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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.
Eur J Pharmacol. 2020 Sep 05; 882:173239.EJ

Abstract

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.

Authors+Show Affiliations

Department of Medicine, School of Medicine, University of Sao Paulo, São Paulo, Brazil; Department of Bioscience, Federal University of Sao Paulo, Santos, Brazil.Department of Medicine, School of Medicine, University of Sao Paulo, São Paulo, Brazil.Department of Biological Science, Federal University of Sao Paulo, Diadema, Brazil.Department of Biological Science, Federal University of Sao Paulo, Diadema, Brazil.Department of Medicine, School of Medicine, University of Sao Paulo, São Paulo, Brazil.Department of Medicine, School of Medicine, University of Sao Paulo, São Paulo, Brazil.Department of Medicine, School of Medicine, University of Sao Paulo, São Paulo, Brazil.Department of Biological Science, Federal University of Sao Paulo, Diadema, Brazil.Department of Biological Science, Federal University of Sao Paulo, Diadema, Brazil.Department of Medicine, School of Medicine, University of Sao Paulo, São Paulo, Brazil.Molecular Medicine Group, Robarts Research Institute, Canada; Department of Physiology & Pharmacology and Department of Anatomy & Cell Biology, University of Western Ontario, London, Canada.Department of Medicine, School of Medicine, University of Sao Paulo, São Paulo, Brazil.Molecular Medicine Group, Robarts Research Institute, Canada; Department of Physiology & Pharmacology and Department of Anatomy & Cell Biology, University of Western Ontario, London, Canada.Department of Medicine, School of Medicine, University of Sao Paulo, São Paulo, Brazil; Department of Bioscience, Federal University of Sao Paulo, Santos, Brazil. Electronic address: carla.prado@unifesp.br.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32619677

Citation

Pinheiro, Nathalia M., et al. "Effects of VAChT Reduction and α7nAChR Stimulation By PNU-282987 in Lung Inflammation in a Model of Chronic Allergic Airway Inflammation." European Journal of Pharmacology, vol. 882, 2020, p. 173239.
Pinheiro NM, Miranda CJCP, Santana FR, et al. Effects of VAChT reduction and α7nAChR stimulation by PNU-282987 in lung inflammation in a model of chronic allergic airway inflammation. Eur J Pharmacol. 2020;882:173239.
Pinheiro, N. M., Miranda, C. J. C. P., Santana, F. R., Bittencourt-Mernak, M., Arantes-Costa, F. M., Olivo, C., Perini, A., Festa, S., Caperuto, L. C., Tibério, I. F. L. C., Prado, M. A. M., Martins, M. A., Prado, V. F., & Prado, C. M. (2020). Effects of VAChT reduction and α7nAChR stimulation by PNU-282987 in lung inflammation in a model of chronic allergic airway inflammation. European Journal of Pharmacology, 882, 173239. https://doi.org/10.1016/j.ejphar.2020.173239
Pinheiro NM, et al. Effects of VAChT Reduction and α7nAChR Stimulation By PNU-282987 in Lung Inflammation in a Model of Chronic Allergic Airway Inflammation. Eur J Pharmacol. 2020 Sep 5;882:173239. PubMed PMID: 32619677.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effects of VAChT reduction and α7nAChR stimulation by PNU-282987 in lung inflammation in a model of chronic allergic airway inflammation. AU - Pinheiro,Nathalia M, AU - Miranda,Claudia J C P, AU - Santana,Fernanda R, AU - Bittencourt-Mernak,Marcia, AU - Arantes-Costa,Fernanda M, AU - Olivo,Clarice, AU - Perini,Adenir, AU - Festa,Sérgio, AU - Caperuto,Luciana C, AU - Tibério,Iolanda F L C, AU - Prado,Marco Antônio M, AU - Martins,Mílton A, AU - Prado,Vânia F, AU - Prado,Carla M, Y1 - 2020/06/30/ PY - 2020/01/09/received PY - 2020/05/26/revised PY - 2020/05/29/accepted PY - 2020/7/4/pubmed PY - 2020/7/4/medline PY - 2020/7/4/entrez KW - Chronic allergic airway inflammation KW - Vesicular acetylcholine transporter KW - α7 nicotinic acetylcholine SP - 173239 EP - 173239 JF - European journal of pharmacology JO - Eur. J. Pharmacol. VL - 882 N2 - 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. SN - 1879-0712 UR - https://www.unboundmedicine.com/medline/citation/32619677/Effects_of_VAChT_reduction_and_α7nAChR_stimulation_by_PNU-282987_in_lung_inflammation_in_a_model_of_chronic_allergic_airway_inflammation L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-2999(20)30331-9 DB - PRIME DP - Unbound Medicine ER -
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