{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T10:26:32Z","timestamp":1780050392765,"version":"3.53.1"},"reference-count":65,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,5,4]],"date-time":"2021-05-04T00:00:00Z","timestamp":1620086400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>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\u00a0mg\/kg twice daily, 3\u00a0mg\/day) administered by oral gavage starting at 1\u00a0h post-LPS and euthanized 24\u00a0h after LPS administration. Other groups were either sham manipulated or received LPS for 3\u00a0days and were treated with vehicle or pyridostigmine and euthanized at 72\u00a0h. 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\u00a0h. Pyridostigmine also reduced the number of macrophages and lymphocytes at 72\u00a0h. In addition, pyridostigmine suppressed the levels of TNF, IL-1\u03b2, IL-6, and IFN-\u03b3 in BALF and plasma at 24 and 72\u00a0h. 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-\u03b3 and IL-10 levels at 24\u00a0h 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.<\/jats:p>","DOI":"10.3389\/fphar.2021.624895","type":"journal-article","created":{"date-parts":[[2021,5,4]],"date-time":"2021-05-04T06:57:26Z","timestamp":1620111446000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":14,"title":["The Cholinergic Drug Pyridostigmine Alleviates Inflammation During LPS-Induced Acute Respiratory Distress Syndrome"],"prefix":"10.3389","volume":"12","author":[{"given":"Pamela Nithzi","family":"Bricher Choque","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rodolfo P.","family":"Vieira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis","family":"Ulloa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caren","family":"Grabulosa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Claudia","family":"Irigoyen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katia","family":"De Angelis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Paula","family":"Ligeiro De Oliveira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin J.","family":"Tracey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentin A.","family":"Pavlov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernanda Marciano","family":"Consolim-Colombo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,5,4]]},"reference":[{"key":"B2","doi-asserted-by":"publisher","first-page":"L709","DOI":"10.1152\/ajplung.00341.2013","article-title":"Diverse Macrophage Populations Mediate Acute Lung Inflammation and Resolution","volume":"306","author":"Aggarwal","year":"2014","journal-title":"Am. J. Physiol-Lung Cell Mol. Physiol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"773","DOI":"10.1002\/lsm.20357","article-title":"Low Level Laser Therapy Partially Restores Trachea Muscle Relaxation Response in Rats with Tumor Necrosis Factor \u03b1-mediated Smooth Airway Muscle Dysfunction","volume":"38","author":"Aimbire","year":"2006","journal-title":"Lasers Surg. Med."},{"key":"B4","doi-asserted-by":"publisher","first-page":"1483","DOI":"10.1007\/s00268-005-0073-2","article-title":"Effect of Neostigmine on Organ Injury in Murine Endotoxemia: Missing Facts about the Cholinergic Antiinflammatory Pathway","volume":"29","author":"Akinci","year":"2005","journal-title":"World J. Surg."},{"key":"B5","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1186\/s10020-020-00172-4","article-title":"Extracellular HMGB1: a Therapeutic Target in Severe Pulmonary Inflammation Including COVID-19?","volume":"26","author":"Andersson","year":"2020","journal-title":"Mol. Med."},{"key":"B6","doi-asserted-by":"publisher","first-page":"1838","DOI":"10.1002\/jcp.29101","article-title":"Cholinergic Anti\u2010inflammatory Pathway Confers Airway Protection against Oxidative Damage and Attenuates Inflammation in an Allergic Asthma Model","volume":"235","author":"Antunes","year":"2020","journal-title":"J. Cel Physiol"},{"key":"B7","doi-asserted-by":"publisher","first-page":"788","DOI":"10.1001\/jama.2016.0291","article-title":"Epidemiology, Patterns of Care, and Mortality for Patients With Acute Respiratory Distress Syndrome in Intensive Care Units in 50 Countries","volume":"315","author":"Bellani","year":"2016","journal-title":"Jama"},{"key":"B8","doi-asserted-by":"publisher","first-page":"901","DOI":"10.1016\/s0091-3057(03)00012-1","article-title":"Effect of Chronic Pyridostigmine Bromide Treatment on Cardiovascular and Behavioral Parameters in Mice","volume":"74","author":"Bernatova","year":"2003","journal-title":"Pharmacol. Biochem. Behav."},{"key":"B9","doi-asserted-by":"publisher","first-page":"948","DOI":"10.1111\/nmo.12792","article-title":"Chronic Vagus Nerve Stimulation in Crohn\u2019s Disease: a 6-month Follow-Up Pilot Study","volume":"28","author":"Bonaz","year":"2016","journal-title":"Neurogastroenterol. Motil."},{"key":"B10","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1186\/s42234-020-00051-7","article-title":"Targeting the Cholinergic Anti-inflammatory Pathway with Vagus Nerve Stimulation in Patients with Covid-19?","volume":"6","author":"Bonaz","year":"2020","journal-title":"Bioelectron. Med."},{"key":"B11","doi-asserted-by":"publisher","first-page":"458","DOI":"10.1038\/35013070","article-title":"Vagus Nerve Stimulation Attenuates the Systemic Inflammatory Response to Endotoxin","volume":"405","author":"Borovikova","year":"2000","journal-title":"Nature"},{"key":"B12","doi-asserted-by":"publisher","first-page":"473","DOI":"10.1007\/s00423-008-0317-3","article-title":"Endotoxemia and Endotoxin Tolerance in Patients with ARDS","volume":"393","author":"Buttenschoen","year":"2008","journal-title":"Langenbecks Arch. Surg."},{"key":"B13","doi-asserted-by":"publisher","first-page":"e93340","DOI":"10.1172\/jci.insight.93340","article-title":"Galantamine Alleviates Inflammation and Insulin Resistance in Patients with Metabolic Syndrome in a Randomized Trial","volume":"2","author":"Consolim-Colombo","year":"2017","journal-title":"JCI insight"},{"key":"B14","doi-asserted-by":"publisher","first-page":"910","DOI":"10.1161\/circulationaha.117.027451","article-title":"Contribution of Impaired Parasympathetic Activity to Right Ventricular Dysfunction and Pulmonary Vascular Remodeling in Pulmonary Arterial Hypertension","volume":"137","author":"da Silva Gon\u00e7alves B\u00f3s","year":"2018","journal-title":"Circulation"},{"key":"B15","doi-asserted-by":"publisher","first-page":"915","DOI":"10.1038\/sj.bjp.0707264","article-title":"The Alpha7 Nicotinic Acetylcholine Receptor as a Pharmacological Target for Inflammation","volume":"151","author":"de Jonge","year":"2007","journal-title":"Br. J. Pharmacol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"610","DOI":"10.1111\/1440-1681.12121","article-title":"Cholinergic Stimulation with Pyridostigmine Improves Autonomic Function in Infarcted Rats","volume":"40","author":"de La Fuente","year":"2013","journal-title":"Clin. Exp. Pharmacol. Physiol."},{"key":"B55","doi-asserted-by":"publisher","first-page":"471","DOI":"10.1164\/rccm.201002-0314oc","article-title":"Neuroimmune Regulation of Ventilator-Induced Lung Injury","volume":"183","author":"dos Santos","year":"2011","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"B17","doi-asserted-by":"publisher","first-page":"e104476","DOI":"10.1371\/journal.pone.0104476","article-title":"Pyridostigmine Restores Cardiac Autonomic Balance after Small Myocardial Infarction in Mice","volume":"9","author":"Durand","year":"2014","journal-title":"PLoS One"},{"key":"B18","doi-asserted-by":"publisher","first-page":"698","DOI":"10.1001\/jama.2017.21907","article-title":"Acute Respiratory Distress Syndrome: Advances in Diagnosis and Treatment","volume":"319","author":"Fan","year":"2018","journal-title":"Jama"},{"key":"B19","doi-asserted-by":"publisher","first-page":"658","DOI":"10.32388\/jflae3","article-title":"Editorial: Nicotine and SARS-CoV-2: COVID-19 May Be a Disease of the Nicotinic Cholinergic System","volume":"7","author":"Farsalinos","year":"2020","journal-title":"Toxicol. Rep."},{"key":"B20","doi-asserted-by":"publisher","first-page":"1407","DOI":"10.1016\/s0140-6736(20)30858-8","article-title":"Trials of Anti-tumour Necrosis Factor Therapy for COVID-19 Are Urgently Needed","volume":"395","author":"Feldmann","year":"2020","journal-title":"The Lancet"},{"key":"B21","doi-asserted-by":"publisher","first-page":"757","DOI":"10.1016\/j.ijcard.2016.10.061","article-title":"Impact of Exercise Training Associated to Pyridostigmine Treatment on Autonomic Function and Inflammatory Profile after Myocardial Infarction in Rats","volume":"227","author":"Feriani","year":"2017","journal-title":"Int. J. Cardiol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"e527","DOI":"10.1016\/s2665-9913(20)30172-7","article-title":"Safety and Efficacy of Neurostimulation with a Miniaturised Vagus Nerve Stimulation Device in Patients with Multidrug-Refractory Rheumatoid Arthritis: a Two-Stage Multicentre, Randomised Pilot Study","volume":"2","author":"Genovese","year":"2020","journal-title":"Lancet Rheumatol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"855","DOI":"10.4049\/jimmunol.1402513","article-title":"The Acute Respiratory Distress Syndrome: from Mechanism to Translation","volume":"194","author":"Han","year":"2015","journal-title":"J. Immunol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"65","DOI":"10.3389\/fimmu.2011.00065","article-title":"Acute Lung Injury: How Macrophages Orchestrate Resolution of Inflammation and Tissue Repair","volume":"2","author":"Herold","year":"2011","journal-title":"Front. Immunol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"1623","DOI":"10.1084\/jem.20052362","article-title":"Splenectomy Inactivates the Cholinergic Antiinflammatory Pathway during Lethal Endotoxemia and Polymicrobial Sepsis","volume":"203","author":"Huston","year":"2006","journal-title":"J. Exp. Med."},{"key":"B27","doi-asserted-by":"publisher","first-page":"335","DOI":"10.1038\/mi.2013.52","article-title":"Central Cholinergic Activation of a Vagus Nerve-To-Spleen Circuit Alleviates Experimental Colitis","volume":"7","author":"Ji","year":"2014","journal-title":"Mucosal Immunol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1165\/rcmb.2012-0090oc","article-title":"Pulmonary Macrophage Subpopulations in the Induction and Resolution of Acute Lung Injury","volume":"47","author":"Johnston","year":"2012","journal-title":"Am. J. Respir. Cel Mol Biol"},{"key":"B29","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1016\/s0091-3057(01)00596-2","article-title":"The Combined Effects of Pyridostigmine and Chronic Stress on Brain Cortical and Blood Acetylcholinesterase, Corticosterone, Prolactin and Alternation Performance in Rats","volume":"70","author":"Kant","year":"2001","journal-title":"Pharmacol. Biochem. Behav."},{"key":"B30","doi-asserted-by":"publisher","first-page":"8284","DOI":"10.1073\/pnas.1605635113","article-title":"Vagus Nerve Stimulation Inhibits Cytokine Production and Attenuates Disease Severity in Rheumatoid Arthritis","volume":"113","author":"Koopman","year":"2016","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B31","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1093\/bja\/aer202","article-title":"\u03b17 Nicotinic Acetylcholine Receptor Agonist GTS-21 Attenuates Ventilator-Induced Tumour Necrosis Factor-\u03b1 Production and Lung Injury","volume":"107","author":"Kox","year":"2011","journal-title":"Br. J. Anaesth."},{"key":"B32","doi-asserted-by":"publisher","first-page":"R908","DOI":"10.1152\/ajpregu.00102.2013","article-title":"Increase in Parasympathetic Tone by Pyridostigmine Prevents Ventricular Dysfunction during the Onset of Heart Failure","volume":"305","author":"Lataro","year":"2013","journal-title":"Am. J. Physiol-Regul., Integr. Comp. Physiol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"585","DOI":"10.3389\/fimmu.2019.00585","article-title":"Forebrain Cholinergic Signaling Regulates Innate Immune Responses and Inflammation","volume":"10","author":"Lehner","year":"2019","journal-title":"Front. Immunol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"1041","DOI":"10.1002\/mus.25625","article-title":"Prescription Profile of Pyridostigmine Use in a Population of Patients with Myasthenia Gravis","volume":"56","author":"Machado-Alba","year":"2017","journal-title":"Muscle Nerve"},{"key":"B35","doi-asserted-by":"publisher","first-page":"L379","DOI":"10.1152\/ajplung.00010.2008","article-title":"Animal Models of Acute Lung Injury","volume":"295","author":"Matute-Bello","year":"2008","journal-title":"Am. J. Physiology-Lung Cell Mol. Physiol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"1303","DOI":"10.1378\/chest.108.5.1303","article-title":"Inflammatory Cytokines in the BAL of Patients with ARDS. Persistent Elevation over Time Predicts Poor Outcome","volume":"108","author":"Meduri","year":"1995","journal-title":"Chest"},{"key":"B1","doi-asserted-by":"publisher","first-page":"1631","DOI":"10.1378\/chest.08-2408","article-title":"Activation and Regulation of Systemic Inflammation in ARDS: Rationale for Prolonged Glucocorticoid Therapy","volume":"136","author":"Meduri","year":"2009","journal-title":"Chest"},{"key":"B36","doi-asserted-by":"publisher","first-page":"1033","DOI":"10.1016\/s0140-6736(20)30628-0","article-title":"COVID-19: Consider Cytokine Storm Syndromes and Immunosuppression","volume":"395","author":"Mehta","year":"2020","journal-title":"The Lancet"},{"key":"B37","doi-asserted-by":"publisher","first-page":"2287","DOI":"10.3892\/or.2018.6616","article-title":"\u03b17nAchR Agonist GTS21 Reduces RadiationInduced Lung Injury","volume":"40","author":"Mei","year":"2018","journal-title":"Oncol. Rep."},{"key":"B38","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1111\/jnc.15243","article-title":"Treating Disorders across the Lifespan by Modulating Cholinergic Signaling with Galantamine","author":"Metz","year":"2020","journal-title":"J. Neurochem."},{"key":"B39","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1016\/s1566-0702(03)00023-7","article-title":"Cholinergic Pathways Modulate Experimental Dinitrobenzene Sulfonic Acid Colitis in Rats","volume":"105","author":"Miceli","year":"2003","journal-title":"Auton. Neurosci."},{"key":"B40","doi-asserted-by":"crossref","first-page":"1485","DOI":"10.1002\/9783527692156.ch59","article-title":"The Neuroimmune Communicatome in Inflammation","volume-title":"Inflammation: From Molecular and Cellular Mechanisms to the Clinic","author":"Olofsson","year":"2017"},{"key":"B41","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1007\/s12026-015-8718-1","article-title":"Neural Circuitry and Immunity","volume":"63","author":"Pavlov","year":"2015","journal-title":"Immunologic Res."},{"key":"B42","doi-asserted-by":"publisher","first-page":"156","DOI":"10.1038\/nn.4477","article-title":"Neural Regulation of Immunity: Molecular Mechanisms and Clinical Translation","volume":"20","author":"Pavlov","year":"2017","journal-title":"Nat. Neurosci."},{"key":"B43","doi-asserted-by":"publisher","first-page":"5219","DOI":"10.1073\/pnas.0600506103","article-title":"Central Muscarinic Cholinergic Regulation of the Systemic Inflammatory Response during Endotoxemia","volume":"103","author":"Pavlov","year":"2006","journal-title":"Proc. Natl. Acad. Sci."},{"key":"B44","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1016\/j.bbi.2008.06.011","article-title":"Brain Acetylcholinesterase Activity Controls Systemic Cytokine Levels through the Cholinergic Anti-inflammatory Pathway","volume":"23","author":"Pavlov","year":"2009","journal-title":"Brain Behav. Immun."},{"key":"B45","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1186\/s42234-019-0021-3","article-title":"Collateral Benefits of Studying the Vagus Nerve in Bioelectronic Medicine","volume":"5","author":"Pavlov","year":"2019","journal-title":"Bioelectronic Med."},{"key":"B46","doi-asserted-by":"publisher","first-page":"107794","DOI":"10.1016\/j.pharmthera.2020.107794","article-title":"The Evolving Obesity Challenge: Targeting the Vagus Nerve and the Inflammatory Reflex in the Response","volume":"222","author":"Pavlov","year":"2021","journal-title":"Pharmacol. Ther."},{"key":"B47","doi-asserted-by":"publisher","first-page":"R1261","DOI":"10.1152\/ajpregu.00362.2017","article-title":"Pharmacological Potentiation of the Efferent Vagus Nerve Attenuates Blood Pressure and Renal Injury in a Murine Model of Systemic Lupus Erythematosus","volume":"315","author":"Pham","year":"2018","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"B49","first-page":"36","article-title":"Aerobic Exercise Inhibits Acute Lung Injury: from Mouse to Human Evidence Exercise Reduced Lung Injury Markers in Mouse and in Cells","volume":"24","author":"Rigonato-Oliveira","year":"2018","journal-title":"Exerc. Immunol. Rev."},{"key":"B50","doi-asserted-by":"publisher","first-page":"101623","DOI":"10.1016\/j.tmaid.2020.101623","article-title":"Clinical, Laboratory and Imaging Features of COVID-19: A Systematic Review and Meta-Analysis","volume":"34","author":"Rodriguez-Morales","year":"2020","journal-title":"Trav. Med. Infect. Dis."},{"key":"B51","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1126\/science.1209985","article-title":"Acetylcholine-synthesizing T Cells Relay Neural Signals in a Vagus Nerve Circuit","volume":"334","author":"Rosas-Ballina","year":"2011","journal-title":"Science"},{"key":"B52","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.bbi.2014.07.010","article-title":"Xanomeline Suppresses Excessive Pro-inflammatory Cytokine Responses through Neural Signal-Mediated Pathways and Improves Survival in Lethal Inflammation","volume":"44","author":"Rosas-Ballina","year":"2015","journal-title":"Brain Behav. Immun."},{"key":"B53","doi-asserted-by":"publisher","first-page":"846","DOI":"10.1007\/s00134-020-05991-x","article-title":"Clinical Predictors of Mortality Due to COVID-19 Based on an Analysis of Data of 150 Patients from Wuhan, China","volume":"46","author":"Ruan","year":"2020","journal-title":"Intensive Care Med."},{"key":"B54","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2021.613979","article-title":"The cholinergic drug galantamine alleviates oxidative stress alongside anti-inflammatory and cardio-metabolic effects in subjects with the metabolic syndrome in a randomized trial","volume":"12","author":"Sangaleti","year":"2021","journal-title":"Front Immunol"},{"key":"B56","doi-asserted-by":"publisher","first-page":"118972","DOI":"10.1016\/j.lfs.2020.118972","article-title":"Exercise and Pyridostigmine Prevents Gastric Emptying Delay and Increase Blood Pressure and Cisplatin-Induced Baroreflex Sensitivity in Rats","volume":"267","author":"Silva","year":"2021","journal-title":"Life Sci."},{"key":"B57","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1186\/s10020-020-00177-z","article-title":"The \u03b17 Nicotinic Acetylcholine Receptor Agonist, GTS-21, Attenuates Hyperoxia-Induced Acute Inflammatory Lung Injury by Alleviating the Accumulation of HMGB1 in the Airways and the Circulation","volume":"26","author":"Sitapara","year":"2020","journal-title":"Mol. Med."},{"key":"B58","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1016\/j.autneu.2004.05.002","article-title":"Cholinergic Stimulation with Pyridostigmine Increases Heart Rate Variability and Baroreflex Sensitivity in Rats","volume":"113","author":"Soares","year":"2004","journal-title":"Auton. Neurosci. : Basic Clin."},{"key":"B59","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s12950-018-0202-y","article-title":"Biomarkers for Acute Respiratory Distress Syndrome and Prospects for Personalised Medicine","volume":"16","author":"Spadaro","year":"2019","journal-title":"J. Inflamm. (London, England)"},{"key":"B60","doi-asserted-by":"publisher","first-page":"784","DOI":"10.1111\/ner.13172","article-title":"Use of Non-invasive Vagus Nerve Stimulation to Treat Respiratory Symptoms Associated with COVID-19: A Theoretical Hypothesis and Early Clinical Experience","volume":"23","author":"Staats","year":"2020","journal-title":"Neuromodulation."},{"key":"B61","doi-asserted-by":"publisher","first-page":"186","DOI":"10.1165\/rcmb.2006-0240oc","article-title":"Activation of the \u03b17 nAChR Reduces Acid-Induced Acute Lung Injury in Mice and Rats","volume":"37","author":"Su","year":"2007","journal-title":"Am. J. Respir. Cel Mol Biol"},{"key":"B62","doi-asserted-by":"publisher","first-page":"1669","DOI":"10.1093\/ntr\/ntaa077","article-title":"Beyond Smoking Cessation: Investigating Medicinal Nicotine to Prevent and Treat COVID-19","volume":"22","author":"Tindle","year":"2020","journal-title":"Nicotine. Tob. Res."},{"key":"B63","doi-asserted-by":"publisher","first-page":"853","DOI":"10.1038\/nature01321","article-title":"The Inflammatory Reflex","volume":"420","author":"Tracey","year":"2002","journal-title":"Nature"},{"key":"B64","doi-asserted-by":"publisher","first-page":"384","DOI":"10.1038\/nature01339","article-title":"Nicotinic Acetylcholine Receptor \u03b17 Subunit Is an Essential Regulator of Inflammation","volume":"421","author":"Wang","year":"2003","journal-title":"Nature"},{"key":"B65","doi-asserted-by":"publisher","first-page":"1216","DOI":"10.1038\/nm1124","article-title":"Cholinergic Agonists Inhibit HMGB1 Release and Improve Survival in Experimental Sepsis","volume":"10","author":"Wang","year":"2004","journal-title":"Nat. Med."},{"key":"B66","doi-asserted-by":"publisher","first-page":"2236","DOI":"10.1007\/s10753-019-01088-w","article-title":"Activation of Alpha-7 Nicotinic Acetylcholine Receptors (\u03b17nAchR) Promotes the Protective Autophagy in LPS-Induced Acute Lung Injury (ALI) In Vitro and In Vivo","volume":"42","author":"Zhao","year":"2019","journal-title":"Inflammation"}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2021.624895\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,5,4]],"date-time":"2021-05-04T06:57:32Z","timestamp":1620111452000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2021.624895\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,4]]},"references-count":65,"alternative-id":["10.3389\/fphar.2021.624895"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2021.624895","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,4]]},"article-number":"624895"}}