Research

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 , Annet B Zuidhof , Johan Zaagsma and Herman Meurs

Department of Molecular Pharmacology, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands

author email corresponding author email

Respiratory Research 2006, 7:121doi:10.1186/1465-9921-7-121

Published:	26 September 2006

Abstract

Background

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). 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.

Methods

Histamine and PGF_2α 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.

Results

In contrast to saline, Y-27632 inhalation significantly decreased the basal responsiveness toward histamine and PGF_2α before OA-challenge, as indicated by increased PC₁₀₀ -values. Both after the allergen-induced EAR and LAR, AHR to histamine and PGF_2α 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 PGF_2α after the EAR and LAR as compared to pre-challenge conditions. Saline inhalations did not affect histamine or PGF_2α PC₁₀₀-values at all. Interestingly, under all conditions Y-27632 was significantly more effective in reducing airway responsiveness to PGF_2α as compared to histamine. Also, there was a clear tendency (P = 0.08) to a more pronounced degree of AHR after the EAR for PGF_2α than for histamine.

Conclusion

The results indicate that inhalation of the Rho-kinase inhibitor Y-27632 causes a considerable bronchoprotection to both histamine and PGF_2α. 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 PGF_2α 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.