Rho-kinase inhibitors protect against neonatal hyperoxia-induced airway hyperreactivity in a rat pup model: Role of prostaglandin F.

Background: Oxygen therapy in preterm neonates is associated with airway hyperreactivity. The role of Rho/Rho-kinase smooth muscle signaling in hyperoxia-induced airway hyperreactivity remains understudied. We hypothesized that inhibition of Rho-kinase will attenuate airway hyperreactivity induced by neonatal hyperoxia.

Methods: Newborn rats were raised in hyperoxia (>95% O ) or ambient air (AA) for 7 days. Subgroups were injected with a Rho-kinase inhibitor: Y-27632 (10 mg·kg ·day ) or fasudil (10 mg·kg ·day ), or a FP receptor antagonist - AS604872 (30 mg·kg ·day ). After exposures, tracheal cylinders were prepared for in vitro wire myography. Contraction to methacholine or PGF was measured in the presence or absence of tissue-bath Y-27632, fasudil, or AS604872. Lung PGF levels, Rho-kinase protein level and Rho-kinase 1 activity were measured by ELISA.

Results: Tracheal smooth muscle contraction was significantly greater in hyperoxic compared to AA groups. Both, Y-27632 and fasudil significantly decreased contractility to MCh or PGF in hyperoxic groups versus hyperoxic controls (p < 0.001), but did not alter AA group responses. Inhibition of FP receptors attenuated responses to PGF . Hyperoxia significantly increased lung PGF compared to AA (p < 0.01), but Rho-kinase inhibition did not influence PGF level. Rho-kinase protein level (p < 0.001) and activity (p < 0.01), were increased by hyperoxia, but blockade of FP receptor reduced the Rho-kinase 1 activity (p < 0.05) under hyperoxic condition.

Conclusions: This study demonstrates an active role of Rho/Rho-kinase signaling on hyperoxia-induced airway hyperreactivity. These findings suggest that Rho-kinase inhibitors might serve as an effective therapy for hyperoxia-induced airway hyperreactivity.