Effects of VAChT reduction and α7nAChR stimulation by PNU-282987 in lung inflammation in a model of chronic allergic airway inflammation
Autor(a) principal: | |
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Data de Publicação: | 2020 |
Outros Autores: | , , , , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UNIFESP |
Texto Completo: | https://doi.org/10.1016/j.ejphar.2020.173239 https://repositorio.unifesp.br/handle/11600/61225 |
Resumo: | The cholinergic anti-inflammatory pathway has been shown to regulate lung inflammation and cytokine release in acute models of inflammation, mainly via α7 nicotinic receptor (α7nAChR). We aimed to evaluate the role of endogenous acetylcholine in chronic allergic airway inflammation in mice and the effects of therapeutic nAChR stimulation in this model. We first evaluated lung inflammation and remodeling on knock-down mice with 65% of vesicular acetylcholine transport (VAChT) gene reduction (KDVAChT) and wild-type(WT) controls that were subcutaneously sensitized and then inhaled with ovalbumin(OVA). We then evaluated the effects of PNU-282987(0.5-to-2mg/kg),(α7nAChR agonist) treatment in BALB/c male mice intraperitoneal sensitized and then inhaled with OVA. Another OVA-sensitized-group was treated with PNU-282987 plus Methyllycaconitine (MLA,1 mg/kg, α7nAChR antagonist) to confirm that the effects observed by PNU were due to α7nAChR. We showed that KDVAChT-OVA mice exhibit exacerbated airway inflammation when compared to WT-OVA mice. In BALB/c, PNU-282987 treatment reduced the number of eosinophils in the blood, BAL fluid, and around airways, and also decreased pulmonary levels of IL-4,IL-13,IL-17, and IgE in the serum of OVA-exposed mice. MLA pre-treatment abolished all the effects of PNU-282987. Additionally, we showed that PNU-282987 inhibited STAT3-phosphorylation and reduced SOCS3 expression in the lung. These data indicate that endogenous cholinergic tone is important to control allergic airway inflammation in a murine model. Moreover, α7nAChR is involved in the control of eosinophilic inflammation and airway remodeling, possibly via inhibition of STAT3/SOCS3 pathways. Together these data suggest that cholinergic anti-inflammatory system mainly α7nAChR should be further considered as a therapeutic target in asthma. |
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Effects of VAChT reduction and α7nAChR stimulation by PNU-282987 in lung inflammation in a model of chronic allergic airway inflammationChronic allergic airway inflammationVesicular acetylcholine transporterα7 nicotinic acetylcholineThe cholinergic anti-inflammatory pathway has been shown to regulate lung inflammation and cytokine release in acute models of inflammation, mainly via α7 nicotinic receptor (α7nAChR). We aimed to evaluate the role of endogenous acetylcholine in chronic allergic airway inflammation in mice and the effects of therapeutic nAChR stimulation in this model. We first evaluated lung inflammation and remodeling on knock-down mice with 65% of vesicular acetylcholine transport (VAChT) gene reduction (KDVAChT) and wild-type(WT) controls that were subcutaneously sensitized and then inhaled with ovalbumin(OVA). We then evaluated the effects of PNU-282987(0.5-to-2mg/kg),(α7nAChR agonist) treatment in BALB/c male mice intraperitoneal sensitized and then inhaled with OVA. Another OVA-sensitized-group was treated with PNU-282987 plus Methyllycaconitine (MLA,1 mg/kg, α7nAChR antagonist) to confirm that the effects observed by PNU were due to α7nAChR. We showed that KDVAChT-OVA mice exhibit exacerbated airway inflammation when compared to WT-OVA mice. In BALB/c, PNU-282987 treatment reduced the number of eosinophils in the blood, BAL fluid, and around airways, and also decreased pulmonary levels of IL-4,IL-13,IL-17, and IgE in the serum of OVA-exposed mice. MLA pre-treatment abolished all the effects of PNU-282987. Additionally, we showed that PNU-282987 inhibited STAT3-phosphorylation and reduced SOCS3 expression in the lung. These data indicate that endogenous cholinergic tone is important to control allergic airway inflammation in a murine model. Moreover, α7nAChR is involved in the control of eosinophilic inflammation and airway remodeling, possibly via inhibition of STAT3/SOCS3 pathways. Together these data suggest that cholinergic anti-inflammatory system mainly α7nAChR should be further considered as a therapeutic target in asthma.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)FAPESP: 2018/15738-9FAPESP: 08/55359-5FAPESP: 14/25689-4CNPq: 476877/2012-1Elsevierhttp://lattes.cnpq.br/8960401765088965Universidade Federal de São Paulo (UNIFESP)Pinheiro, Nathalia MontouroMiranda, Cláudia Jeane Claudino de PontesSantana, Fernanda Paula Roncon [UNIFESP]Bittencourt-Mernak, Marcia Isabel [UNIFESP]Arantes-Costas, Fernanda MagalhãesOlivo, Clarice RosaPerini, AdenirFesta, Sergio [UNIFESP]Caperuto, Luciana Chagas [UNIFESP]Tiberio, Iolanda de Fátima Lopes CalvoPrado, Marco Antônio MáximoMartins, Milton de ArrudaPrado, Vânia FerreiraPrado, Carla Máximo [UNIFESP]2021-06-25T19:26:25Z2021-06-25T19:26:25Z2020-09-05info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://doi.org/10.1016/j.ejphar.2020.173239https://repositorio.unifesp.br/handle/11600/61225engEur J Pharmacolinfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da UNIFESPinstname:Universidade Federal de São Paulo (UNIFESP)instacron:UNIFESP2024-08-03T12:39:08Zoai:repositorio.unifesp.br/:11600/61225Repositório InstitucionalPUBhttp://www.repositorio.unifesp.br/oai/requestbiblioteca.csp@unifesp.bropendoar:34652024-08-03T12:39:08Repositório Institucional da UNIFESP - Universidade Federal de São Paulo (UNIFESP)false |
dc.title.none.fl_str_mv |
Effects of VAChT reduction and α7nAChR stimulation by PNU-282987 in lung inflammation in a model of chronic allergic airway inflammation |
title |
Effects of VAChT reduction and α7nAChR stimulation by PNU-282987 in lung inflammation in a model of chronic allergic airway inflammation |
spellingShingle |
Effects of VAChT reduction and α7nAChR stimulation by PNU-282987 in lung inflammation in a model of chronic allergic airway inflammation Pinheiro, Nathalia Montouro Chronic allergic airway inflammation Vesicular acetylcholine transporter α7 nicotinic acetylcholine |
title_short |
Effects of VAChT reduction and α7nAChR stimulation by PNU-282987 in lung inflammation in a model of chronic allergic airway inflammation |
title_full |
Effects of VAChT reduction and α7nAChR stimulation by PNU-282987 in lung inflammation in a model of chronic allergic airway inflammation |
title_fullStr |
Effects of VAChT reduction and α7nAChR stimulation by PNU-282987 in lung inflammation in a model of chronic allergic airway inflammation |
title_full_unstemmed |
Effects of VAChT reduction and α7nAChR stimulation by PNU-282987 in lung inflammation in a model of chronic allergic airway inflammation |
title_sort |
Effects of VAChT reduction and α7nAChR stimulation by PNU-282987 in lung inflammation in a model of chronic allergic airway inflammation |
author |
Pinheiro, Nathalia Montouro |
author_facet |
Pinheiro, Nathalia Montouro Miranda, Cláudia Jeane Claudino de Pontes Santana, Fernanda Paula Roncon [UNIFESP] Bittencourt-Mernak, Marcia Isabel [UNIFESP] Arantes-Costas, Fernanda Magalhães Olivo, Clarice Rosa Perini, Adenir Festa, Sergio [UNIFESP] Caperuto, Luciana Chagas [UNIFESP] Tiberio, Iolanda de Fátima Lopes Calvo Prado, Marco Antônio Máximo Martins, Milton de Arruda Prado, Vânia Ferreira Prado, Carla Máximo [UNIFESP] |
author_role |
author |
author2 |
Miranda, Cláudia Jeane Claudino de Pontes Santana, Fernanda Paula Roncon [UNIFESP] Bittencourt-Mernak, Marcia Isabel [UNIFESP] Arantes-Costas, Fernanda Magalhães Olivo, Clarice Rosa Perini, Adenir Festa, Sergio [UNIFESP] Caperuto, Luciana Chagas [UNIFESP] Tiberio, Iolanda de Fátima Lopes Calvo Prado, Marco Antônio Máximo Martins, Milton de Arruda Prado, Vânia Ferreira Prado, Carla Máximo [UNIFESP] |
author2_role |
author author author author author author author author author author author author author |
dc.contributor.none.fl_str_mv |
http://lattes.cnpq.br/8960401765088965 Universidade Federal de São Paulo (UNIFESP) |
dc.contributor.author.fl_str_mv |
Pinheiro, Nathalia Montouro Miranda, Cláudia Jeane Claudino de Pontes Santana, Fernanda Paula Roncon [UNIFESP] Bittencourt-Mernak, Marcia Isabel [UNIFESP] Arantes-Costas, Fernanda Magalhães Olivo, Clarice Rosa Perini, Adenir Festa, Sergio [UNIFESP] Caperuto, Luciana Chagas [UNIFESP] Tiberio, Iolanda de Fátima Lopes Calvo Prado, Marco Antônio Máximo Martins, Milton de Arruda Prado, Vânia Ferreira Prado, Carla Máximo [UNIFESP] |
dc.subject.por.fl_str_mv |
Chronic allergic airway inflammation Vesicular acetylcholine transporter α7 nicotinic acetylcholine |
topic |
Chronic allergic airway inflammation Vesicular acetylcholine transporter α7 nicotinic acetylcholine |
description |
The cholinergic anti-inflammatory pathway has been shown to regulate lung inflammation and cytokine release in acute models of inflammation, mainly via α7 nicotinic receptor (α7nAChR). We aimed to evaluate the role of endogenous acetylcholine in chronic allergic airway inflammation in mice and the effects of therapeutic nAChR stimulation in this model. We first evaluated lung inflammation and remodeling on knock-down mice with 65% of vesicular acetylcholine transport (VAChT) gene reduction (KDVAChT) and wild-type(WT) controls that were subcutaneously sensitized and then inhaled with ovalbumin(OVA). We then evaluated the effects of PNU-282987(0.5-to-2mg/kg),(α7nAChR agonist) treatment in BALB/c male mice intraperitoneal sensitized and then inhaled with OVA. Another OVA-sensitized-group was treated with PNU-282987 plus Methyllycaconitine (MLA,1 mg/kg, α7nAChR antagonist) to confirm that the effects observed by PNU were due to α7nAChR. We showed that KDVAChT-OVA mice exhibit exacerbated airway inflammation when compared to WT-OVA mice. In BALB/c, PNU-282987 treatment reduced the number of eosinophils in the blood, BAL fluid, and around airways, and also decreased pulmonary levels of IL-4,IL-13,IL-17, and IgE in the serum of OVA-exposed mice. MLA pre-treatment abolished all the effects of PNU-282987. Additionally, we showed that PNU-282987 inhibited STAT3-phosphorylation and reduced SOCS3 expression in the lung. These data indicate that endogenous cholinergic tone is important to control allergic airway inflammation in a murine model. Moreover, α7nAChR is involved in the control of eosinophilic inflammation and airway remodeling, possibly via inhibition of STAT3/SOCS3 pathways. Together these data suggest that cholinergic anti-inflammatory system mainly α7nAChR should be further considered as a therapeutic target in asthma. |
publishDate |
2020 |
dc.date.none.fl_str_mv |
2020-09-05 2021-06-25T19:26:25Z 2021-06-25T19:26:25Z |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
https://doi.org/10.1016/j.ejphar.2020.173239 https://repositorio.unifesp.br/handle/11600/61225 |
url |
https://doi.org/10.1016/j.ejphar.2020.173239 https://repositorio.unifesp.br/handle/11600/61225 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Eur J Pharmacol |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
Elsevier |
publisher.none.fl_str_mv |
Elsevier |
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 |
biblioteca.csp@unifesp.br |
_version_ |
1814268281833390080 |