Sistema FMUSP-HC: Faculdade de Medicina da Universidade de São Paulo (FMUSP) e Hospital das Clínicas da FMUSPPINHEIRO, Nathalia M.MIRANDA, Claudia J. C. P.SANTANA, Fernanda R.BITTENCOURT-MERNAK, MarciaARANTES-COSTA, Fernanda M.OLIVO, ClaricePERINI, AdenirFESTA, SergioCAPERUTO, Luciana C.TIBERIO, Iolanda F. L. C.PRADO, Marco Antonio M.MARTINS, Milton A.PRADO, Vania F.PRADO, Carla M.2020-10-152020-10-152020EUROPEAN JOURNAL OF PHARMACOLOGY, v.882, article ID 173239, 16p, 20200014-2999https://observatorio.fm.usp.br/handle/OPI/37654The 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.engrestrictedAccessVesicular acetylcholine transporterChronic allergic airway inflammationa7 nicotinic acetylcholinenitric-oxideacetylcholine synthesissmooth-muscleactivationexpressionasthmainjurymicemodulationcomponentsarticleCopyright ELSEVIER10.1016/j.ejphar.2020.173239Pharmacology & Pharmacy1879-0712