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Respiratory Research
Published in: Respiratory Research 1/2007

Open Access 01-12-2007 | Research

Antagonism of the prostaglandin D2 receptor CRTH2 attenuates asthma pathology in mouse eosinophilic airway inflammation

Authors: Lena Uller, Jesper Mosolff Mathiesen, Lisa Alenmyr, Magnus Korsgren, Trond Ulven, Thomas Högberg, Gunnar Andersson, Carl GA Persson, Evi Kostenis

Published in: Respiratory Research | Issue 1/2007

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Abstract

Background

Mast cell-derived prostaglandin D2 (PGD2), may contribute to eosinophilic inflammation and mucus production in allergic asthma. Chemoattractant receptor homologous molecule expressed on TH2 cells (CRTH2), a high affinity receptor for prostaglandin D2, mediates trafficking of TH2-cells, mast cells, and eosinophils to inflammatory sites, and has recently attracted interest as target for treatment of allergic airway diseases. The present study involving mice explores the specificity of CRTH2 antagonism of TM30089, which is structurally closely related to the dual TP/CRTH2 antagonist ramatroban, and compares the ability of ramatroban and TM30089 to inhibit asthma-like pathology.

Methods

Affinity for and antagonistic potency of TM30089 on many mouse receptors including thromboxane A2 receptor mTP, CRTH2 receptor, and selected anaphylatoxin and chemokines receptors were determined in recombinant expression systems in vitro. In vivo effects of TM30089 and ramatroban on tissue eosinophilia and mucus cell histopathology were examined in a mouse asthma model.

Results

TM30089, displayed high selectivity for and antagonistic potency on mouse CRTH2 but lacked affinity to TP and many other receptors including the related anaphylatoxin C3a and C5a receptors, selected chemokine receptors and the cyclooxygenase isoforms 1 and 2 which are all recognized players in allergic diseases. Furthermore, TM30089 and ramatroban, the latter used as a reference herein, similarly inhibited asthma pathology in vivo by reducing peribronchial eosinophilia and mucus cell hyperplasia.

Conclusion

This is the first report to demonstrate anti-allergic efficacy in vivo of a highly selective small molecule CRTH2 antagonist. Our data suggest that CRTH2 antagonism alone is effective in mouse allergic airway inflammation even to the extent that this mechanism can explain the efficacy of ramatroban.
Literature
1.
Lewis RA, Soter NA, Diamond PT, Austen KF, Oates JA, Roberts LJ 2nd: Prostaglandin D2 generation after activation of rat and human mast cells with anti-IgE. J Immunol 1982,129(4):1627–1631.PubMed
2.
Moore ML, Peebles RS Jr.: Update on the role of prostaglandins in allergic lung inflammation: Separating friends from foes, harder than you might think. J Allergy Clin Immunol 2006,117(5):1036–1039.CrossRefPubMed
3.
Luster AD, Tager AM: T-cell trafficking in asthma: lipid mediators grease the way. Nat Rev Immunol 2004,4(9):711–724.CrossRefPubMed
4.
Hata AN, Breyer RM: Pharmacology and signaling of prostaglandin receptors: multiple roles in inflammation and immune modulation. Pharmacol Ther 2004,103(2):147–166.CrossRefPubMed
5.
Fujishima H, Fukagawa K, Okada N, Takano Y, Tsubota K, Hirai H, Nagata K, Matsumoto K, Saito H: Prostaglandin D2 induces chemotaxis in eosinophils via its receptor CRTH2 and eosinophils may cause severe ocular inflammation in patients with allergic conjunctivitis. Cornea 2005,24(8 Suppl):S66-S70.CrossRefPubMed
6.
Boie Y, Sawyer N, Slipetz DM, Metters KM, Abramovitz M: Molecular cloning and characterization of the human prostanoid DP receptor. J Biol Chem 1995,270(32):18910–18916.CrossRefPubMed
7.
Hirai H, Tanaka K, Yoshie O, Ogawa K, Kenmotsu K, Takamori Y, Ichimasa M, Sugamura K, Nakamura M, Takano S, Nagata K: Prostaglandin D2 selectively induces chemotaxis in T helper type 2 cells, eosinophils, and basophils via seven-transmembrane receptor CRTH2. J Exp Med 2001,193(2):255–261.CrossRefPubMedPubMedCentral
8.
Underwood DC, Muccitelli RM, Luttmann MA, Hay DW, Torphy TJ, Wasserman MA: Differential antagonism of airway contractile responses to prostaglandin (PG)D2 and 9 alpha, 11 beta-PGF2 by atropine, SK&F 88046 and SQ 29,548 in the guinea pig. J Pharmacol Exp Ther 1994,268(1):304–310.PubMed
9.
Matsuoka T, Hirata M, Tanaka H, Takahashi Y, Murata T, Kabashima K, Sugimoto Y, Kobayashi T, Ushikubi F, Aze Y, Eguchi N, Urade Y, Yoshida N, Kimura K, Mizoguchi A, Honda Y, Nagai H, Narumiya S: Prostaglandin D2 as a mediator of allergic asthma. Science 2000,287(5460):2013–2017.CrossRefPubMed
10.
Till S, Dickason R, Huston D, Humbert M, Robinson D, Larche M, Durham S, Kay AB, Corrigan C: IL-5 secretion by allergen-stimulated CD4+ T cells in primary culture: relationship to expression of allergic disease. J Allergy Clin Immunol 1997,99(4):563–569.CrossRefPubMed
11.
Humbles AA, Lloyd CM, McMillan SJ, Friend DS, Xanthou G, McKenna EE, Ghiran S, Gerard NP, Yu C, Orkin SH, Gerard C: A critical role for eosinophils in allergic airways remodeling. Science 2004,305(5691):1776–1779.CrossRefPubMed
12.
Lee JJ, Dimina D, Macias MP, Ochkur SI, McGarry MP, O'Neill KR, Protheroe C, Pero R, Nguyen T, Cormier SA, Lenkiewicz E, Colbert D, Rinaldi L, Ackerman SJ, Irvin CG, Lee NA: Defining a link with asthma in mice congenitally deficient in eosinophils. Science 2004,305(5691):1773–1776.CrossRefPubMed
13.
14.
Prussin C, Metcalfe DD: 5. IgE, mast cells, basophils, and eosinophils. J Allergy Clin Immunol 2006,117(2 Suppl Mini-Primer):S450–6.CrossRefPubMed
15.
Marone G, Triggiani M, de Paulis A: Mast cells and basophils: friends as well as foes in bronchial asthma? Trends Immunol 2005,26(1):25–31.CrossRefPubMed
16.
Yoshimura-Uchiyama C, Iikura M, Yamaguchi M, Nagase H, Ishii A, Matsushima K, Yamamoto K, Shichijo M, Bacon KB, Hirai K: Differential modulation of human basophil functions through prostaglandin D2 receptors DP and chemoattractant receptor-homologous molecule expressed on Th2 cells/DP2. Clin Exp Allergy 2004,34(8):1283–1290.CrossRefPubMed
17.
Heinemann A, Schuligoi R, Sabroe I, Hartnell A, Peskar BA: Delta 12-prostaglandin J2, a plasma metabolite of prostaglandin D2, causes eosinophil mobilization from the bone marrow and primes eosinophils for chemotaxis. J Immunol 2003,170(9):4752–4758.CrossRefPubMed
18.
Spik I, Brenuchon C, Angeli V, Staumont D, Fleury S, Capron M, Trottein F, Dombrowicz D: Activation of the prostaglandin D2 receptor DP2/CRTH2 increases allergic inflammation in mouse. J Immunol 2005,174(6):3703–3708.CrossRefPubMed
19.
Shichijo M, Sugimoto H, Nagao K, Inbe H, Encinas JA, Takeshita K, Bacon KB, Gantner F: Chemoattractant receptor-homologous molecule expressed on Th2 cells activation in vivo increases blood leukocyte counts and its blockade abrogates 13,14-dihydro-15-keto-prostaglandin D2-induced eosinophilia in rats. J Pharmacol Exp Ther 2003,307(2):518–525.CrossRefPubMed
20.
Shiraishi Y, Asano K, Nakajima T, Oguma T, Suzuki Y, Shiomi T, Sayama K, Niimi K, Wakaki M, Kagyo J, Ikeda E, Hirai H, Yamaguchi K, Ishizaka A: Prostaglandin D2-induced eosinophilic airway inflammation is mediated by CRTH2 receptor. J Pharmacol Exp Ther 2005,312(3):954–960.CrossRefPubMed
21.
Almishri W, Cossette C, Rokach J, Martin JG, Hamid Q, Powell WS: Effects of prostaglandin D2, 15-deoxy-Delta12,14-prostaglandin J2, and selective DP1 and DP2 receptor agonists on pulmonary infiltration of eosinophils in Brown Norway rats. J Pharmacol Exp Ther 2005,313(1):64–69.CrossRefPubMed
22.
Chevalier E, Stock J, Fisher T, Dupont M, Fric M, Fargeau H, Leport M, Soler S, Fabien S, Pruniaux MP, Fink M, Bertrand CP, McNeish J, Li B: Cutting Edge: Chemoattractant Receptor-Homologous Molecule Expressed on TH2 Cells Plays a Restricting Role on IL-5 Production and Eosinophil Recruitment. J Immunol 2005,175(4):2056–2060.CrossRefPubMed
23.
Satoh T, Moroi R, Aritake K, Urade Y, Kanai Y, Sumi K, Yokozeki H, Hirai H, Nagata K, Hara T, Utsuyama M, Hirokawa K, Sugamura K, Nishioka K, Nakamura M: Prostaglandin D2 plays an essential role in chronic allergic inflammation of the skin via CRTH2 receptor. J Immunol 2006,177(4):2621–2629.CrossRefPubMed
24.
Gonzalo J, Qiu Y, Coyle AJ, Hodge MR: CRTH2(DP2) and not the DP1 receptor mediate allergen induced mucus production and airway hyperresponsiveness. Am J Respir Crit Care Med 2005,163(5):A811.
25.
Sugimoto H, Shichijo M, Iino T, Manabe Y, Watanabe A, Shimazaki M, Gantner F, Bacon KB: An orally bioavailable small molecule antagonist of CRTH2, ramatroban (BAY u3405), inhibits prostaglandin D2-induced eosinophil migration in vitro. J Pharmacol Exp Ther 2003,305(1):347–352.CrossRefPubMed
26.
Ulven T, Kostenis E: Minor structural modifications convert the dual TP/CRTH2 antagonist ramatroban into a highly selective and potent CRTH2 antagonist. J Med Chem 2005,48(4):897–900.CrossRefPubMed
27.
Mathiesen JM, Christopoulos A, Ulven T, Royer JF, Campillo M, Heinemann A, Pardo L, Kostenis E: On the mechanism of interaction of potent surmountable and insurmountable antagonists with the prostaglandin D2 receptor CRTH2. Mol Pharmacol 2006,69(4):1441–1453.CrossRefPubMed
28.
Brandish PE, Hill LA, Zheng W, Scolnick EM: Scintillation proximity assay of inositol phosphates in cell extracts: high-throughput measurement of G-protein-coupled receptor activation. Anal Biochem 2003,313(2):311–318.CrossRefPubMed
29.
Kostenis E, Martini L, Ellis J, Waldhoer M, Heydorn A, Rosenkilde MM, Norregaard PK, Jorgensen R, Whistler JL, Milligan G: A highly conserved glycine within linker I and the extreme C terminus of G protein alpha subunits interact cooperatively in switching G protein-coupled receptor-to-effector specificity. J Pharmacol Exp Ther 2005,313(1):78–87.CrossRefPubMed
30.
(http://​www.​cerep.​fr/​Cerep/​Users/​pages/​ProductsServices​/​InVitro.​asp).: .
31.
Korsgren M, Erjefalt JS, Korsgren O, Sundler F, Persson CG: Allergic eosinophil-rich inflammation develops in lungs and airways of B cell-deficient mice. J Exp Med 1997,185(5):885–892.CrossRefPubMedPubMedCentral
32.
Uller L, Lloyd CM, Rydell-Tormanen K, Persson CG, Erjefalt JS: Effects of steroid treatment on lung CC chemokines, apoptosis and transepithelial cell clearance during development and resolution of allergic airway inflammation. Clin Exp Allergy 2006,36(1):111–121.CrossRefPubMedPubMedCentral
33.
Ten RM, Pease LR, McKean DJ, Bell MP, Gleich GJ: Molecular cloning of the human eosinophil peroxidase. Evidence for the existence of a peroxidase multigene family. J Exp Med 1989,169(5):1757–1769.CrossRefPubMed
34.
Uller L, Lloyd CM, Rydell-Tormanen K, Persson CG, Erjefalt JS: Resolution of airway disease: removal of inflammatory cells through apoptosis, egression or both? Trends Pharmacol Sci 2006,27(9):461–466.CrossRefPubMed
35.
Hata AN, Lybrand TP, Marnett LJ, Breyer RM: Structural determinants of arylacetic acid nonsteroidal anti-inflammatory drugs necessary for binding and activation of the prostaglandin D2 receptor CRTH2. Mol Pharmacol 2005,67(3):640–647.CrossRefPubMed
36.
Peebles RS Jr., Hashimoto K, Morrow JD, Dworski R, Collins RD, Hashimoto Y, Christman JW, Kang KH, Jarzecka K, Furlong J, Mitchell DB, Talati M, Graham BS, Sheller JR: Selective cyclooxygenase-1 and -2 inhibitors each increase allergic inflammation and airway hyperresponsiveness in mice. Am J Respir Crit Care Med 2002,165(8):1154–1160.CrossRefPubMed
37.
Gavett SH, Madison SL, Chulada PC, Scarborough PE, Qu W, Boyle JE, Tiano HF, Lee CA, Langenbach R, Roggli VL, Zeldin DC: Allergic lung responses are increased in prostaglandin H synthase-deficient mice. J Clin Invest 1999,104(6):721–732.CrossRefPubMedPubMedCentral
38.
Persson CG, Erjefalt JS, Korsgren M, Sundler F: The mouse trap. Trends Pharmacol Sci 1997,18(12):465–467.CrossRefPubMed
39.
Uller L, Persson CG, Kallstrom L, Erjefalt JS: Lung tissue eosinophils may be cleared through luminal entry rather than apoptosis: effects of steroid treatment. Am J Respir Crit Care Med 2001,164(10 Pt 1):1948–1956.CrossRefPubMed
40.
Gervais FG, Cruz RP, Chateauneuf A, Gale S, Sawyer N, Nantel F, Metters KM, O'Neill G P: Selective modulation of chemokinesis, degranulation, and apoptosis in eosinophils through the PGD2 receptors CRTH2 and DP. J Allergy Clin Immunol 2001,108(6):982–988.CrossRefPubMed
41.
Monneret G, Gravel S, Diamond M, Rokach J, Powell WS: Prostaglandin D2 is a potent chemoattractant for human eosinophils that acts via a novel DP receptor. Blood 2001,98(6):1942–1948.CrossRefPubMed
42.
Bohm E, Sturm GJ, Weiglhofer I, Sandig H, Shichijo M, McNamee A, Pease JE, Kollroser M, Peskar BA, Heinemann A: 11-Dehydro-thromboxane B2, a stable thromboxane metabolite, is a full agonist of chemoattractant receptor-homologous molecule expressed on TH2 cells (CRTH2) in human eosinophils and basophils. J Biol Chem 2004,279(9):7663–7670.CrossRefPubMed
43.
Johnston SL, Bardin PG, Harrison J, Ritter W, Joubert JR, Holgate ST: The effects of an oral thromboxane TP receptor antagonist BAY u 3405, on prostaglandin D2- and histamine-induced bronchoconstriction in asthma, and relationship to plasma drug concentrations. Br J Clin Pharmacol 1992,34(5):402–408.CrossRefPubMedPubMedCentral
44.
Nagai H, Takeda H, Yamaguchi S, Tanaka H, Matsuo A, Inagaki N: The effect of a thromboxane A2 receptor antagonist BAY-u-3405 on experimental allergic reactions. Prostaglandins 1995,50(2):75–87.CrossRefPubMed
45.
Aizawa H, Shigyo M, Nogami H, Hirose T, Hara N: BAY u3405, a thromboxane A2 antagonist, reduces bronchial hyperresponsiveness in asthmatics. Chest 1996,109(2):338–342.CrossRefPubMed
46.
Narita S, Asakura K, Kataura A: Effects of thromboxane A2 receptor antagonist (Bay u 3405) on nasal symptoms after antigen challenge in sensitized guinea pigs. Int Arch Allergy Immunol 1996,109(2):161–166.CrossRefPubMed
47.
Terada N, Yamakoshi T, Hasegawa M, Tanikawa H, Maesako K, Ishikawa K, Konno A: The effect of ramatroban (BAY u 3405), a thromboxane A2 receptor antagonist, on nasal cavity volume and minimum cross-sectional area and nasal mucosal hemodynamics after nasal mucosal allergen challenge in patients with perennial allergic rhinitis. Acta Otolaryngol Suppl 1998, 537:32–37.CrossRefPubMed
48.
Dogne JM, de Leval X, Benoit P, Delarge J, Masereel B: Thromboxane A2 inhibition: therapeutic potential in bronchial asthma. Am J Respir Med 2002,1(1):11–17.CrossRefPubMed
49.
Kayasuga R, Iba Y, Hossen MA, Watanabe T, Kamei C: The role of chemical mediators in eosinophil infiltration in allergic rhinitis in mice. Int Immunopharmacol 2003,3(4):469–473.CrossRefPubMed
50.
Honda K, Arima M, Cheng G, Taki S, Hirata H, Eda F, Fukushima F, Yamaguchi B, Hatano M, Tokuhisa T, Fukuda T: Prostaglandin D2 reinforces Th2 type inflammatory responses of airways to low-dose antigen through bronchial expression of macrophage-derived chemokine. J Exp Med 2003,198(4):533–543.CrossRefPubMedPubMedCentral
51.
Ishizuka T, Kawakami M, Hidaka T, Matsuki Y, Takamizawa M, Suzuki K, Kurita A, Nakamura H: Stimulation with thromboxane A2 (TXA2) receptor agonist enhances ICAM-1, VCAM-1 or ELAM-1 expression by human vascular endothelial cells. Clin Exp Immunol 1998,112(3):464–470.CrossRefPubMedPubMedCentral
52.
53.
Ward C, Walters H: Airway wall remodelling: the influence of corticosteroids. Curr Opin Allergy Clin Immunol 2005,5(1):43–48.CrossRefPubMed
54.
Sandig H, Andrew D, Barnes AA, Sabroe I, Pease J: 9alpha,11beta-PGF2 and its stereoisomer PGF2alpha are novel agonists of the chemoattractant receptor, CRTH2. FEBS Lett 2006,580(2):373–379.CrossRefPubMed
Metadata
Title
Antagonism of the prostaglandin D2 receptor CRTH2 attenuates asthma pathology in mouse eosinophilic airway inflammation
Authors
Lena Uller
Jesper Mosolff Mathiesen
Lisa Alenmyr
Magnus Korsgren
Trond Ulven
Thomas Högberg
Gunnar Andersson
Carl GA Persson
Evi Kostenis
Publication date
01-12-2007
Publisher
BioMed Central
Published in
Respiratory Research / Issue 1/2007
Electronic ISSN: 1465-993X
DOI
https://doi.org/10.1186/1465-9921-8-16

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