Inhibition of p21 activated kinase (PAK) reduces airway responsiveness in vivo and in vitro in murine and human airways.

The p21-activated protein kinases (Paks) have been implicated in the regulation of smooth muscle contractility, but the physiologic effects of Pak activation on airway reactivity in vivo are unknown. A mouse model with a genetic deletion of Pak1 (Pak1(-/-)) was used to determine the role of Pak in t...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Wyn C Hoover, Wenwu Zhang, Zhidong Xue, Huanling Gao, Jonathan Chernoff, D Wade Clapp, Susan J Gunst, Robert S Tepper
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/e70f8d114cec47d19054a3fefe910f9b
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:e70f8d114cec47d19054a3fefe910f9b
record_format	dspace
spelling	oai:doaj.org-article:e70f8d114cec47d19054a3fefe910f9b2021-11-18T07:09:08ZInhibition of p21 activated kinase (PAK) reduces airway responsiveness in vivo and in vitro in murine and human airways.1932-620310.1371/journal.pone.0042601https://doaj.org/article/e70f8d114cec47d19054a3fefe910f9b2012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22900031/?tool=EBIhttps://doaj.org/toc/1932-6203The p21-activated protein kinases (Paks) have been implicated in the regulation of smooth muscle contractility, but the physiologic effects of Pak activation on airway reactivity in vivo are unknown. A mouse model with a genetic deletion of Pak1 (Pak1(-/-)) was used to determine the role of Pak in the response of the airways in vivo to challenge with inhaled or intravenous acetylcholine (ACh). Pulmonary resistance was measured in anesthetized mechanically ventilated Pak1(-/-) and wild type mice. Pak1(-/-) mice exhibited lower airway reactivity to ACh compared with wild type mice. Tracheal segments dissected from Pak1(-/-) mice and studied in vitro also exhibited reduced responsiveness to ACh compared with tracheas from wild type mice. Morphometric assessment and pulmonary function analysis revealed no differences in the structure of the airways or lung parenchyma, suggesting that that the reduced airway responsiveness did not result from structural abnormalities in the lungs or airways due to Pak1 deletion. Inhalation of the small molecule synthetic Pak1 inhibitor, IPA3, also significantly reduced in vivo airway responsiveness to ACh and 5-hydroxytryptamine (5-Ht) in wild type mice. IPA3 inhibited the contractility of isolated human bronchial tissues to ACh, confirming that this inhibitor is also effective in human airway smooth muscle tissue. The results demonstrate that Pak is a critical component of the contractile activation process in airway smooth muscle, and suggest that Pak inhibition could provide a novel strategy for reducing airway hyperresponsiveness.Wyn C HooverWenwu ZhangZhidong XueHuanling GaoJonathan ChernoffD Wade ClappSusan J GunstRobert S TepperPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 8, p e42601 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Wyn C Hoover Wenwu Zhang Zhidong Xue Huanling Gao Jonathan Chernoff D Wade Clapp Susan J Gunst Robert S Tepper Inhibition of p21 activated kinase (PAK) reduces airway responsiveness in vivo and in vitro in murine and human airways.
description	The p21-activated protein kinases (Paks) have been implicated in the regulation of smooth muscle contractility, but the physiologic effects of Pak activation on airway reactivity in vivo are unknown. A mouse model with a genetic deletion of Pak1 (Pak1(-/-)) was used to determine the role of Pak in the response of the airways in vivo to challenge with inhaled or intravenous acetylcholine (ACh). Pulmonary resistance was measured in anesthetized mechanically ventilated Pak1(-/-) and wild type mice. Pak1(-/-) mice exhibited lower airway reactivity to ACh compared with wild type mice. Tracheal segments dissected from Pak1(-/-) mice and studied in vitro also exhibited reduced responsiveness to ACh compared with tracheas from wild type mice. Morphometric assessment and pulmonary function analysis revealed no differences in the structure of the airways or lung parenchyma, suggesting that that the reduced airway responsiveness did not result from structural abnormalities in the lungs or airways due to Pak1 deletion. Inhalation of the small molecule synthetic Pak1 inhibitor, IPA3, also significantly reduced in vivo airway responsiveness to ACh and 5-hydroxytryptamine (5-Ht) in wild type mice. IPA3 inhibited the contractility of isolated human bronchial tissues to ACh, confirming that this inhibitor is also effective in human airway smooth muscle tissue. The results demonstrate that Pak is a critical component of the contractile activation process in airway smooth muscle, and suggest that Pak inhibition could provide a novel strategy for reducing airway hyperresponsiveness.
format	article
author	Wyn C Hoover Wenwu Zhang Zhidong Xue Huanling Gao Jonathan Chernoff D Wade Clapp Susan J Gunst Robert S Tepper
author_facet	Wyn C Hoover Wenwu Zhang Zhidong Xue Huanling Gao Jonathan Chernoff D Wade Clapp Susan J Gunst Robert S Tepper
author_sort	Wyn C Hoover
title	Inhibition of p21 activated kinase (PAK) reduces airway responsiveness in vivo and in vitro in murine and human airways.
title_short	Inhibition of p21 activated kinase (PAK) reduces airway responsiveness in vivo and in vitro in murine and human airways.
title_full	Inhibition of p21 activated kinase (PAK) reduces airway responsiveness in vivo and in vitro in murine and human airways.
title_fullStr	Inhibition of p21 activated kinase (PAK) reduces airway responsiveness in vivo and in vitro in murine and human airways.
title_full_unstemmed	Inhibition of p21 activated kinase (PAK) reduces airway responsiveness in vivo and in vitro in murine and human airways.
title_sort	inhibition of p21 activated kinase (pak) reduces airway responsiveness in vivo and in vitro in murine and human airways.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/e70f8d114cec47d19054a3fefe910f9b
work_keys_str_mv	AT wynchoover inhibitionofp21activatedkinasepakreducesairwayresponsivenessinvivoandinvitroinmurineandhumanairways AT wenwuzhang inhibitionofp21activatedkinasepakreducesairwayresponsivenessinvivoandinvitroinmurineandhumanairways AT zhidongxue inhibitionofp21activatedkinasepakreducesairwayresponsivenessinvivoandinvitroinmurineandhumanairways AT huanlinggao inhibitionofp21activatedkinasepakreducesairwayresponsivenessinvivoandinvitroinmurineandhumanairways AT jonathanchernoff inhibitionofp21activatedkinasepakreducesairwayresponsivenessinvivoandinvitroinmurineandhumanairways AT dwadeclapp inhibitionofp21activatedkinasepakreducesairwayresponsivenessinvivoandinvitroinmurineandhumanairways AT susanjgunst inhibitionofp21activatedkinasepakreducesairwayresponsivenessinvivoandinvitroinmurineandhumanairways AT robertstepper inhibitionofp21activatedkinasepakreducesairwayresponsivenessinvivoandinvitroinmurineandhumanairways
_version_	1718423887821144064

Inhibition of p21 activated kinase (PAK) reduces airway responsiveness in vivo and in vitro in murine and human airways.

Ejemplares similares