title: Cyclooxygenase-2/prostaglandin D2/CRTH2 pathway mediates double-stranded RNA-induced enhancement of allergic airway inflammation.
abstract: Respiratory RNA viruses responsible for the common cold often worsen airway inflammation and bronchial responsiveness, two characteristic features of human asthma. We studied the effects of dsRNA, a nucleotide synthesized during viral replication, on airway inflammation and bronchial hyperresponsiveness in murine models of asthma. Intratracheal instillation of poly I:C, a synthetic dsRNA, increased the airway eosinophilia and enhanced bronchial hyperresponsiveness to methacholine in OVA-sensitized, exposed rats. These changes were associated with induction of cyclooxygenase-2 (COX-2) expression and COX-2-dependent PGD2 synthesis in the lungs, particularly in alveolar macrophages. The direct intratracheal instillation of PGD2 enhanced the eosinophilic inflammation in OVA-exposed animals, whereas pretreatment with a dual antagonist against the PGD2 receptor-(CRTH2) and the thromboxane A2 receptor, but not with a thromboxane A2 receptor-specific antagonist, nearly completely eliminated the dsRNA-induced worsening of airway inflammation and bronchial hyperresponsiveness. CRTH2-deficient mice had the same degree of allergen-induced airway eosinophilia as wild-type mice, but they did not exhibit a dsRNA-induced increase in eosinophil accumulation. Our data demonstrate that COX-2-dependent production of PGD2 followed by eosinophil recruitment into the airways via a CRTH2 receptor are the major pathogenetic factors responsible for the dsRNA-induced enhancement of airway inflammation and responsiveness.
authors: Division of Pulmonary Medicine, Department of Medicine, Shinanomachi Research Park, Keio University School of Medicine, Tokyo, Japan.
authors: Yoshiki
authors: Y
authors: Shiraishi
authors: Koichiro
authors: K
authors: Asano
authors: Kyoko
authors: K
authors: Niimi
authors: Koichi
authors: K
authors: Fukunaga
authors: Misa
authors: M
authors: Wakaki
authors: Junko
authors: J
authors: Kagyo
authors: Takahisa
authors: T
authors: Takihara
authors: Soichiro
authors: S
authors: Ueda
authors: Takeshi
authors: T
authors: Nakajima
authors: Tsuyoshi
authors: T
authors: Oguma
authors: Yusuke
authors: Y
authors: Suzuki
authors: Tetsuya
authors: T
authors: Shiomi
authors: Koichi
authors: K
authors: Sayama
authors: Shizuko
authors: S
authors: Kagawa
authors: Eiji
authors: E
authors: Ikeda
authors: Hiroyuki
authors: H
authors: Hirai
authors: Kinya
authors: K
authors: Nagata
authors: Masataka
authors: M
authors: Nakamura
authors: Taku
authors: T
authors: Miyasho
authors: Akitoshi
authors: A
authors: Ishizaka
mesh_terms: D000818:Animals; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D004804:Eosinophils / Q000276:immunology; D016676:Macrophages, Alveolar / Q000276:immunology; D051379:Mice; D008817:Mice, Mutant Strains; D011070:Poly I-C / Q000276:immunology; D015230:Prostaglandin D2 / Q000378:metabolism*; D012330:RNA, Double-Stranded / Q000276:immunology*; D051381:Rats; D011919:Rats, Inbred Strains; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D011982:Receptors, Prostaglandin / Q000235:genetics / Q000378:metabolism*; D012130:Respiratory Hypersensitivity / Q000276:immunology* / Q000473:pathology
chemical_list: D012330:RNA, Double-Stranded; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat; D011070:Poly I-C; D015230:Prostaglandin D2; C036293:prostaglandin D2 receptor