Rho-kinase inhibition attenuates airway responsiveness, inflammation, matrix remodeling, and oxidative stress activation induced by chronic inflammation
Main Author: | |
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Publication Date: | 2012 |
Other Authors: | , , , , , , , , , |
Format: | Article |
Language: | eng |
Source: | Repositório Institucional da UNIFESP |
Download full: | http://repositorio.unifesp.br/handle/11600/35529 http://dx.doi.org/10.1152/ajplung.00034.2012 |
Summary: | Possa SS, Charafeddine HT, Righetti RF, da Silva PA, Almeida-Reis R, Saraiva-Romanholo BM, Perini A, Prado CM, Leick-Maldonado EA, Martins MA, Tiberio ID. Rho-kinase inhibition attenuates airway responsiveness, inflammation, matrix remodeling, and oxidative stress activation induced by chronic inflammation. Am J Physiol Lung Cell Mol Physiol 303: L939-L952, 2012. First published September 21, 2012; doi:10.1152/ajplung.00034.2012.-Several studies have demonstrated the importance of Rho-kinase in the modulation of smooth muscle contraction, airway hyperresponsiveness, and inflammation. However, the effects of repeated treatment with a specific inhibitor of this pathway have not been previously investigated. We evaluated the effects of repeated treatment with Y-27632, a highly selective Rho-kinase inhibitor, on airway hyperresponsiveness, oxidative stress activation, extracellular matrix remodeling, eosinophilic inflammation, and cytokine expression in an animal model of chronic airway inflammation. Guinea pigs were subjected to seven ovalbumin or saline exposures. the treatment with Y-27632 (1 mM) started at the fifth inhalation. Seventy-two hours after the seventh inhalation, the animals' pulmonary mechanics were evaluated, and exhaled nitric oxide (E-NO) was collected. the lungs were removed, and histological analysis was performed using morphometry. Treatment with Y-27632 in sensitized animals reduced E-NO concentrations, maximal responses of resistance, elastance of the respiratory system, eosinophil counts, collagen and elastic fiber contents, the numbers of cells positive for IL-2, IL-4, IL-5, IL-13, inducible nitric oxide synthase, matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1, transforming growth factor-beta, NF-kappa B, IFN-gamma, and 8-iso-prostaglandin F2 alpha contents compared with the untreated group (P < 0.05). We observed positive correlations among the functional responses and inflammation, remodeling, and oxidative stress pathway activation markers evaluated. in conclusion, Rho-kinase pathway activation contributes to the potentiation of the hyperresponsiveness, inflammation, the extracellular matrix remodeling process, and oxidative stress activation. These results suggest that Rho-kinase inhibitors represent potential pharmacological tools for the control of asthma. |
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Possa, Samantha SouzaCharafeddine, Homar ToledoRighetti, Renato FragaSilva, Patricia Angeli daAlmeida-Reis, RafaelSaraiva-Romanholo, Beatriz MangueiraPerini, AdenirPrado, Carla Maximo [UNIFESP]Leick-Maldonado, Edna AparecidaMartins, Milton A.Lopes Calvo Tiberio, Iolanda de FatimaUniversidade de São Paulo (USP)Universidade Federal de São Paulo (UNIFESP)2016-01-24T14:28:03Z2016-01-24T14:28:03Z2012-12-01American Journal of Physiology-lung Cellular and Molecular Physiology. Bethesda: Amer Physiological Soc, v. 303, n. 11, p. L939-L952, 2012.1040-0605http://repositorio.unifesp.br/handle/11600/35529http://dx.doi.org/10.1152/ajplung.00034.201210.1152/ajplung.00034.2012WOS:000311905600001Possa SS, Charafeddine HT, Righetti RF, da Silva PA, Almeida-Reis R, Saraiva-Romanholo BM, Perini A, Prado CM, Leick-Maldonado EA, Martins MA, Tiberio ID. Rho-kinase inhibition attenuates airway responsiveness, inflammation, matrix remodeling, and oxidative stress activation induced by chronic inflammation. Am J Physiol Lung Cell Mol Physiol 303: L939-L952, 2012. First published September 21, 2012; doi:10.1152/ajplung.00034.2012.-Several studies have demonstrated the importance of Rho-kinase in the modulation of smooth muscle contraction, airway hyperresponsiveness, and inflammation. However, the effects of repeated treatment with a specific inhibitor of this pathway have not been previously investigated. We evaluated the effects of repeated treatment with Y-27632, a highly selective Rho-kinase inhibitor, on airway hyperresponsiveness, oxidative stress activation, extracellular matrix remodeling, eosinophilic inflammation, and cytokine expression in an animal model of chronic airway inflammation. Guinea pigs were subjected to seven ovalbumin or saline exposures. the treatment with Y-27632 (1 mM) started at the fifth inhalation. Seventy-two hours after the seventh inhalation, the animals' pulmonary mechanics were evaluated, and exhaled nitric oxide (E-NO) was collected. the lungs were removed, and histological analysis was performed using morphometry. Treatment with Y-27632 in sensitized animals reduced E-NO concentrations, maximal responses of resistance, elastance of the respiratory system, eosinophil counts, collagen and elastic fiber contents, the numbers of cells positive for IL-2, IL-4, IL-5, IL-13, inducible nitric oxide synthase, matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1, transforming growth factor-beta, NF-kappa B, IFN-gamma, and 8-iso-prostaglandin F2 alpha contents compared with the untreated group (P < 0.05). We observed positive correlations among the functional responses and inflammation, remodeling, and oxidative stress pathway activation markers evaluated. in conclusion, Rho-kinase pathway activation contributes to the potentiation of the hyperresponsiveness, inflammation, the extracellular matrix remodeling process, and oxidative stress activation. These results suggest that Rho-kinase inhibitors represent potential pharmacological tools for the control of asthma.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Univ São Paulo, Sch Med, Dept Med, BR-01246903 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Biol Sci, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Biol Sci, São Paulo, BrazilWeb of ScienceL939-L952engAmer Physiological SocAmerican Journal of Physiology-lung Cellular and Molecular Physiologyasthmaguinea pigsRho-associated kinasesRho-kinase inhibition attenuates airway responsiveness, inflammation, matrix remodeling, and oxidative stress activation induced by chronic inflammationinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleinfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da UNIFESPinstname:Universidade Federal de São Paulo (UNIFESP)instacron:UNIFESP11600/355292022-11-04 14:22:10.518metadata only accessoai:repositorio.unifesp.br:11600/35529Repositório InstitucionalPUBhttp://www.repositorio.unifesp.br/oai/requestopendoar:34652023-05-25T12:28:16.036366Repositório Institucional da UNIFESP - Universidade Federal de São Paulo (UNIFESP)false |
dc.title.en.fl_str_mv |
Rho-kinase inhibition attenuates airway responsiveness, inflammation, matrix remodeling, and oxidative stress activation induced by chronic inflammation |
title |
Rho-kinase inhibition attenuates airway responsiveness, inflammation, matrix remodeling, and oxidative stress activation induced by chronic inflammation |
spellingShingle |
Rho-kinase inhibition attenuates airway responsiveness, inflammation, matrix remodeling, and oxidative stress activation induced by chronic inflammation Possa, Samantha Souza asthma guinea pigs Rho-associated kinases |
title_short |
Rho-kinase inhibition attenuates airway responsiveness, inflammation, matrix remodeling, and oxidative stress activation induced by chronic inflammation |
title_full |
Rho-kinase inhibition attenuates airway responsiveness, inflammation, matrix remodeling, and oxidative stress activation induced by chronic inflammation |
title_fullStr |
Rho-kinase inhibition attenuates airway responsiveness, inflammation, matrix remodeling, and oxidative stress activation induced by chronic inflammation |
title_full_unstemmed |
Rho-kinase inhibition attenuates airway responsiveness, inflammation, matrix remodeling, and oxidative stress activation induced by chronic inflammation |
title_sort |
Rho-kinase inhibition attenuates airway responsiveness, inflammation, matrix remodeling, and oxidative stress activation induced by chronic inflammation |
author |
Possa, Samantha Souza |
author_facet |
Possa, Samantha Souza Charafeddine, Homar Toledo Righetti, Renato Fraga Silva, Patricia Angeli da Almeida-Reis, Rafael Saraiva-Romanholo, Beatriz Mangueira Perini, Adenir Prado, Carla Maximo [UNIFESP] Leick-Maldonado, Edna Aparecida Martins, Milton A. Lopes Calvo Tiberio, Iolanda de Fatima |
author_role |
author |
author2 |
Charafeddine, Homar Toledo Righetti, Renato Fraga Silva, Patricia Angeli da Almeida-Reis, Rafael Saraiva-Romanholo, Beatriz Mangueira Perini, Adenir Prado, Carla Maximo [UNIFESP] Leick-Maldonado, Edna Aparecida Martins, Milton A. Lopes Calvo Tiberio, Iolanda de Fatima |
author2_role |
author author author author author author author author author author |
dc.contributor.institution.none.fl_str_mv |
Universidade de São Paulo (USP) Universidade Federal de São Paulo (UNIFESP) |
dc.contributor.author.fl_str_mv |
Possa, Samantha Souza Charafeddine, Homar Toledo Righetti, Renato Fraga Silva, Patricia Angeli da Almeida-Reis, Rafael Saraiva-Romanholo, Beatriz Mangueira Perini, Adenir Prado, Carla Maximo [UNIFESP] Leick-Maldonado, Edna Aparecida Martins, Milton A. Lopes Calvo Tiberio, Iolanda de Fatima |
dc.subject.eng.fl_str_mv |
asthma guinea pigs Rho-associated kinases |
topic |
asthma guinea pigs Rho-associated kinases |
description |
Possa SS, Charafeddine HT, Righetti RF, da Silva PA, Almeida-Reis R, Saraiva-Romanholo BM, Perini A, Prado CM, Leick-Maldonado EA, Martins MA, Tiberio ID. Rho-kinase inhibition attenuates airway responsiveness, inflammation, matrix remodeling, and oxidative stress activation induced by chronic inflammation. Am J Physiol Lung Cell Mol Physiol 303: L939-L952, 2012. First published September 21, 2012; doi:10.1152/ajplung.00034.2012.-Several studies have demonstrated the importance of Rho-kinase in the modulation of smooth muscle contraction, airway hyperresponsiveness, and inflammation. However, the effects of repeated treatment with a specific inhibitor of this pathway have not been previously investigated. We evaluated the effects of repeated treatment with Y-27632, a highly selective Rho-kinase inhibitor, on airway hyperresponsiveness, oxidative stress activation, extracellular matrix remodeling, eosinophilic inflammation, and cytokine expression in an animal model of chronic airway inflammation. Guinea pigs were subjected to seven ovalbumin or saline exposures. the treatment with Y-27632 (1 mM) started at the fifth inhalation. Seventy-two hours after the seventh inhalation, the animals' pulmonary mechanics were evaluated, and exhaled nitric oxide (E-NO) was collected. the lungs were removed, and histological analysis was performed using morphometry. Treatment with Y-27632 in sensitized animals reduced E-NO concentrations, maximal responses of resistance, elastance of the respiratory system, eosinophil counts, collagen and elastic fiber contents, the numbers of cells positive for IL-2, IL-4, IL-5, IL-13, inducible nitric oxide synthase, matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1, transforming growth factor-beta, NF-kappa B, IFN-gamma, and 8-iso-prostaglandin F2 alpha contents compared with the untreated group (P < 0.05). We observed positive correlations among the functional responses and inflammation, remodeling, and oxidative stress pathway activation markers evaluated. in conclusion, Rho-kinase pathway activation contributes to the potentiation of the hyperresponsiveness, inflammation, the extracellular matrix remodeling process, and oxidative stress activation. These results suggest that Rho-kinase inhibitors represent potential pharmacological tools for the control of asthma. |
publishDate |
2012 |
dc.date.issued.fl_str_mv |
2012-12-01 |
dc.date.accessioned.fl_str_mv |
2016-01-24T14:28:03Z |
dc.date.available.fl_str_mv |
2016-01-24T14:28:03Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.citation.fl_str_mv |
American Journal of Physiology-lung Cellular and Molecular Physiology. Bethesda: Amer Physiological Soc, v. 303, n. 11, p. L939-L952, 2012. |
dc.identifier.uri.fl_str_mv |
http://repositorio.unifesp.br/handle/11600/35529 http://dx.doi.org/10.1152/ajplung.00034.2012 |
dc.identifier.issn.none.fl_str_mv |
1040-0605 |
dc.identifier.doi.none.fl_str_mv |
10.1152/ajplung.00034.2012 |
dc.identifier.wos.none.fl_str_mv |
WOS:000311905600001 |
identifier_str_mv |
American Journal of Physiology-lung Cellular and Molecular Physiology. Bethesda: Amer Physiological Soc, v. 303, n. 11, p. L939-L952, 2012. 1040-0605 10.1152/ajplung.00034.2012 WOS:000311905600001 |
url |
http://repositorio.unifesp.br/handle/11600/35529 http://dx.doi.org/10.1152/ajplung.00034.2012 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.ispartof.none.fl_str_mv |
American Journal of Physiology-lung Cellular and Molecular Physiology |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
L939-L952 |
dc.publisher.none.fl_str_mv |
Amer Physiological Soc |
publisher.none.fl_str_mv |
Amer Physiological Soc |
dc.source.none.fl_str_mv |
reponame:Repositório Institucional da UNIFESP instname:Universidade Federal de São Paulo (UNIFESP) instacron:UNIFESP |
instname_str |
Universidade Federal de São Paulo (UNIFESP) |
instacron_str |
UNIFESP |
institution |
UNIFESP |
reponame_str |
Repositório Institucional da UNIFESP |
collection |
Repositório Institucional da UNIFESP |
repository.name.fl_str_mv |
Repositório Institucional da UNIFESP - Universidade Federal de São Paulo (UNIFESP) |
repository.mail.fl_str_mv |
|
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1783460294991806464 |