Inhalation of the Rho-kinase inhibitor Y-27632 reverses allergen-induced airway hyperresponsiveness after the early and late asthmatic reaction

Dedmer Schaafsma,I Sophie T Bos,Johan Zaagsma,Herman Meurs,Annet B Zuidhof

doi:10.1186/1465-9921-7-121

Dedmer Schaafsma, I Sophie T Bos + Show 3 more

Open Access

https://doi.org/10.1186/1465-9921-7-121

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Journal: Respiratory research	Publication Date: Sep 26, 2006
Citations: 64	License type: cc-by

Affiliation: University of Groningen

Abstract

BackgroundIn guinea pigs, we have previously demonstrated that the contribution of Rho-kinase to airway responsiveness in vivo and ex vivo is enhanced after active sensitization with ovalbumin (OA). Using conscious, unrestrained OA-sensitized guina pigs, we now investigated the role of Rho-kinase in the development of airway hyperresponsiveness (AHR) after the allergen-induced early (EAR) and late asthmatic reaction (LAR) in vivo.MethodsHistamine and PGF2α PC100-values (provocation concentrations causing 100% increase in pleural pressure) were assessed before OA-challenge (basal airway responsiveness) and after the OA-induced EAR (5 h after challenge) and LAR (23 h after challenge). Thirty minutes later, saline or the specific Rho-kinase inhibitor Y-27632 (5 mM, nebulizer concentration) were nebulized, after which PC100-values were reassessed.ResultsIn contrast to saline, Y-27632 inhalation significantly decreased the basal responsiveness toward histamine and PGF2α before OA-challenge, as indicated by increased PC100 -values. Both after the allergen-induced EAR and LAR, AHR to histamine and PGF2α was present, which was reversed by Y-27632 inhalation. Moreover, there was an increased effectiveness of Y-27632 to reduce airway responsiveness to histamine and PGF2α after the EAR and LAR as compared to pre-challenge conditions. Saline inhalations did not affect histamine or PGF2α PC100-values at all. Interestingly, under all conditions Y-27632 was significantly more effective in reducing airway responsiveness to PGF2α as compared to histamine. Also, there was a clear tendency (P = 0.08) to a more pronounced degree of AHR after the EAR for PGF2α than for histamine.ConclusionThe results indicate that inhalation of the Rho-kinase inhibitor Y-27632 causes a considerable bronchoprotection to both histamine and PGF2α. Moreover, the results are indicative of a differential involvement of Rho-kinase in the agonist-induced airway obstruction in vivo. Increased Rho-kinase activity contributes to the allergen-induced AHR to histamine and PGF2α after both the EAR and the LAR, which is effectively reversed by inhalation of Y-27632. Therefore, Rho-kinase can be considered as a potential pharmacotherapeutical target in allergic asthma.

Highlights

In guinea pigs, we have previously demonstrated that the contribution of Rho-kinase to airway responsiveness in vivo and ex vivo is enhanced after active sensitization with ovalbumin (OA)
In vivo, using permanently instrumented, unanaesthetized, unrestrained guinea pigs, we found that the contribution of Rho-kinase to airway responsiveness to histamine was augmented after active allergic sensitization [9]
We demonstrate that there is a differential role of Rho-kinase in the agonistinduced airway obstructions and that inhalation of the specific Rho-kinase inhibitorY-27632 results in a strong bronchoprotection to both agonists the results indicate that increased Rho-kinase activity contributes to allergen-induced airway hyperresponsiveness (AHR) to histamine and prostaglandin F2α (PGF2α) after both the EAR and the late asthmatic reaction (LAR), which is effectively reversed by Y27632 inhalation

Summary

Introduction

We have previously demonstrated that the contribution of Rho-kinase to airway responsiveness in vivo and ex vivo is enhanced after active sensitization with ovalbumin (OA). Using conscious, unrestrained OA-sensitized guina pigs, we investigated the role of Rho-kinase in the development of airway hyperresponsiveness (AHR) after the allergen-induced early (EAR) and late asthmatic reaction (LAR) in vivo. Agonist-induced smooth muscle contraction is largely governed by phosphorylation of the 20kDa myosin light chain (MLC20) [5]. MLC20 phosphorylation is initiated by an increase in intracellular Ca2+-concentration ([Ca2+]i) and subsequent formation of Ca2+-calmodulin, resulting in activation of myosin light chain kinase (MLCK). Activated Rho-kinase interferes with the equilibrium of MLCK and MLCP activities by phosphorylating and thereby inactivating the myosin binding subunit of MLCP. This leads to an augmentation of MLC20 phosphorylation and an elevated level of contraction at an established [Ca2+]i [7,8]

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