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INFLAMMATION AND IMMUNOPHARMACOLOGY
Division of Pulmonary Medicine, Department of Medicine (Y.S., K.A., T.N., T.O., Y.S., T.S., K.S., K.N., M.W., J.K., K.Y., A.I.), Department of Pathology (E.I.), Pfizer-Keio Research Laboratories, Shinanomachi Research Park (Y.S., K.A., T.N., K.N., M.W., J.K., K.Y., A.I.), Keio University School of Medicine, Tokyo, Japan; and R&D Center, BML Laboratories, Saitama, Japan (H.H.)
Received September 21, 2004; accepted November 2, 2004.
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Abstract |
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,2
(5Z), 3(1E,3R*),4)]-7-[3-(3-hydroxy-4-(4'-iodophenoxy)-1-butenyl)-7-oxabicyclo-[2.2.1]heptan-2-yl]-5-heptenoic acid) showed no effect. PGD2 or CRTH2 agonist-induced BAL eosinophilia was almost completely inhibited by pretreatment with a CRTH2/TP antagonist, ramatroban [BAY-u3405; (+)-(3R)-3-(4-fluorobenzenesulfonamido)-1,2,3,4-tetra-hydrocarbazole-9-propionic acid], whereas a TP-specific antagonist, SQ29,548 (5-heptenoic, 7-[3-[[2-[(phenylamino)carbonyl]hydrazino]methyl]-7-oxabicyclo[2.2.1]-hept-2-yl]-[1S-[1,2(Z),3,4]]), or a DP-specific antagonist, BW A868C [3-benzyl-5-(6-carboxyhexyl)-1-(2-cyclohexy-2-hydroxyethylamino)-hydantoin], did not inhibit the effects of PGD2. These results suggest that CRTH2 plays a significant role in the eosinophil trafficking from the bloodstream into the airways in PGD2-related airway inflammation.
; Bochenek et al., 2004). PGD2 is released during the early and late asthmatic responses following allergen exposure in patients with asthma (O'Sullivan et al., 1998; Bochenek et al., 2004) and has been demonstrated to be a potent chemoattractant for eosinophils in vitro (Hirai et al., 2001; Monneret et al., 2001) and in vivo (Emery et al., 1989; Woodward et al., 1990). We previously reported that cyclooxygenase-2 inhibitors, which abolished PGD2 synthesis in the lungs of allergen-sensitized and exposed guinea pigs, attenuated eosinophil accumulation in the airways (Oguma et al., 2002). Other researchers reported that overexpression of PGD2 synthase or inhalation of aerosolized PGD2 enhanced eosinophilic and lymphocytic airway inflammation in mice following allergen exposure (Fujitani et al., 2002; Honda et al., 2003).
The bioactivity of PGD2 is mediated by two G protein-coupled receptors, DP and CRTH2, both of which are expressed on the surface of eosinophils (Gervais et al., 2001). DP receptor expression in the lungs is up-regulated in allergic inflammation in mice (Matsuoka et al., 2000; Fujitani et al., 2002), and disruption of the DP gene abolished the accumulation of eosinophils and lymphocytes in a murine model of asthma (Matsuoka et al., 2000). DP receptor antagonists, such as S-5751 [(Z)-7-[(1R,2R,3S,5S)-2-(5-hydroxybenzo[b]-thiophen-3-ylcarbonylamino)-10-norpinan-3-yl]hept-5-enoic acid] and BW A868C, also reduced the number of eosinophils in allergen-induced upper and lower airway inflammation in guinea pigs (Arimura et al., 2001). However, a DP-specific agonist, BW 245C, did not replicate the effects of PGD2 on eosinophil mobilization in vitro (Hirai et al., 2001; Monneret et al., 2001) and in vivo (Woodward et al., 1990), suggesting that PGD2-induced eosinophil chemotaxis is mediated by a receptor other than DP.
A second PGD2 receptor, CRTH2, which has been identified as a molecule preferentially expressed on Th2 lymphocytes, eosinophils, and basophils, has been demonstrated to transduce direct chemotactic or chemokinetic activity of PGD2 for eosinophils (Nagata et al., 1999a,b; Hirai et al., 2001; Monneret et al., 2001). A CRTH2-specific agonist, 13,14-dihydro-15-keto (DK)-PGD2, enhances eosinophil migration and activation as potently as PGD2 in vitro (Gervais et al., 2001; Hirai et al., 2001; Monneret et al., 2001). Therefore, it is likely that CRTH2, at least partially, mediates PGD2-dependent eosinophil migration to inflammatory sites. However, there is no evidence suggesting that CRTH2-mediated signals are important in vivo for the accumulation of eosinophils in local organs such as the airways. We thus examined the role of the CRTH2 receptor in PGD2-induced airway eosinophilic inflammation.
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Materials and Methods |
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Either rat interleukin-5 (IL-5; 0.2 ng/kg; R&D Systems, Minneapolis, MN) or PBS was injected intravenously 1 h prior to administration of prostanoid receptor agonists. The agonists, including PGD2, two CRTH2-specific agonists, DK-PGD2 and 11-deoxy-11-methylene-15-keto-PGD2 (MK-PGD2), a DP-specific agonist, BW 245C, and a thromboxane A2 receptor (TP)-specific agonist, I-BOP, were purchased from Cayman Chemical (Ann Arbor, MI), and indomethacin was purchased from Nacalai Tesque (Kyoto, Japan). Each reagent was dissolved at a concentration of 0.01 to 1 mM in 100 µl of PBS (pH 7.4) containing ethanol (PGD2, BW 245C, I-BOP, indomethacin) or methylacetate (DK-PGD2, MK-PGD2). Since the eosinophil count in bronchoalveolar lavage fluid was equivalent regardless of the type of vehicle (PBS alone, 0.14 ± 0.11 x 104 cells/ml, n = 3; PBS with ethanol, 0.27 ± 0.11 x 104 cells/ml, n = 3; PBS with methylacetate, 0.47 ± 0.05 x 104 cells/ml, n = 4), the combined data from all vehicle-treated rats were used in the analysis. Tracheostomy was performed under anesthetization with intraperitoneal ketamine (100 mg/kg) and xylazine (10 mg/kg), and the agonists or vehicles were sprayed intratracheally using a MicroSprayer Aerosolizer (model IA-1C with FMJ-250 high-pressure syringe; Penn-Century, Philadelphia, PA). After the neck incision was sutured, the rats were allowed to awaken and were then returned to the cages.
In some experiments, a CRTH2/TP antagonist, ramatroban [BAY-u3405; (+)-(3R)-3-(4-fluorobenzenesulfonamido)-1,2,3,4-tetra-hydrocarbazole-9-propionic acid; 3–10 mg/kg in 0.5% methyl cellulose p.o.], a DP antagonist, BW A868C (1 mg/kg in normal saline containing ethanol i.v., Cayman Chemical), or a TP antagonist, SQ29,548 (2.5 mg/kg in normal saline containing ethanol i.v., Cayman Chemical) was administered 2 h prior to administration of agonists. A previous study demonstrated that 1 to 10 mg/kg ramatroban administered orally in male rats resulted in the peak plasma concentration of 0.16 to 4.6 mg/l (385–11,000 nM) (Boberg et al., 1997), which is far above the concentration of ramatroban to block PGD2 binding to rat CRTH2 in vitro (IC50; 45 nM) (Shichijo et al., 2003).
The experimental protocol was reviewed and approved by the Laboratory Animal Care and Use Committee of Keio University School of Medicine.
Bronchoalveolar Lavage (BAL). The rats were sacrificed by injection of an overdose of pentobarbital at 2, 8, and 24 h after the agonists were administrated. The trachea was cannulated, and the lungs were lavaged three times with 8 ml of PBS (pH 7.4).
Total cells in BAL fluid were counted using a hemocytometer, and the cell types were determined on Diff-Quik-stained cytospin slides prepared with Auto Smear CF12D (Sakura Fineteck, Tokyo, Japan). Four hundred cells in duplicate slides were counted in a blinded fashion.
Histological Examination. After BAL was performed, the chest was opened, and the pulmonary circulation was thoroughly flushed with PBS using a peristaltic pump (flow rate 5 ml/min) through a catheter inserted in the pulmonary artery. The lungs were removed and fixed in 4% (w/v) neutralized buffered paraformaldehyde (pH 7.4) at 4°C. Lung tissues were paraffin embedded, and the sliced sections were stained with Giemsa stain. A semiquantitative scoring system was used to grade the degree of eosinophil accumulation. Each bronchus or vessel was graded from 0 (no eosinophils) to 4 (abundant eosinophilic infiltration) in a blinded manner. Five bronchi and vessels were evaluated in each side of the lungs, and the lung score (0–40) represents the sum of the scores of both lungs. The lungs were examined independently by three investigators, and the scores were averaged.
Peripheral Blood Cell Count. In an independent experiment, the rats received intravenous injection of IL-5 (0.2 ng/kg) or PBS 1 h prior to intratracheal administration of PGD2 (100 nmol/animal) or vehicle. A peripheral blood sample was collected every h after administration of IL-5 to determine the kinetics of blood eosinophils. The blood sample (10 µl), 0.05% (w/v) phloxine B solution (40 µl), and 0.05% (w/v) methylene blue solution (50 µl) were mixed gently for 15 min, and the number of total leukocytes and eosinophils was determined.
Statistical Analysis. All values are expressed as mean and S.E.M. Comparisons were performed by one-way analysis of variance followed by Bonferroni/Dunn procedure as a post hoc test. p < 0.05 was considered statistically significant (STATVIEW 1992-98; SAS Institute, Cary, NC).
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The biological activities of PGD2 are mediated through multiple eicosanoid receptors on the cell surface, including CRTH2, DP, and TP (Hamid-Bloomfield et al., 1990; Boie et al., 1995; Gervais et al., 2001; Hirai et al., 2001; Monneret et al., 2001). We thus examined the specific receptor essential for PGD2-induced eosinophil accumulation in the lungs. Two PGD2 derivatives specific for CRTH2 (DK-PGD2, MK-PGD2), at a dose of 100 nmol/animal, demonstrated an equivalent effect on eosinophil accumulation in BAL fluid to that of 100 nmol/animal PGD2 (Fig. 4). Furthermore, indomethacin, which has a significantly different structure from PGD2 or its derivatives but exhibits similar agonistic activity for CRTH2 (Hirai et al., 2002), also showed potent eosinophil chemotactic activity in vivo (Fig. 4). In contrast, a DP agonist, BW 245C (100 nmol/animal), or a TP agonist, I-BOP (100 nmol/animal), demonstrated little effect on eosinophil accumulation in BAL fluid (Fig. 4). PGD2-induced BAL eosinophilia was significantly inhibited by pretreatment with a CRTH2/TP antagonist, ramatroban, in a dose-dependent manner (3–10 mg/kg, p < 0.05–0.01, Fig. 5A). Ramatroban (10 mg/kg) also inhibited the accumulation of eosinophils induced by CRTH2 agonists (DK-PGD2, MK-PGD2, indomethacin, p < 0.01, Fig. 5B). In contrast, a TP-specific antagonist, SQ29,548, or a DP antagonist, BW A868C, did not inhibit the effects of PGD2 on BAL eosinophilia (Fig. 5A).
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Histological examination demonstrated that intratracheal administration of PGD2 in rats pretreated with IL-5 resulted in significant eosinophil accumulation in the perivascular and peribronchial spaces (p < 0.01, Figs. 6 and 7). Neither IL-5 nor PGD2 alone could induce accumulation of eosinophils around bronchi or blood vessels. Treatment with ramatroban (10 mg/kg) almost completely abolished PGD2-induced eosinophil accumulation in the lungs (data not shown).
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; Hirai et al., 2001; Monneret et al., 2001). Recent studies have demonstrated that an intravenous injection of a CRTH2 agonist such as 
12-PGJ2 or DK-PGD2 induced eosinophil recruitment from the bone marrow into the bloodstream (Heinemann et al., 2003; Shichijo et al., 2003). The present study clearly demonstrated that CRTH2 is also essential for PGD2-induced recruitment of eosinophils from the bloodstream into organs.
Since PGD2 can activate multiple receptors including CRTH2, DP, and TP (Hamid-Bloomfield et al., 1990; Boie et al., 1995; Gervais et al., 2001; Hirai et al., 2001; Monneret et al., 2001), we used a combination of receptor-specific agonists and antagonists to confirm the role of CRTH2. As CRTH2 agonists, we used DK-PGD2, a well established CRTH2-specific agonist in vitro, and MK-PGD2, a stable analog of DK-PGD2, although their specificity in vivo is not known. We thus performed additional experiments using another compound, indomethacin. Indomethacin has a significantly different structure from PGD2 or its derivatives such as DK-PGD2 and MK-PGD2 but has been demonstrated to exhibit potent agonistic activity for CRTH2 (Hirai et al., 2002). All the CRTH2 agonists including indomethacin demonstrated equivalent activity to induce pulmonary eosinophilia to that of PGD2, whereas a DP-specific agonist, BW 245C, or a TP-specific agonist, I-BOP, did not have such activity. Furthermore, a CRTH2/TP dual antagonist, ramatroban (3–10 mg/kg), abolished the effects of PGD2 and all the CRTH2-specific agonists on BAL eosinophilia, but neither a DP antagonist, BW A868C, nor a TP antagonist, SQ29,548, did. We thus concluded that PGD2 in the airway lumen can attract eosinophils through the activation of CRTH2.
Previous studies demonstrated that an intravenous injection of PGD2 or a CRTH2 agonist can induce peripheral blood eosinophilia (Heinemann et al., 2003; Shichijo et al., 2003). In the present study, however, intratracheally administered PGD2, at a dose that induced significant BAL eosinophilia, exhibited no effect on the number of blood eosinophils. The discrepancy is possibly due to the difference in dose of agonists required to induce eosinophilia in peripheral blood and in local organs. Shichijo et al. (2003) reported that at least 100 µg of DK-PGD2 per rat (3 x 10–7 mol/rat) was necessary to induce peripheral blood eosinophilia when administered intravenously. In the present study, PGD2 and CRTH2 agonists administered intratracheally induced significant eosinophilia in BAL at a lower dose of 10–9 to 10–7 mol/rat.
Intratracheally administered PGD2 alone could not induce pulmonary eosinophilia as previously reported (Fujitani et al., 2002; Honda et al., 2003). We thus examined the synergistic activity of PGD2 and systemic IL-5. Such an interaction between eosinophil chemoattractants and IL-5 in eosinophil trafficking to peripheral organs has been thoroughly examined for eotaxin, a well established eosinophilic CC chemokine. Eotaxin-induced accumulation of eosinophils in the skin or lungs of guinea pigs or mice is amplified by either intravenous administration of IL-5 or overexpression of the IL-5 gene, but is completely abolished in IL-5-deficient mice (Collins et al., 1995; Rothenberg et al., 1996; Mould et al., 1997). Peripheral blood eosinophilia alone induced by adoptive transfer of eosinophils could not mimic the effects of systemic IL-5, suggesting that priming of circulating eosinophils by IL-5 is essential for eotaxin-induced tissue eosinophilia. In contrast, IL-5 has been shown to desensitize eosinophils to PGD2 by down-regulating the expression of CRTH2 (Hamada et al., 2004). Similar phenomenon has been observed in vivo; eosinophils isolated from IL-5 transgenic mice cannot bind to PGD2 (Hirai et al., 2003). Further study is required to determine the interaction of PGD2 and IL-5 during the induction of pulmonary eosinophilia.
Fukuyama et al. (2000) previously reported that intratracheally administered human eotaxin-induced airway eosinophilia in guinea pigs. The magnitude of airway eosinophilia induced by eotaxin (2–200 nmol/animals) was almost equivalent to that induced by PGD2 (100 nmol/animals) in the present study, but more persistent. Increased number of eosinophils in BAL fluid was observed within 6 h and persisted for 7 days in the eotaxin-injected guinea pigs, whereas PGD2-induced airway eosinophilia disappeared within 8 h in our model. However, sustained PGD2 release during the early and late phase of allergic inflammation, which has been observed in the airways exposed to an allergen in animal models (Fujitani et al., 2002; Oguma et al., 2002) and in atopic subjects (O'Sullivan et al., 1998; Bochenek et al., 2004), may result in prolonged airway eosinophilia. This is supported by the fact that a CRTH2/TP antagonist, ramatroban, effectively suppressed the airway eosinophil accumulation in sensitized guinea pigs even at 24 h after the final allergen exposure (Nagai et al., 1995). There may be an alternative pathway for PGD2 to induce eosinophil accumulation in the late phase of allergic inflammation, which was not examined in the present study. In a murine model of asthma, an inhalation of aerosolized PGD2 induced the expression of macrophage-derived chemokine (MDC, CCL22) through an unidentified PGD2 receptor on bronchial epithelial cells and recruited Th2 lymphocytes into the airway (Honda et al., 2003). PGD2 may then enhance the production of eosinophilic cytokines such as IL-4, IL-5, and IL-13 from activated Th2 lymphocytes via CRTH2 receptor (Tanaka et al., 2004).
In conclusion, the present study demonstrated that CRTH2 receptor activation by PGD2 released at the site of inflammation is essential for the pathogenesis of eosinophilic airway inflammation, suggesting that PGD2 synthase inhibitors or CRTH2 antagonists can be useful to control allergic airway diseases such as asthma and allergic rhinitis.
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ABBREVIATIONS: PGD2, prostaglandin D2; BW 245C, 5-(6-carboxyhexyl)-1-(3-cyclohexyl-3-hydroxypropyl)-hydantoin; DK-PGD2, 13,14-dihydro-15-keto PGD2; IL-5, interleukin-5; PBS, phosphate-buffered saline; MK-PGD2, 11-deoxy-11-methylene-15-keto PGD2; TP, thromboxane A2 receptor; I-BOP, [1S-1,2(5Z),3(1E,3R*),4)]-7-[3-(3-hydroxy-4-(4'-iodophenoxy)-1-butenyl)-7-oxabicyclo-[2.2.1]heptan-2-yl]-5-heptenoic acid; BAY-u3405, (+)-(3R)-3-(4-fluorobenzenesulfonamido)-1,2,3,4-tetra-hydrocarbazole-9-propionic acid; BW A868C, 3-benzyl-5-(6-carboxyhexyl)-1-(2-cyclohexy-2-hydro-xyethylamino)-hydantoin; SQ29,548, 5-heptenoic, 7-[3-[[2-[(phenylamino)carbonyl]hydrazino]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-[1S-[1,2(Z),3,4]]; BAL, bronchoalveolar lavage; DP, prostaglandin D2 receptor; CRTH2, chemoattractant receptor-homologous molecule expressed on Th2 cells; S-5751, (Z)-7-[(1R,2R,3S,5S)-2-(5-hydroxybenzo[b]thiophen-3-ylcarbonylamino)-10-norpinan-3-yl]hept-5-enoic acid.
Address correspondence to: Dr. Koichiro Asano, Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. E-mail: ko-asano{at}qa2.so-net.ne.jp
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 J. M. Mathiesen, A. Christopoulos, T. Ulven, J. F. Royer, M. Campillo, A. Heinemann, L. Pardo, and E. Kostenis On the Mechanism of Interaction of Potent Surmountable and Insurmountable Antagonists with the Prostaglandin D2 Receptor CRTH2 Mol. Pharmacol., April 1, 2006; 69(4): 1441 - 1453. [Abstract] [Full Text] [PDF]
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L. Xue, S. L. Gyles, F. R. Wettey, L. Gazi, E. Townsend, M. G. Hunter, and R. Pettipher Prostaglandin D2 Causes Preferential Induction of Proinflammatory Th2 Cytokine Production through an Action on Chemoattractant Receptor-Like Molecule Expressed on Th2 Cells J. Immunol., November 15, 2005; 175(10): 6531 - 6536. [Abstract] [Full Text] [PDF]
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 A. N. Hata, T. P. Lybrand, and R. M. Breyer Identification of Determinants of Ligand Binding Affinity and Selectivity in the Prostaglandin D2 Receptor CRTH2 J. Biol. Chem., September 16, 2005; 280(37): 32442 - 32451. [Abstract] [Full Text] [PDF]
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