Mast cell-derived
prostaglandin D(2) (
PGD(2)) is one of the essential modulators of eosinophilic airway
inflammation in
asthma and
allergic rhinitis. Two
G protein-coupled receptors for
PGD(2),
prostaglandin D(2) receptor (DP) and
chemoattractant receptor-homologous molecule expressed on Th(2) cells (CRTH2), are both expressed on the surface of eosinophils, and CRTH2 has been demonstrated to mediate PGD(2)-induced eosinophil mobilization in vitro. However, it has not yet been determined whether
PGD(2) and its receptors mediate in vivo eosinophil trafficking into the airways or other organs. We demonstrated that intratracheal administration of
PGD(2) in rats pretreated with systemic
interleukin-5 (IL-5) injection induced marked airway
eosinophilia, determined by the differential counts of cells in bronchoalveolar lavage (BAL) fluid and lung histology, within 2 h. Systemic
IL-5 alone significantly increased the number of eosinophils in the peripheral blood but showed no effect on airway
eosinophilia. Three CRTH2-specific agonists (13,14-dihydro-15-keto-PGD(2), 11-deoxy-11-methylene-15-keto-PGD(2), and indomethacin) demonstrated equivalent induction of BAL
eosinophilia to that of
PGD(2), but a DP agonist (
BW 245C [5-(6-carboxyhexyl)-1-(3-cyclohexyl-3-hydroxypropyl)-
hydantoin]) or a
thromboxane A(2)
receptor (TP) agonist ([1S-1alpha,2beta(5Z), 3alpha(1E,3R*),4alpha)]-7-[3-(3-hydroxy-4-(4'-iodophenoxy)-1-butenyl)-7-oxabicyclo-[2.2.1]heptan-2-yl]-5-heptenoic
acid) showed no effect.
PGD(2) 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-[1alpha,2alpha(Z),3alpha,4alpha]]), or a DP-specific antagonist,
BW A868C [3-benzyl-5-(6-carboxyhexyl)-1-(2-cyclohexy-2-hydroxyethylamino)-
hydantoin], did not inhibit the effects of
PGD(2). These results suggest that CRTH2 plays a significant role in the eosinophil trafficking from the bloodstream into the airways in
PGD(2)-related airway
inflammation.