Prostaglandin D(2) Induces Ca(2+) Sensitization of Contraction without Affecting Cytosolic Ca(2+) Level in Bronchial Smooth Muscle

Prostaglandin D(2) (PGD(2)) is one of the key lipid mediators of allergic airway inflammation, including bronchial asthma. However, the role of PGD(2) in the pathogenesis of asthma is not fully understood. In the present study, the effect of PGD(2) on smooth muscle contractility of the airways was determined to elucidate its role in the development of airway hyperresponsiveness (AHR). In isolated bronchial smooth muscles (BSMs) of naive mice, application of PGD(2) (10(−9)–10(−5) M) had no effect on the baseline tension. However, when the tissues were precontracted partially with 30 mM K(+) (in the presence of 10(−6) M atropine), PGD(2) markedly augmented the contraction induced by the high K(+) depolarization. The PGD(2)-induced augmentation of contraction was significantly inhibited both by 10(−6) M laropiprant (a selective DP(1) antagonist) and 10(−7) M Y-27632 (a Rho-kinase inhibitor), indicating that a DP(1) receptor-mediated activation of Rho-kinase is involved in the PGD(2)-induced BSM hyperresponsiveness. Indeed, the GTP-RhoA pull-down assay revealed an increase in active form of RhoA in the PGD(2)-treated mouse BSMs. On the other hand, in the high K(+)-depolarized cultured human BSM cells, PGD(2) caused no further increase in cytosolic Ca(2+) concentration. These findings suggest that PGD(2) causes RhoA/Rho-kinase-mediated Ca(2+) sensitization of BSM contraction to augment its contractility. Increased PGD(2) level in the airways might be a cause of the AHR in asthma.