PGD2 metabolism in plasma: Kinetics and relationship with bioactivity on DP1 and CRTH2 receptors

Schuligoi, Rufina; Schmidt, Ronald; Geißlinger, Gerd; Kollroser, Manfred; Peskar, Bernhard A.; Heinemann, Ákos

doi:10.1016/j.bcp.2007.03.023

Cited by 64 publications

(62 citation statements)

References 24 publications

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“…The biological effects of PGD 2 are mediated by two G protein-coupled receptors, DP 1 and DP 2 (23). Expression of DP 1 and DP 2 receptors has been identified in central and peripheral neurons (7,17,22). DP 1 receptor activation leads to G s protein-mediated increases in intracellular cAMP, while DP 2 receptor activation leads to G i protein-mediated decreases in intracellular cAMP.…”

Section: Discussionmentioning

confidence: 99%

Role of prostaglandin D₂ in mast cell activation-induced sensitization of esophageal vagal afferents

Zhang

Grabauskas

Joo

et al. 2013

American Journal of Physiology-Gastrointestinal and Liver Physi

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S. Role of prostaglandin D 2 in mast cell activationinduced sensitization of esophageal vagal afferents. Am J Physiol Gastrointest Liver Physiol 304: G908 -G916, 2013. First published March 7, 2013 doi:10.1152/ajpgi.00448.2012.-Sensitization of esophageal afferents plays an important role in esophageal nociception, but the mechanism is less clear. Our previous studies demonstrated that mast cell (MC) activation releases the preformed mediators histamine and tryptase, which play important roles in sensitization of esophageal vagal nociceptive C fibers. PGD 2 is a lipid mediator released by activated MCs. Whether PGD2 plays a role in this sensitization process has yet to be determined. Expression of the PGD 2 DP1 and DP2 receptors in nodose ganglion neurons was determined by immunofluorescence staining, Western blotting, and RT-PCR. Extracellular recordings were performed in ex vivo esophageal-vagal preparations. Action potentials evoked by esophageal distension were compared before and after perfusion of PGD 2, DP1 and DP2 receptor agonists, and MC activation, with or without pretreatment with antagonists. The effect of PGD2 on 1,1=-dioctadecyl-3,3,3=,3=-tetramethylindocarbocyanine perchlorate (DiI)-labeled esophageal nodose neurons was determined by patch-clamp recording. Our results demonstrate that DP1 and DP2 receptor mRNA and protein were expressed mainly in small-and medium-diameter neurons in nodose ganglia. PGD2 significantly increased esophageal distension-evoked action potential discharges in esophageal nodose C fibers. The DP1 receptor agonist BW 245C mimicked this effect. PGD2 directly sensitized DiI-labeled esophageal nodose neurons by decreasing the action potential threshold. Pretreatment with the DP1 receptor antagonist BW A868C significantly inhibited PGD2 perfusion-or MC activation-induced increases in esophageal distensionevoked action potential discharges in esophageal nodose C fibers. In conclusion, PGD2 plays an important role in MC activation-induced sensitization of esophageal nodose C fibers. This adds a novel mechanism of visceral afferent sensitization.

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Section: Discussionmentioning

confidence: 99%

Role of prostaglandin D₂ in mast cell activation-induced sensitization of esophageal vagal afferents

Zhang

Grabauskas

Joo

et al. 2013

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…Platelet aggregation was recorded at 37°C with constant stirring (1000 rpm) in an Aggrecorder-II (KDK Corp, Kyoto, Japan) as described. [25][26][27] Platelet aggregation was measured as the increase in light transmission for 5 minutes, starting with the addition of ADP (2.5 to 20 mol/L) or collagen (1.25 to 10 g/mL) as proaggregatory stimulus. CaCl 2 at a final concentration of 1 mmol/L was added 2 minutes before ADP or collagen.…”

Section: Platelet Aggregationmentioning

confidence: 99%

The Prostaglandin E ₂ Receptor EP4 Is Expressed by Human Platelets and Potently Inhibits Platelet Aggregation and Thrombus Formation

Philipose

Kónya

Sreckovic

et al. 2010

ATVB

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Objective-Low concentrations of prostaglandin (PG) E 2 enhance platelet aggregation, whereas high concentrations inhibit it. The effects of PGE 2 are mediated through 4 G protein-coupled receptors, termed E-type prostaglindin (EP) receptor EP1, EP2, EP3, and EP4. The platelet-stimulating effect of PGE 2 has been suggested to involve EP3 receptors. Here we analyzed the receptor usage relating to the inhibitory effect of PGE 2 . Methods and Results-Using flow cytometry, we found that human platelets expressed EP4 receptor protein. A selective EP4 agonist (ONO AE1-329) potently inhibited the platelet aggregation as induced by ADP or collagen. This effect could be completely reversed by an EP4 antagonist, but not by PGI 2 , PGD 2 , and thromboxane receptor antagonists or cyclooxygenase inhibition. Moreover, an EP4 antagonist enhanced the PGE 2 -induced stimulation of platelet aggregation, indicating a physiological antiaggregatory activity of EP4 receptors. The inhibitory effect of the EP4 agonist was accompanied by attenuated Ca 2ϩ flux, inhibition of glycoprotein IIb/IIIa, and downregulation of P-selectin. Most importantly, adhesion of platelets to fibrinogen under flow and in vitro thrombus formation were effectively prevented by the EP4 agonist. In this respect, the EP4 agonist synergized with acetylsalicylic acid. Key Words: aspirin Ⅲ pharmacology Ⅲ platelet receptor blockers Ⅲ platelets Ⅲ prostacyclin Ⅲ prostaglandins Ⅲ thromboxanes S ubjects with increased platelet reactivity are at increased prospective risk for coronary events and death. A number of pathophysiological states, such as atherosclerosis, diabetes, and metabolic syndrome, are associated with increased platelet reactivity and thrombogenic potential. Under inflammatory conditions, the synthesis of prostanoids in endothelial cells and smooth muscle cells is highly increased. Predominantly, the biosynthesis of prostaglandin (PG) E 2 is enhanced in vascular smooth muscle cells 1 and macrophages 2,3 by inflammatory mediators. Conclusion-TheseProstanoids are involved in hemostasis by differentially influencing platelet aggregation. Although thromboxane (TX) A 2 , produced in platelets, and PGH 2 , released untransformed from activated/dysfunctional endothelium, are potent stimulators of platelet aggregation, 4 PGI 2 and PGD 2 are known to inhibit platelet aggregation. 5 PGE 2 shows a biphasic, concentration-dependent effect on platelet aggregation. Although high concentrations inhibit platelet aggregation, lower concentrations enhance it. 6 -11 PGE 2 binds and activates 4 G protein-coupled receptors, EP1, EP2, EP3, and EP4. Each of these receptors has a distinct pharmacological signature and intracellular signal transduction. 12,13,14 Stimulation of the EP3 receptors results in elevation of free intracellular Ca 2ϩ levels, whereas stimulation of the EP2 and EP4 receptors usually increases intracellular cAMP levels through activation of G s protein, 12 resulting in a decrease of intracellular Ca 2ϩ levels. Human platelets contain mRNA for EP1 receptors,...

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“…Assay buffer was prepared from Dulbeccomodified PBS (with 0.9 mmol/L Ca 21 and 0.5 mmol/L Mg 21 ; Invitrogen, Vienna, Austria), 0.1% BSA, 10 mmol/L HEPES, and 10 mmol/L glucose, pH 7.4 [49]. Fixative solution was made by adding 9 mL of distilled water and 30 mL of FACS-Flow to 1 mL of CellFix [50]. Drugs were dissolved in distilled water, ethanol, or dimethyl sulfoxide and further diluted in assay buffer to have a final concentration of the solvents of o0.1%.…”

Section: Chemicalsmentioning

confidence: 99%

Interaction of eosinophils with endothelial cells is modulated by prostaglandin EP4 receptors

et al. 2011

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Eosinophil extravasation across the endothelium is a key feature of allergic inflammation. Here, we investigated the role of PGE 2 and its receptor, E-type prostanoid receptor (EP)-4, in the regulation of eosinophil interaction with human pulmonary microvascular endothelial cells. PGE 2 and the EP4 receptor agonist ONO AE1-329 significantly reduced eotaxininduced eosinophil adhesion to fibronectin, and formation of filamentous actin and gelsolin-rich adhesive structures. These inhibitory effects were reversed by a selective EP4 receptor antagonist, ONO AE3-208. PGE 2 and the EP4 agonist prevented the activation and cell-surface clustering of b2 integrins, and L-selectin shedding of eosinophils. Under physiological flow conditions, eosinophils that were treated with the EP4 agonist showed reduced adhesion to endothelial monolayers upon stimulation with eotaxin, as well as after TNF-a-induced activation of the endothelial cells. Selective activation of EP1, EP2, and EP3 receptors did not alter eosinophil adhesion to endothelial cells, whereas the EP4 antagonist prevented PGE 2 from decreasing eosinophil adhesion. Finally, eosinophil transmigration across thrombin-and TNF-a-activated endothelial cells was effectively reduced by the EP4 agonist. These data suggest that PGE 2 -EP4 signaling might be protective against allergic responses by inhibiting the interaction of eosinophils with the endothelium and might hence be a useful therapeutic option for controlling inappropriate eosinophil infiltration.Keywords: Adhesion . Endothelium . Eosinophils . Migration . Prostaglandins Supporting Information available online IntroductionEosinophil granulocytes are important effector cells in allergic inflammation and are recruited to the tissue by chemotactic signals [1][2][3][4][5]. The infiltrating eosinophils release several toxic and proinflammatory mediators which induce epithelial injury, airway hyper-responsiveness, and airway remodeling [6][7][8]. Therefore, eosinophils are regarded as potential therapeutic targets in allergic diseases and asthma [9].Prostaglandins (PGs) play diverse roles in inflammation, depending on the cellular context, the type of PG being released, and the differential expression of PG receptors [10,11]. While PGD 2, which is the predominant PG formed in mast cells, exerts proinflammatory effects by regulating the recruitment of eosino- Eur. J. Immunol. 2011. 41: 2379-2389 DOI 10.1002 Leukocyte signaling 2379 phils, basophils, and Th2 lymphocytes to the sites of allergic inflammation [12], PGE 2 seems to attenuate inflammatory responses and reduce tissue injury in airways [13]. PGE 2 was found to exert bronchoprotective effects in patients with asthma [14]. In rats, the ovalbumin-induced early and late phase airway responses were inhibited by intratracheally administered PGE 2 [15]. The activity of PGE 2 is mediated by four subtypes of E-type prostanoid receptors (EP), EP1, EP2, EP3, and EP4 [16]. These G protein-coupled receptors have distinct biological imprints depending on their affinity with...

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PGD2 metabolism in plasma: Kinetics and relationship with bioactivity on DP1 and CRTH2 receptors

Cited by 64 publications

References 24 publications

Role of prostaglandin D₂ in mast cell activation-induced sensitization of esophageal vagal afferents

Role of prostaglandin D₂ in mast cell activation-induced sensitization of esophageal vagal afferents

The Prostaglandin E ₂ Receptor EP4 Is Expressed by Human Platelets and Potently Inhibits Platelet Aggregation and Thrombus Formation

Interaction of eosinophils with endothelial cells is modulated by prostaglandin EP4 receptors

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PGD2 metabolism in plasma: Kinetics and relationship with bioactivity on DP1 and CRTH2 receptors

Cited by 64 publications

References 24 publications

Role of prostaglandin D2 in mast cell activation-induced sensitization of esophageal vagal afferents

Role of prostaglandin D2 in mast cell activation-induced sensitization of esophageal vagal afferents

The Prostaglandin E 2 Receptor EP4 Is Expressed by Human Platelets and Potently Inhibits Platelet Aggregation and Thrombus Formation

Interaction of eosinophils with endothelial cells is modulated by prostaglandin EP4 receptors

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Role of prostaglandin D₂ in mast cell activation-induced sensitization of esophageal vagal afferents

Role of prostaglandin D₂ in mast cell activation-induced sensitization of esophageal vagal afferents

The Prostaglandin E ₂ Receptor EP4 Is Expressed by Human Platelets and Potently Inhibits Platelet Aggregation and Thrombus Formation