Cyclooxygenase-2/prostaglandin D2/CRTH2 pathway mediates double-stranded RNA-induced enhancement of allergic airway inflammation.
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.
Shiraishi
Yoshiki
Y
Division of Pulmonary Medicine, Department of Medicine, Shinanomachi Research Park, Keio University School of Medicine, Tokyo, Japan.
Asano
Koichiro
K
Niimi
Kyoko
K
Fukunaga
Koichi
K
Wakaki
Misa
M
Kagyo
Junko
J
Takihara
Takahisa
T
Ueda
Soichiro
S
Nakajima
Takeshi
T
Oguma
Tsuyoshi
T
Suzuki
Yusuke
Y
Shiomi
Tetsuya
T
Sayama
Koichi
K
Kagawa
Shizuko
S
Ikeda
Eiji
E
Hirai
Hiroyuki
H
Nagata
Kinya
K
Nakamura
Masataka
M
Miyasho
Taku
T
Ishizaka
Akitoshi
A
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
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