Sustained exposure to prostaglandin D2 augments the contraction induced by acetylcholine via a DP1 receptor-mediated activation of p38 in bronchial smooth muscle of naive mice.

Abstract

Prostaglandin D₂ (PGD₂), one of the key lipid mediators of allergic airway inflammation, is increased in the airways of asthmatics. However, the role of PGD₂ in the pathogenesis of asthma is not fully understood. In the present study, effects of PGD₂ on smooth muscle contractility of the airways were determined to elucidate its role in the development of airway hyperresponsiveness (AHR). In a murine model of allergic asthma, antigen challenge to the sensitized animals caused a sustained increase in PGD₂ levels in bronchoalveolar lavage (BAL) fluids, indicating that smooth muscle cells of the airways are continually exposed to PGD₂ after the antigen exposure. In bronchial smooth muscles (BSMs) isolated from naive mice, a prolonged incubation with PGD₂ (10^-5 M, for 24 h) induced an augmentation of contraction induced by acetylcholine (ACh): the ACh concentration-response curve was significantly shifted upward by the 24-h incubation with PGD₂. Application of PGD₂ caused phosphorylation of ERK1/2 and p38 in cultured BSM cells: both of the PGD₂-induced events were abolished by laropiprant (a DP₁ receptor antagonist) but not by fevipiprant (a DP₂ receptor antagonist). In addition, the BSM hyperresponsiveness to ACh induced by the 24-h incubation with PGD₂ was significantly inhibited by co-incubation with SB203580 (a p38 inhibitor), whereas U0126 (a ERK1/2 inhibitor) had no effect on it. These findings suggest that prolonged exposure to PGD₂ causes the BSM hyperresponsiveness via the DP₁ receptor-mediated activation of p38. A sustained increase in PGD₂ in the airways might be a cause of the AHR in allergic asthmatics.