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

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Abstract

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 DP2 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.

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APA

Suto, W., Sakai, H., & Chiba, Y. (2019). 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. Journal of Smooth Muscle Research, 55, 1–13. https://doi.org/10.1540/JSMR.55.1

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