PGE2 – EP3 Receptor Signaling Involves Rho‐kinase Pathway in Hyperoxia‐Induced Airway Hyperresponsiveness

Abstract

Hyperoxic exposure is associated with airway hyperresponsiveness and it was shown that hyperoxia upregulates synthesis of prostaglandin E2 (PGE2), which induces contraction of airway smooth muscle via EP1 and EP3 receptors. It is not clear through which signaling pathway PGE2 exerts contractile effect on airway smooth muscle under hyperoxic conditions. Therefore, we hypothesized that under hyperoxic condition PGE2 induces contraction of airway smooth muscle via EP3 receptors by activating Rho‐kinase signaling pathway. Tracheal cylinders were obtained from 12 days Wistar rat pups exposed to hyperoxia (≥ 95% O2) or room air for seven days. These cylinders were used to study contractile responses evoked by EP3 agonist (sulprostone, 10−9 – 10−5 M); methacholine (MCh, 10−8 – 10−4 M) in absence or presence of an EP3 antagonist (L‐798106, 10 μM) or Rho‐kinase inhibitors (Y‐27632, 10 μM or fasudil, 10 μM).Both, sulprostone and MCh induced dose‐dependent contractile responses of airway smooth muscle, respectively. The contractile responses were significantly higher in preparations obtained from animals exposed to hyperoxia as compared to those obtained from room air controls. These enhanced contractile responses in hyperoxic tissues were reversed by pre‐incubating tissues with Y‐27632 or fasudil. EP3 antagonist also significantly attenuated contractile responses evoked by sulprostone. The results of this study revealed that PGE2 – EP3 receptor signaling involves Rho‐kinase pathway and we speculate that the use of Rho‐kinase inhibitors or EP3 antagonist could attenuate the contractile effects of PGE2 and this might be an effective therapeutic approach to reverse hyperoxia‐induced airway hyperresponsiveness.Support or Funding InformationSupported by MEST