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* Division of Pulmonary Medicine, Department of Medicine,
Department of Pathology, and
Shinanomachi Research Park, Keio University School of Medicine, Tokyo, Japan;
Department of Advanced Medicine and Development, BML, Inc., Saitama, Japan;
¶ Human Gene Sciences Center, Tokyo Medical and Dental University, Tokyo, Japan; and
|| Laboratory of Veterinary Biochemistry, Rakuno Gakuen University, Ebetsu, Japan
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.
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1 This work was supported by Grants-in-Aid from the Japanese Ministries of Education, Culture, Sports, Science and Technology and of Health, Labour and Welfare, the Japan Society for the Promotion of Science, and a Keio Gijuku Academic Development Fund.
2 Address correspondence and reprint requests 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 address: ko-asano{at}qa2.so-net.ne.jp
3 Abbreviations used in this paper: COX, cyclooxygenase; SPF, specific pathogen free; VAF, virus Ab free; BN, Brown Norway; BAL, bronchoalveolar lavage; hPGDS, hemopoietic PGD synthase; poly I:C, polyinosine-polycytidylic acid; TP, thromboxane A2 receptor.
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