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The Cholinergic Drug Pyridostigmine Alleviates Inflammation During LPS-Induced Acute Respiratory Distress Syndrome

Acute respiratory distress syndrome (ARDS) is a critical illness complication that is associated with high mortality. ARDS is documented in severe cases of COVID-19. No effective pharmacological treatments for ARDS are currently available. Dysfunctional immune responses and pulmonary and systemic in...

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Autores principales: Bricher Choque, Pamela Nithzi, Vieira, Rodolfo P., Ulloa, Luis, Grabulosa, Caren, Irigoyen, Maria Claudia, De Angelis, Katia, Ligeiro De Oliveira, Ana Paula, Tracey, Kevin J., Pavlov, Valentin A., Consolim-Colombo, Fernanda Marciano
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8129580/
https://www.ncbi.nlm.nih.gov/pubmed/34017249
http://dx.doi.org/10.3389/fphar.2021.624895
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author Bricher Choque, Pamela Nithzi
Vieira, Rodolfo P.
Ulloa, Luis
Grabulosa, Caren
Irigoyen, Maria Claudia
De Angelis, Katia
Ligeiro De Oliveira, Ana Paula
Tracey, Kevin J.
Pavlov, Valentin A.
Consolim-Colombo, Fernanda Marciano
author_facet Bricher Choque, Pamela Nithzi
Vieira, Rodolfo P.
Ulloa, Luis
Grabulosa, Caren
Irigoyen, Maria Claudia
De Angelis, Katia
Ligeiro De Oliveira, Ana Paula
Tracey, Kevin J.
Pavlov, Valentin A.
Consolim-Colombo, Fernanda Marciano
author_sort Bricher Choque, Pamela Nithzi
collection PubMed
description Acute respiratory distress syndrome (ARDS) is a critical illness complication that is associated with high mortality. ARDS is documented in severe cases of COVID-19. No effective pharmacological treatments for ARDS are currently available. Dysfunctional immune responses and pulmonary and systemic inflammation are characteristic features of ARDS pathogenesis. Recent advances in our understanding of the regulation of inflammation point to an important role of the vagus-nerve-mediated inflammatory reflex and neural cholinergic signaling. We examined whether pharmacological cholinergic activation using a clinically approved (for myasthenia gravis) cholinergic drug, the acetylcholinesterase inhibitor pyridostigmine alters pulmonary and systemic inflammation in mice with lipopolysaccharide (LPS)-induced ARDS. Male C57Bl/6 mice received one intratracheal instillation of LPS or were sham manipulated (control). Both groups were treated with either vehicle or pyridostigmine (1.5 mg/kg twice daily, 3 mg/day) administered by oral gavage starting at 1 h post-LPS and euthanized 24 h after LPS administration. Other groups were either sham manipulated or received LPS for 3 days and were treated with vehicle or pyridostigmine and euthanized at 72 h. Pyridostigmine treatment reduced the increased total number of cells and neutrophils in the bronchoalveolar lavage fluid (BALF) in mice with ARDS at 24 and 72 h. Pyridostigmine also reduced the number of macrophages and lymphocytes at 72 h. In addition, pyridostigmine suppressed the levels of TNF, IL-1β, IL-6, and IFN-γ in BALF and plasma at 24 and 72 h. However, this cholinergic agent did not significantly altered BALF and plasma levels of the anti-inflammatory cytokine IL-10. Neither LPS nor pyridostigmine affected BALF IFN-γ and IL-10 levels at 24 h post-LPS. In conclusion, treatments with the cholinergic agent pyridostigmine ameliorate pulmonary and systemic inflammatory responses in mice with endotoxin-induced ARDS. Considering that pyridostigmine is a clinically approved drug, these findings are of substantial interest for implementing pyridostigmine in therapeutic strategies for ARDS.
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spelling pubmed-81295802021-05-19 The Cholinergic Drug Pyridostigmine Alleviates Inflammation During LPS-Induced Acute Respiratory Distress Syndrome Bricher Choque, Pamela Nithzi Vieira, Rodolfo P. Ulloa, Luis Grabulosa, Caren Irigoyen, Maria Claudia De Angelis, Katia Ligeiro De Oliveira, Ana Paula Tracey, Kevin J. Pavlov, Valentin A. Consolim-Colombo, Fernanda Marciano Front Pharmacol Pharmacology Acute respiratory distress syndrome (ARDS) is a critical illness complication that is associated with high mortality. ARDS is documented in severe cases of COVID-19. No effective pharmacological treatments for ARDS are currently available. Dysfunctional immune responses and pulmonary and systemic inflammation are characteristic features of ARDS pathogenesis. Recent advances in our understanding of the regulation of inflammation point to an important role of the vagus-nerve-mediated inflammatory reflex and neural cholinergic signaling. We examined whether pharmacological cholinergic activation using a clinically approved (for myasthenia gravis) cholinergic drug, the acetylcholinesterase inhibitor pyridostigmine alters pulmonary and systemic inflammation in mice with lipopolysaccharide (LPS)-induced ARDS. Male C57Bl/6 mice received one intratracheal instillation of LPS or were sham manipulated (control). Both groups were treated with either vehicle or pyridostigmine (1.5 mg/kg twice daily, 3 mg/day) administered by oral gavage starting at 1 h post-LPS and euthanized 24 h after LPS administration. Other groups were either sham manipulated or received LPS for 3 days and were treated with vehicle or pyridostigmine and euthanized at 72 h. Pyridostigmine treatment reduced the increased total number of cells and neutrophils in the bronchoalveolar lavage fluid (BALF) in mice with ARDS at 24 and 72 h. Pyridostigmine also reduced the number of macrophages and lymphocytes at 72 h. In addition, pyridostigmine suppressed the levels of TNF, IL-1β, IL-6, and IFN-γ in BALF and plasma at 24 and 72 h. However, this cholinergic agent did not significantly altered BALF and plasma levels of the anti-inflammatory cytokine IL-10. Neither LPS nor pyridostigmine affected BALF IFN-γ and IL-10 levels at 24 h post-LPS. In conclusion, treatments with the cholinergic agent pyridostigmine ameliorate pulmonary and systemic inflammatory responses in mice with endotoxin-induced ARDS. Considering that pyridostigmine is a clinically approved drug, these findings are of substantial interest for implementing pyridostigmine in therapeutic strategies for ARDS. Frontiers Media S.A. 2021-05-04 /pmc/articles/PMC8129580/ /pubmed/34017249 http://dx.doi.org/10.3389/fphar.2021.624895 Text en Copyright © 2021 Bricher Choque, Vieira, Ulloa, Grabulosa, Irigoyen, De Angelis, Ligeiro De Oliveira, Tracey, Pavlov and Consolim-Colombo. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Bricher Choque, Pamela Nithzi
Vieira, Rodolfo P.
Ulloa, Luis
Grabulosa, Caren
Irigoyen, Maria Claudia
De Angelis, Katia
Ligeiro De Oliveira, Ana Paula
Tracey, Kevin J.
Pavlov, Valentin A.
Consolim-Colombo, Fernanda Marciano
The Cholinergic Drug Pyridostigmine Alleviates Inflammation During LPS-Induced Acute Respiratory Distress Syndrome
title The Cholinergic Drug Pyridostigmine Alleviates Inflammation During LPS-Induced Acute Respiratory Distress Syndrome
title_full The Cholinergic Drug Pyridostigmine Alleviates Inflammation During LPS-Induced Acute Respiratory Distress Syndrome
title_fullStr The Cholinergic Drug Pyridostigmine Alleviates Inflammation During LPS-Induced Acute Respiratory Distress Syndrome
title_full_unstemmed The Cholinergic Drug Pyridostigmine Alleviates Inflammation During LPS-Induced Acute Respiratory Distress Syndrome
title_short The Cholinergic Drug Pyridostigmine Alleviates Inflammation During LPS-Induced Acute Respiratory Distress Syndrome
title_sort cholinergic drug pyridostigmine alleviates inflammation during lps-induced acute respiratory distress syndrome
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8129580/
https://www.ncbi.nlm.nih.gov/pubmed/34017249
http://dx.doi.org/10.3389/fphar.2021.624895
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