Sustained exposure to prostaglandin D(2) augments the contraction induced by acetylcholine via a DP(1) receptor-mediated activation of p38 in bronchial smooth muscle of naive mice

Prostaglandin D(2) (PGD(2)), one of the key lipid mediators of allergic airway inflammation, is increased in the airways of asthmatics. However, the role of PGD(2) in the pathogenesis of asthma is not fully understood. In the present study, effects of PGD(2) 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 PGD(2) levels in bronchoalveolar lavage (BAL) fluids, indicating that smooth muscle cells of the airways are continually exposed to PGD(2) after the antigen exposure. In bronchial smooth muscles (BSMs) isolated from naive mice, a prolonged incubation with PGD(2) (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 PGD(2). Application of PGD(2) caused phosphorylation of ERK1/2 and p38 in cultured BSM cells: both of the PGD(2)-induced events were abolished by laropiprant (a DP(1) receptor antagonist) but not by fevipiprant (a DP(2) receptor antagonist). In addition, the BSM hyperresponsiveness to ACh induced by the 24-h incubation with PGD(2) 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 PGD(2) causes the BSM hyperresponsiveness via the DP(1) receptor-mediated activation of p38. A sustained increase in PGD(2) in the airways might be a cause of the AHR in allergic asthmatics.