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length 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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Autor(es):
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Pinheiro, Nathalia M. [1, 2] ; Miranda, Claudia J. C. P. [2] ; Santana, Fernanda R. [3] ; Bittencourt-Mernak, Marcia [3] ; Arantes-Costa, Fernanda M. [2] ; Olivo, Clarice [2] ; Perini, Adenir [2] ; Festa, Sergio [3] ; Caperuto, Luciana C. [3] ; Tiberio, Iolanda F. L. C. [2] ; Prado, Marco Antonio M. [4, 5, 6] ; Martins, Milton A. [2] ; Prado, Vania F. [4, 5, 6] ; Prado, Carla M. [1, 2]
Número total de Autores: 14
Afiliação do(s) autor(es):
[1] Univ Fed Sao Paulo, Dept Biosci, Rua Silva Jardim, 136 Vila Mathias, BR-11015020 Santos, SP - Brazil
[2] Univ Sao Paulo, Dept Med, Sch Med, Sao Paulo - Brazil
[3] Univ Fed Sao Paulo, Dept Biol Sci, Diadema - Brazil
[4] Univ Western Ontario, Dept Physiol & Pharmacol, London, ON - Canada
[5] Univ Western Ontario, Dept Anat & Cell Biol, London, ON - Canada
[6] Robarts Res Inst, Mol Med Grp, London, ON - Canada
Número total de Afiliações: 6
Tipo de documento: Artigo Científico
Fonte: European Journal of Pharmacology; v. 882, SEP 5 2020.
Citações Web of Science: 0
Resumo

The 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. (AU)

Processo FAPESP: 14/25689-4 - Efeito do sistema colinérgico na inflamação pulmonar aguda e crônica.
Beneficiário:Carla Máximo Prado
Linha de fomento: Auxílio à Pesquisa - Regular
Processo FAPESP: 08/55359-5 - Avaliação da função e da histopatologia pulmonar em modelo experimental de redução da função colinérgica em camundongos geneticamente modificados
Beneficiário:Carla Máximo Prado
Linha de fomento: Auxílio à Pesquisa - Apoio a Jovens Pesquisadores