Long-term endogenous acetylcholine deficiency potentiates pulmonary inflammation in a murine model of elastase-induced emphysema

Abstract Acetylcholine (ACh), the neurotransmitter of the cholinergic system, regulates inflammation in several diseases including pulmonary diseases. ACh is also involved in a non-neuronal mechanism that modulates the innate immune response. Because inflammation and release of pro-inflammatory cyto...

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Autores principales:	Rosana Banzato, Nathalia M. Pinheiro, Clarice R. Olivo, Fernanda R. Santana, Fernanda D. T. Q. S. Lopes, Luciana C. Caperuto, Niels O. Câmara, Milton A. Martins, Iolanda F. L. C. Tibério, Marco Antônio M. Prado, Vânia F. Prado, Carla M. Prado
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/81713456707246e290513a0f1cc1a61e
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spelling	oai:doaj.org-article:81713456707246e290513a0f1cc1a61e2021-12-02T18:49:34ZLong-term endogenous acetylcholine deficiency potentiates pulmonary inflammation in a murine model of elastase-induced emphysema10.1038/s41598-021-95211-32045-2322https://doaj.org/article/81713456707246e290513a0f1cc1a61e2021-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-95211-3https://doaj.org/toc/2045-2322Abstract Acetylcholine (ACh), the neurotransmitter of the cholinergic system, regulates inflammation in several diseases including pulmonary diseases. ACh is also involved in a non-neuronal mechanism that modulates the innate immune response. Because inflammation and release of pro-inflammatory cytokines are involved in pulmonary emphysema, we hypothesized that vesicular acetylcholine transport protein (VAChT) deficiency, which leads to reduction in ACh release, can modulate lung inflammation in an experimental model of emphysema. Mice with genetical reduced expression of VAChT (VAChT KDHOM 70%) and wild-type mice (WT) received nasal instillation of 50 uL of porcine pancreatic elastase (PPE) or saline on day 0. Twenty-eight days after, animals were evaluated. Elastase instilled VAChT KDHOM mice presented an increase in macrophages, lymphocytes, and neutrophils in bronchoalveolar lavage fluid and MAC2-positive macrophages in lung tissue and peribronchovascular area that was comparable to that observed in WT mice. Conversely, elastase instilled VAChT KDHOM mice showed significantly larger number of NF-κB-positive cells and isoprostane staining in the peribronchovascular area when compared to elastase-instilled WT-mice. Moreover, elastase-instilled VAChT-deficient mice showed increased MCP-1 levels in the lungs. Other cytokines, extracellular matrix remodeling, alveolar enlargement, and lung function were not worse in elastase-instilled VAChT deficiency than in elastase-instilled WT-controls. These data suggest that decreased VAChT expression may contribute to the pathogenesis of emphysema, at least in part, through NF-κB activation, MCP-1, and oxidative stress pathways. This study highlights novel pathways involved in lung inflammation that may contribute to the development of chronic obstrutive lung disease (COPD) in cholinergic deficient individuals such as Alzheimer’s disease patients.Rosana BanzatoNathalia M. PinheiroClarice R. OlivoFernanda R. SantanaFernanda D. T. Q. S. LopesLuciana C. CaperutoNiels O. CâmaraMilton A. MartinsIolanda F. L. C. TibérioMarco Antônio M. PradoVânia F. PradoCarla M. PradoNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Rosana Banzato Nathalia M. Pinheiro Clarice R. Olivo Fernanda R. Santana Fernanda D. T. Q. S. Lopes Luciana C. Caperuto Niels O. Câmara Milton A. Martins Iolanda F. L. C. Tibério Marco Antônio M. Prado Vânia F. Prado Carla M. Prado Long-term endogenous acetylcholine deficiency potentiates pulmonary inflammation in a murine model of elastase-induced emphysema
description	Abstract Acetylcholine (ACh), the neurotransmitter of the cholinergic system, regulates inflammation in several diseases including pulmonary diseases. ACh is also involved in a non-neuronal mechanism that modulates the innate immune response. Because inflammation and release of pro-inflammatory cytokines are involved in pulmonary emphysema, we hypothesized that vesicular acetylcholine transport protein (VAChT) deficiency, which leads to reduction in ACh release, can modulate lung inflammation in an experimental model of emphysema. Mice with genetical reduced expression of VAChT (VAChT KDHOM 70%) and wild-type mice (WT) received nasal instillation of 50 uL of porcine pancreatic elastase (PPE) or saline on day 0. Twenty-eight days after, animals were evaluated. Elastase instilled VAChT KDHOM mice presented an increase in macrophages, lymphocytes, and neutrophils in bronchoalveolar lavage fluid and MAC2-positive macrophages in lung tissue and peribronchovascular area that was comparable to that observed in WT mice. Conversely, elastase instilled VAChT KDHOM mice showed significantly larger number of NF-κB-positive cells and isoprostane staining in the peribronchovascular area when compared to elastase-instilled WT-mice. Moreover, elastase-instilled VAChT-deficient mice showed increased MCP-1 levels in the lungs. Other cytokines, extracellular matrix remodeling, alveolar enlargement, and lung function were not worse in elastase-instilled VAChT deficiency than in elastase-instilled WT-controls. These data suggest that decreased VAChT expression may contribute to the pathogenesis of emphysema, at least in part, through NF-κB activation, MCP-1, and oxidative stress pathways. This study highlights novel pathways involved in lung inflammation that may contribute to the development of chronic obstrutive lung disease (COPD) in cholinergic deficient individuals such as Alzheimer’s disease patients.
format	article
author	Rosana Banzato Nathalia M. Pinheiro Clarice R. Olivo Fernanda R. Santana Fernanda D. T. Q. S. Lopes Luciana C. Caperuto Niels O. Câmara Milton A. Martins Iolanda F. L. C. Tibério Marco Antônio M. Prado Vânia F. Prado Carla M. Prado
author_facet	Rosana Banzato Nathalia M. Pinheiro Clarice R. Olivo Fernanda R. Santana Fernanda D. T. Q. S. Lopes Luciana C. Caperuto Niels O. Câmara Milton A. Martins Iolanda F. L. C. Tibério Marco Antônio M. Prado Vânia F. Prado Carla M. Prado
author_sort	Rosana Banzato
title	Long-term endogenous acetylcholine deficiency potentiates pulmonary inflammation in a murine model of elastase-induced emphysema
title_short	Long-term endogenous acetylcholine deficiency potentiates pulmonary inflammation in a murine model of elastase-induced emphysema
title_full	Long-term endogenous acetylcholine deficiency potentiates pulmonary inflammation in a murine model of elastase-induced emphysema
title_fullStr	Long-term endogenous acetylcholine deficiency potentiates pulmonary inflammation in a murine model of elastase-induced emphysema
title_full_unstemmed	Long-term endogenous acetylcholine deficiency potentiates pulmonary inflammation in a murine model of elastase-induced emphysema
title_sort	long-term endogenous acetylcholine deficiency potentiates pulmonary inflammation in a murine model of elastase-induced emphysema
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/81713456707246e290513a0f1cc1a61e
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Long-term endogenous acetylcholine deficiency potentiates pulmonary inflammation in a murine model of elastase-induced emphysema

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