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.