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Abstract
Prostaglandin D2 (PGD2) is one of the key lipid mediators of allergic airway inflammation, including bronchial asthma. However, the role of PGD2 in the pathogenesis of asthma is not fully understood. In the present study, the effect of PGD2 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 PGD2 (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), PGD2 markedly augmented the contraction induced by the high K+ depolarization. The PGD2-induced augmentation of contraction was significantly inhibited both by 10−6 M laropiprant (a selective DP1 antagonist) and 10−7 M Y-27632 (a Rho-kinase inhibitor), indicating that a DP1 receptor-mediated activation of Rho-kinase is involved in the PGD2-induced BSM hyperresponsiveness. Indeed, the GTP-RhoA pull-down assay revealed an increase in active form of RhoA in the PGD2-treated mouse BSMs. On the other hand, in the high K+-depolarized cultured human BSM cells, PGD2 caused no further increase in cytosolic Ca2+ concentration. These findings suggest that PGD2 causes RhoA/Rho-kinase-mediated Ca2+ sensitization of BSM contraction to augment its contractility. Increased PGD2 level in the airways might be a cause of the AHR in asthma.
Highlights
Augmented airway responsiveness to a wide variety of nonspecific stimuli, called airway hyperresponsiveness (AHR), is a common feature of allergic asthma
These findings suggest that Prostaglandin D2 (PGD2) acts on DP1 receptors to cause RhoA/Rho-kinase-mediated Ca2+ sensitization of contraction in bronchial smooth muscles (BSMs)
In the high K+-depolarized cultured human BSM cells (hBSMCs), PGD2 caused no further increase in cytosolic Ca2+ concentration (Figure 4)
Summary
Augmented airway responsiveness to a wide variety of nonspecific stimuli, called airway hyperresponsiveness (AHR), is a common feature of allergic asthma. The current study for the first time, to our knowledge, demonstrated that PGD2 activates the RhoA/Rho-kinase signaling to induce Ca2+ sensitization of contraction in the BSMs. Previous studies, including ours, demonstrated that muscarinic receptor stimulation of airway smooth muscle caused both an increase in cytosolic Ca2+ concentration and an activation of RhoA/Rho-kinase signaling, resulting in the contraction [17,23,24]. The current study revealed that PGD2 did not have the ability to increase cytosolic Ca2+ level in the BSMs (Figure 4) This may be a reason that PGD2 did not cause any contraction from the baseline tension: the cytosolic Ca2+ level at the baseline tension might not have been enough to induce BSM contraction even if the RhoA/Rho-kinase signaling was activated. Increased PGD2 level in the airways might be one of the causes of the enhanced airway responsiveness to nonspecific stimuli, one of the characteristic features of bronchial asthma
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