Effects of VAChT reduction and alpha 7nAChR stimulation by PNU-282987 in lung inflammation in a model of chronic allergic airway inflammation

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dc.contributorSistema FMUSP-HC: Faculdade de Medicina da Universidade de São Paulo (FMUSP) e Hospital das Clínicas da FMUSP
dc.contributor.authorPINHEIRO, Nathalia M.
dc.contributor.authorMIRANDA, Claudia J. C. P.
dc.contributor.authorSANTANA, Fernanda R.
dc.contributor.authorBITTENCOURT-MERNAK, Marcia
dc.contributor.authorARANTES-COSTA, Fernanda M.
dc.contributor.authorOLIVO, Clarice
dc.contributor.authorPERINI, Adenir
dc.contributor.authorFESTA, Sergio
dc.contributor.authorCAPERUTO, Luciana C.
dc.contributor.authorTIBERIO, Iolanda F. L. C.
dc.contributor.authorPRADO, Marco Antonio M.
dc.contributor.authorMARTINS, Milton A.
dc.contributor.authorPRADO, Vania F.
dc.contributor.authorPRADO, Carla M.
dc.date.accessioned2020-10-15T14:30:49Z
dc.date.available2020-10-15T14:30:49Z
dc.date.issued2020
dc.description.abstractThe cholinergic anti-inflammatory pathway has been shown to regulate lung inflammation and cytokine release in acute models of inflammation, mainly via alpha 7 nicotinic receptor (alpha 7nAChR). 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 PNU282987(0.5-to-2mg/kg),( alpha 7nAChR 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, alpha 7nAChR antagonist) to confirm that the effects observed by PNU were due to alpha 7nAChR. 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 pretreatment abolished all the effects of PNU-282987. Additionally, we showed that PNU-282987 inhibited STAT3phosphorylation 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, alpha 7nAChR 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 alpha 7nAChR should be further considered as a therapeutic target in asthma.eng
dc.description.indexMEDLINEeng
dc.description.sponsorshipFundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [08/55359-5, 14/25689-4]
dc.description.sponsorshipConselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq)National Council for Scientific and Technological Development (CNPq) [476877/2012-1]
dc.identifier.citationEUROPEAN JOURNAL OF PHARMACOLOGY, v.882, article ID 173239, 16p, 2020
dc.identifier.doi10.1016/j.ejphar.2020.173239
dc.identifier.eissn1879-0712
dc.identifier.issn0014-2999
dc.identifier.urihttps://observatorio.fm.usp.br/handle/OPI/37654
dc.language.isoeng
dc.publisherELSEVIEReng
dc.relation.ispartofEuropean Journal of Pharmacology
dc.rightsrestrictedAccesseng
dc.rights.holderCopyright ELSEVIEReng
dc.subjectVesicular acetylcholine transportereng
dc.subjectChronic allergic airway inflammationeng
dc.subjecta7 nicotinic acetylcholineeng
dc.subject.othernitric-oxideeng
dc.subject.otheracetylcholine synthesiseng
dc.subject.othersmooth-muscleeng
dc.subject.otheractivationeng
dc.subject.otherexpressioneng
dc.subject.otherasthmaeng
dc.subject.otherinjuryeng
dc.subject.othermiceeng
dc.subject.othermodulationeng
dc.subject.othercomponentseng
dc.subject.wosPharmacology & Pharmacyeng
dc.titleEffects of VAChT reduction and alpha 7nAChR stimulation by PNU-282987 in lung inflammation in a model of chronic allergic airway inflammationeng
dc.typearticleeng
dc.type.categoryoriginal articleeng
dc.type.versionpublishedVersioneng
dspace.entity.typePublication
hcfmusp.affiliation.countryCanadá
hcfmusp.affiliation.countryisoca
hcfmusp.author.externalMIRANDA, Claudia J. C. P.:Univ Sao Paulo, Dept Med, Sch Med, Sao Paulo, Brazil
hcfmusp.author.externalSANTANA, Fernanda R.:Univ Fed Sao Paulo, Dept Biol Sci, Diadema, Brazil
hcfmusp.author.externalBITTENCOURT-MERNAK, Marcia:Univ Fed Sao Paulo, Dept Biol Sci, Diadema, Brazil
hcfmusp.author.externalFESTA, Sergio:Univ Fed Sao Paulo, Dept Biol Sci, Diadema, Brazil
hcfmusp.author.externalCAPERUTO, Luciana C.:Univ Fed Sao Paulo, Dept Biol Sci, Diadema, Brazil
hcfmusp.author.externalPRADO, Marco Antonio M.:Robarts Res Inst, Mol Med Grp, London, ON, Canada; Univ Western Ontario, Dept Physiol & Pharmacol, London, ON, Canada; Univ Western Ontario, Dept Anat & Cell Biol, London, ON, Canada
hcfmusp.author.externalPRADO, Vania F.:Robarts Res Inst, Mol Med Grp, London, ON, Canada; Univ Western Ontario, Dept Physiol & Pharmacol, London, ON, Canada; Univ Western Ontario, Dept Anat & Cell Biol, London, ON, Canada
hcfmusp.citation.scopus12
hcfmusp.contributor.author-fmusphcNATHALIA MONTOURO PINHEIRO MENEGASSO
hcfmusp.contributor.author-fmusphcFERNANDA MAGALHAES ARANTES COSTA
hcfmusp.contributor.author-fmusphcCLARICE ROSA OLIVO
hcfmusp.contributor.author-fmusphcADENIR PERINI
hcfmusp.contributor.author-fmusphcIOLANDA DE FATIMA LOPES CALVO TIBERIO
hcfmusp.contributor.author-fmusphcMILTON DE ARRUDA MARTINS
hcfmusp.contributor.author-fmusphcCARLA MAXIMO PRADO
hcfmusp.description.articlenumber173239
hcfmusp.description.volume882
hcfmusp.origemWOS
hcfmusp.origem.pubmed32619677
hcfmusp.origem.scopus2-s2.0-85087422633
hcfmusp.origem.wosWOS:000554894800007
hcfmusp.publisher.cityAMSTERDAMeng
hcfmusp.publisher.countryNETHERLANDSeng
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