A novel antagonist of prostaglandin D<sub>2</sub> blocks the locomotion of eosinophils and basophils

Royer, Julia F.; Schratl, Petra; Carrillo, Juan J.; Jupp, Rachael; Barker, Jane E.; Weyman-Jones, C.; Beri, Raj K.; Sargent, Carol A.; Schmidt, J; Lang‐Loidolt, Doris; Heinemann, Ákos

doi:10.1111/j.1365-2362.2008.01989.x

Cited by 32 publications

(25 citation statements)

References 44 publications

(63 reference statements)

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“…Only a few inflammatory mediators have been described to regulate eosinophil release from the bone marrow, including IL-5, eotaxin and PGD 2 (33,39,40). In the present study we found that PGE 2 via EP2 receptors also controls agonist-induced rapid mobilization of eosinophils from bone marrow.…”

Section: Discussionsupporting

confidence: 66%

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Prostaglandin E2 Inhibits Eosinophil Trafficking through E-Prostanoid 2 Receptors

Sturm

Schratl

Schuligoi

et al. 2008

The Journal of Immunology

105

106

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The accumulation of eosinophils in lung tissue is a hallmark of asthma, and it is believed that eosinophils play a crucial pathogenic role in allergic inflammation. Prostaglandin (PG) E2 exerts anti-inflammatory and bronchoprotective mechanisms in asthma, but the underlying mechanisms have remained unclear. In this study we show that PGE2 potently inhibits the chemotaxis of purified human eosinophils toward eotaxin, PGD2, and C5a. Activated monocytes similarly attenuated eosinophil migration, and this was reversed after pretreatment of the monocytes with a cyclooxygenase inhibitor. The selective E-prostanoid (EP) 2 receptor agonist butaprost mimicked the inhibitory effect of PGE2 on eosinophil migration, whereas an EP2 antagonist completely prevented this effect. Butaprost, and also PGE2, inhibited the C5a-induced degranulation of eosinophils. Moreover, selective kinase inhibitors revealed that the inhibitory effect of PGE2 on eosinophil migration depended upon activation of PI3K and protein kinase C, but not cAMP. In animal models, the EP2 agonist butaprost inhibited the rapid mobilization of eosinophils from bone marrow of the in situ perfused guinea pig hind limb and prevented the allergen-induced bronchial accumulation of eosinophils in OVA-sensitized mice. Immunostaining showed that human eosinophils express EP2 receptors and that EP2 receptor expression in the murine lungs is prominent in airway epithelium and, after allergen challenge, in peribronchial infiltrating leukocytes. In summary, these data show that EP2 receptor agonists potently inhibit eosinophil trafficking and activation and might hence be a useful therapeutic option in eosinophilic diseases.

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Section: Discussionsupporting

confidence: 66%

“…The guinea pig hind limb was perfused as previously described (29,33). The external iliac artery and vein were exposed and the caudal abdominal artery, superficial iliac circumflex artery, and pudendoepigastric trunk along with their satellite veins were ligated.…”

Section: In Situ Perfusion Of the Guinea Pig Hind Limbmentioning

confidence: 99%

Prostaglandin E2 Inhibits Eosinophil Trafficking through E-Prostanoid 2 Receptors

Sturm

Schratl

Schuligoi

et al. 2008

The Journal of Immunology

105

106

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“…To determine which DP was involved in the PGD 2 -mediated induction of HA, we first utilized well described selective pharmacological antagonists directed against either DP1 (MK-0524) (32,33) or DP2 (ramatroban) (30,34). Fibroblasts were untreated or were pretreated with either MK-0524 or ramatroban for 1 h with or without PGD 2 or PGJ 2 .…”

Section: Differential Expression Of Pgd 2 -Induced Hyaluronidase (Hyamentioning

confidence: 99%

Mast Cell-derived Prostaglandin D2 Controls Hyaluronan Synthesis in Human Orbital Fibroblasts via DP1 Activation

Guo

Baglole

O’Loughlin

et al. 2010

Journal of Biological Chemistry

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Thyroid eye disease (TED) is a debilitating disorder characterized by the accumulation of adipocytes and hyaluronan (HA).Production of HA by fibroblasts leads to remarkable increases in tissue volume and to the anterior displacement of the eyes. Prostaglandin D 2 (PGD 2 ), mainly produced by mast cells, promotes orbital fibroblast adipogenesis. The mechanism by which PGD 2 influences orbital fibroblasts and their synthesis of HA is poorly understood. We report here that mast cell-derived PGD 2 is a key factor that promotes HA biosynthesis by orbital fibroblasts. Primary orbital fibroblasts from TED patients were isolated and used to test the effects of PGD 2 , prostaglandin J 2 , as well as prostaglandin D receptor (DP) agonists and antagonists on HA synthesis. The expression of HA synthase (HAS), hyaluronidase, DP1, and DP2 mRNA levels was assessed by PCR. Small interfering RNAs against HAS1 or HAS2 were used to assess the importance

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“…CRTH2 (chemoattractant receptor expressed on Th2 cells) is a G-proteincoupled receptor expressed by Th2 lymphocytes, eosinophils and basophils that mediates chemotaxis and activation of these cells in response to PGD 2 [4]. CRTH2 antagonists inhibit the activation and chemotaxis of lymphocytes, eosinophils and basophils in vitro [2,5], and reduce airway inflammation in animal models of allergic inflammation [6]. These data suggest that inhibition of CRTH2 can suppress allergic inflammation in asthma.…”

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confidence: 97%

Inhibition of the asthmatic allergen challenge response by the CRTH2 antagonist OC000459

Singh

Cadden

Hunter

et al. 2012

European Respiratory Journal

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CRTH2 (chemoattractant receptor expressed on T-helper (Th) type 2 cells) is a Gprotein-coupled receptor expressed by Th2 lymphocytes and eosinophils that mediates prostaglandin (PG)D 2 -driven chemotaxis. We studied the efficacy of the oral CRTH2 antagonist OC000459 in steroid-naïve asthmatic patients.A randomised, double-blind, placebo-controlled, two-way crossover study of 16 days' treatment with OC000459 (200 mg twice daily) on the late (LAR) and early (EAR) asthmatic responses to bronchial allergen challenge was conducted, with 16 subjects completing the study.There was a 25.4% (95% CI 5.1-45.6%) reduction in the LAR area under the curve (AUC) for change in forced expiratory volume in 1 s with OC000459 compared with placebo (p50.018) but no effect on the EAR. Sputum eosinophil counts at 1 day post-allergen challenge were lower after OC000459 treatment (p50.002). PGD 2 -induced blood eosinophil shape change ex vivo was assessed at day 7 (n57). The AUC of eosinophil shift for OC000459 was lower than placebo; the mean difference was -33.6% (95% CI -66.8--0.4%; p50.048).OC000459 treatment inhibited LAR and post-allergen increase in sputum eosinophils. This CRTH2 antagonist appears to inhibit allergic inflammation in asthma.

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A novel antagonist of prostaglandin D₂ blocks the locomotion of eosinophils and basophils

Abstract: AZ11665362 is a potent CRTH2 antagonist that is capable of blocking the migration of eosinophils and basophils, and the rapid mobilization of eosinophils from bone marrow. AZ11665362 might hence be useful for the treatment of allergic diseases.

Cited by 32 publications

References 44 publications

Prostaglandin E2 Inhibits Eosinophil Trafficking through E-Prostanoid 2 Receptors

Prostaglandin E2 Inhibits Eosinophil Trafficking through E-Prostanoid 2 Receptors

Mast Cell-derived Prostaglandin D2 Controls Hyaluronan Synthesis in Human Orbital Fibroblasts via DP1 Activation

Inhibition of the asthmatic allergen challenge response by the CRTH2 antagonist OC000459

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A novel antagonist of prostaglandin D2 blocks the locomotion of eosinophils and basophils

Abstract: AZ11665362 is a potent CRTH2 antagonist that is capable of blocking the migration of eosinophils and basophils, and the rapid mobilization of eosinophils from bone marrow. AZ11665362 might hence be useful for the treatment of allergic diseases.

Cited by 32 publications

References 44 publications

Prostaglandin E2 Inhibits Eosinophil Trafficking through E-Prostanoid 2 Receptors

Prostaglandin E2 Inhibits Eosinophil Trafficking through E-Prostanoid 2 Receptors

Mast Cell-derived Prostaglandin D2 Controls Hyaluronan Synthesis in Human Orbital Fibroblasts via DP1 Activation

Inhibition of the asthmatic allergen challenge response by the CRTH2 antagonist OC000459

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A novel antagonist of prostaglandin D₂ blocks the locomotion of eosinophils and basophils