Effects of VAChT reduction and α7nAChR stimulation by PNU-282987 in lung inflammation in a model of chronic allergic airway inflammation

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dc.contributor.authorPinheiro, Nathalia Montouro
dc.contributor.authorMiranda, Cláudia Jeane Claudino de Pontes
dc.contributor.authorSantana, Fernanda Paula Roncon [UNIFESP]
dc.contributor.authorBittencourt-Mernak, Marcia Isabel [UNIFESP]
dc.contributor.authorArantes-Costas, Fernanda Magalhães
dc.contributor.authorOlivo, Clarice Rosa
dc.contributor.authorPerini, Adenir
dc.contributor.authorFesta, Sergio [UNIFESP]
dc.contributor.authorCaperuto, Luciana Chagas [UNIFESP]
dc.contributor.authorTiberio, Iolanda de Fátima Lopes Calvo
dc.contributor.authorPrado, Marco Antônio Máximo
dc.contributor.authorMartins, Milton de Arruda
dc.contributor.authorPrado, Vânia Ferreira
dc.contributor.authorPrado, Carla Máximo [UNIFESP]
dc.contributor.authorLatteshttp://lattes.cnpq.br/8960401765088965pt_BR
dc.contributor.institutionUniversidade Federal de São Paulo (UNIFESP)
dc.date.accessioned2021-06-25T19:26:25Z
dc.date.available2021-06-25T19:26:25Z
dc.date.issued2020-09-05
dc.description.abstractThe 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.en
dc.description.sponsorshipFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)pt_BR
dc.description.sponsorshipConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)pt
dc.description.sponsorshipIDFAPESP: 2018/15738-9pt_BR
dc.description.sponsorshipIDFAPESP: 08/55359-5pt
dc.description.sponsorshipIDFAPESP: 14/25689-4pt
dc.description.sponsorshipIDCNPq: 476877/2012-1pt
dc.identifier.doihttps://doi.org/10.1016/j.ejphar.2020.173239pt_BR
dc.identifier.urihttps://repositorio.unifesp.br/handle/11600/61225
dc.languageengpt_BR
dc.publisherElsevierpt_BR
dc.relation.ispartofEur J Pharmacolpt_BR
dc.rightsinfo:eu-repo/semantics/openAccesspt_BR
dc.subjectChronic allergic airway inflammationen
dc.subjectVesicular acetylcholine transporteren
dc.subjectα7 nicotinic acetylcholineen
dc.titleEffects of VAChT reduction and α7nAChR stimulation by PNU-282987 in lung inflammation in a model of chronic allergic airway inflammationen
dc.typeinfo:eu-repo/semantics/articlept_BR
unifesp.campusInstituto de Saúde e Sociedade (ISS)pt_BR
unifesp.departamentoBiociênciaspt_BR
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Effects of VAChT reduction and α7nAChR stimulation by PNU-282987 in lung inflammation in a model of chronic allergic airway inflammation
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