title: Role of hematopoietic prostaglandin D synthase in biphasic nasal obstruction in guinea pig model of experimental allergic rhinitis.
abstract: We investigated the role of hematopoietic prostaglandin D synthase (H-PGDS) in biphasic nasal obstruction in allergic rhinitis using a new specific inhibitor, (N-methoxy-N-methyl)-4-(5-benzoylbenzimidazole-2-yl)-3,5-dimethylpyrrole-2-carboxamide hydrochloride (TAS-204). First, we developed a novel guinea pig model of allergic rhinitis. Guinea pigs sensitized to ovalbumin without adjuvant were challenged with intranasal exposure to ovalbumin once a week. After the 3rd antigen challenge, they exhibited biphasic nasal obstruction. Additionally, analysis of nasal lavage fluid revealed an increase in the level of prostaglandin D(2) in both early and late phases. Treatment with oral TAS-204 for 15 days during the period of antigen challenges suppressed increases in nasal airway resistance in both phases. It is noteworthy that the late phase nasal obstruction was almost completely abrogated by inhibiting H-PGDS alone. Eosinophil infiltration in nasal lavage fluid and nasal hyperresponsiveness to histamine was also reduced by TAS-204 administration. These findings suggest that H-PGDS plays a critical role in the development of allergic rhinitis, especially in the induction of late phase nasal obstruction.
authors.affiliation: Discovery & Development Laboratory 2, Taiho Pharmaceutical Co. Ltd., 3, Ohkubo, Tsukuba, Ibaraki 300-2611, Japan. dai-kaziwara@taiho.co.jp
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kajiwara
authors.forename: Hiroki
authors.initials: H
authors.lastname: Aoyagi
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Shigeno
authors.forename: Michinori
authors.initials: M
authors.lastname: Togawa
authors.forename: Katsunao
authors.initials: K
authors.lastname: Tanaka
authors.forename: Naoki
authors.initials: N
authors.lastname: Inagaki
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Miyoshi
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D015232:Dinoprostone / Q000378:metabolism; D004195:Disease Models, Animal; D004804:Eosinophils / Q000276:immunology; D006168:Guinea Pigs; D006632:Histamine / Q000276:immunology / Q000378:metabolism; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015289:Leukotrienes / Q000378:metabolism; D054834:Lipocalins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D017817:Nasal Lavage Fluid / Q000276:immunology; D009297:Nasal Mucosa / Q000187:drug effects / Q000276:immunology; D015508:Nasal Obstruction / Q000188:drug therapy / Q000201:enzymology* / Q000276:immunology / Q000378:metabolism; D010047:Ovalbumin / Q000276:immunology; D015230:Prostaglandin D2 / Q000096:biosynthesis / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology* / Q000627:therapeutic use; D012220:Rhinitis / Q000188:drug therapy / Q000201:enzymology* / Q000276:immunology / Q000378:metabolism; D013997:Time Factors
chemical_list: C568815:(N-methoxy-N-methyl)-4-(5-benzoylbenzimidazole-2-yl)-3,5-dimethylpyrrole-2-carboxamide hydrochloride; D001562:Benzimidazoles; D015289:Leukotrienes; D054834:Lipocalins; D011758:Pyrroles; D006632:Histamine; D010047:Ovalbumin; D019746:Intramolecular Oxidoreductases; C022466:prostaglandin R2 D-isomerase; D015232:Dinoprostone; D015230:Prostaglandin D2