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

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...

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Autores principales: Schaafsma, Dedmer, Bos, I Sophie T, Zuidhof, Annet B, Zaagsma, Johan, Meurs, Herman
Formato: Texto
Lenguaje:English
Publicado: BioMed Central 2006
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1586199/
https://www.ncbi.nlm.nih.gov/pubmed/17002806
http://dx.doi.org/10.1186/1465-9921-7-121
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author Schaafsma, Dedmer
Bos, I Sophie T
Zuidhof, Annet B
Zaagsma, Johan
Meurs, Herman
author_facet Schaafsma, Dedmer
Bos, I Sophie T
Zuidhof, Annet B
Zaagsma, Johan
Meurs, Herman
author_sort Schaafsma, Dedmer
collection PubMed
description 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 )PC(100)-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 PC(100)-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 PC(100 )-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 )PC(100)-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.
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spelling pubmed-15861992006-10-03 Inhalation of the Rho-kinase inhibitor Y-27632 reverses allergen-induced airway hyperresponsiveness after the early and late asthmatic reaction Schaafsma, Dedmer Bos, I Sophie T Zuidhof, Annet B Zaagsma, Johan Meurs, Herman Respir Res Research 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 )PC(100)-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 PC(100)-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 PC(100 )-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 )PC(100)-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. BioMed Central 2006 2006-09-26 /pmc/articles/PMC1586199/ /pubmed/17002806 http://dx.doi.org/10.1186/1465-9921-7-121 Text en Copyright © 2006 Schaafsma et al; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( (http://creativecommons.org/licenses/by/2.0) ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research
Schaafsma, Dedmer
Bos, I Sophie T
Zuidhof, Annet B
Zaagsma, Johan
Meurs, Herman
Inhalation of the Rho-kinase inhibitor Y-27632 reverses allergen-induced airway hyperresponsiveness after the early and late asthmatic reaction
title Inhalation of the Rho-kinase inhibitor Y-27632 reverses allergen-induced airway hyperresponsiveness after the early and late asthmatic reaction
title_full Inhalation of the Rho-kinase inhibitor Y-27632 reverses allergen-induced airway hyperresponsiveness after the early and late asthmatic reaction
title_fullStr Inhalation of the Rho-kinase inhibitor Y-27632 reverses allergen-induced airway hyperresponsiveness after the early and late asthmatic reaction
title_full_unstemmed Inhalation of the Rho-kinase inhibitor Y-27632 reverses allergen-induced airway hyperresponsiveness after the early and late asthmatic reaction
title_short Inhalation of the Rho-kinase inhibitor Y-27632 reverses allergen-induced airway hyperresponsiveness after the early and late asthmatic reaction
title_sort inhalation of the rho-kinase inhibitor y-27632 reverses allergen-induced airway hyperresponsiveness after the early and late asthmatic reaction
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1586199/
https://www.ncbi.nlm.nih.gov/pubmed/17002806
http://dx.doi.org/10.1186/1465-9921-7-121
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