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

Author(s):Show less -

Banzato, Rosana ^[1] ; Pinheiro, Nathalia M. ^[2] ; Olivo, Clarice R. ^[1] ; Santana, Fernanda R. ^{[3, 4]} ; Lopes, Fernanda D. T. Q. S. ^[1] ; Caperuto, Luciana C. ^[3] ; Camara, Niels O. ^[5] ; Martins, Milton A. ^[1] ; Tiberio, Iolanda F. L. C. ^[1] ; Prado, Marco Antonio M. ^{[6, 7, 8]} ; Prado, Vania F. ^{[6, 7, 8]} ; Prado, Carla M. ^{[1, 2]}

Affiliation

^[1] Univ Sao Paulo, Sch Med, Dept Med, Sao Paulo - Brazil

^[2] Univ Fed Sao Paulo, Dept Biosci, Rua Silva Jardim 136, Santos, SP - Brazil

^[3] Univ Fed Sao Paulo, Dept Biol Sci, Diadema - Brazil

^[4] Univ Fed Sao Paulo, Dept Med Nephrol, Sao Paulo - Brazil

^[5] Univ Sao Paulo, Immunol, Sao Paulo - Brazil

^[6] Univ Western Ontario, Dept Physiol & Pharmacol, London, ON - Canada

^[7] Univ Western Ontario, Dept Anat & Cell Biol, London, ON - Canada

^[8] Robarts Res Inst, Mol Med Grp, London, ON - Canada

• Document type: Journal article
• Source: SCIENTIFIC REPORTS; v. 11, n. 1 AUG 5 2021.
• Web of Science Citations: 0

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-kappa B-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-kappa B 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. (AU)

• FAPESP's process: 18/06088-0 - Effects of eugenol and dehidrodieugenol isolated from Nectandra leucantha (Lauraceae) treatments in experimental models of acute and chronic lung disease
• Grantee: Carla Máximo Prado
• Support Opportunities: Regular Research Grants
• FAPESP's process: 11/15817-7 - CHOLINERGIC HYPOFUNCTION EFFECTS IN THE MECHANICAL AND LUNG HISTOPATHOLOGY IN AN EXPERIMENTAL MODEL OF LUNG INFLAMMATION INDUCED BY AIR POLLUTANT INSTILLATION IN MICE
• Grantee: Fernanda Paula Roncon Santana Novelli
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 18/02537-5 - Characterization of asthma-COPD overlap syndrome (ACOS): experimental and clinical studies
• Grantee: Iolanda de Fátima Lopes Calvo Tibério
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 18/15738-9 - Modulatory effects of the cholinergic system and nicotinic receptors on a murine model of acute lung injury induced by LPS
• Grantee: Nathalia Montouro Pinheiro Menegasso
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 13/02881-4 - Effects of cholinergic function deficiency on pulmonary mechanics and histopathology in an experimental model of acute inflammation induced by LPS instillation in genetically modified mice
• Grantee: Nathalia Montouro Pinheiro Menegasso
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)