disease. Studies with EP3 gene deficient mice and with EP3 agonists have suggested anti inflammatory actions for this receptor [48], while EP-2 and EP-4 receptor agonist have been proposed to mediate protective actions in ovalbumin induced bronchoconstriction in animal models [49]. On the other hand, PGE 2 has been demonstrated to augment IgE production and histamine release through EP1 and EP3 receptors [50]. ...
Tryptases, the dominant secretory granular proteins from human mast cells, are emerging as important mediators in asthma and allergy. The β- and α- tryptases have highly similar nucleotide sequences and located on the same locus. While the entire population expresses β-tryptase, the α-tryptase gene exhibits copy number variation (CNV). We have studied the association of expression of these allelic variants with asthma or allergic diseases. We have investigated also the potential actions of β- and α-tryptases in vitro and in vivo. We have found that the one alpha tryptase copy allele was significantly associated with lower total serum IgE levels (Z= -2.39, p=0.01) and a tri-allelic architecture with alleles carrying no, one or two copies of the α-tryptase gene was postulated. The addition of βtryptase to epithelial cells induced upregulation of mRNA for IL-8, IL-6 and TNF-α, while α-tryptase on the other hand was without effect in this model. Injection of β-tryptase into the mouse peritoneum induced great accumulation of neutrophils but accumulation of other cell types was less marked. Under the same conditions, injection of α- tryptase induced less neutrophilia but eosinophils, macrophages and mast cells numbers were significantly increased. The actions of β-tryptase seemed be independent of PAR-2 receptors but not the case for α-tryptase, where PAR-2 pathway might take the leads. In conclusion, recombinant α-tryptase may be a stimulus for the recruitment of inflammatory cells and altered cytokine gene expression with effects distinct from those of β-tryptase.
