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J Immunotoxicol ; 18(1): 23-29, 2021 12.
Article in English | MEDLINE | ID: covidwho-1593522


The coronavirus SARS-CoV-2 of 2019 (COVID-19) causes a pandemic that has been diagnosed in more than 70 million people worldwide. Mild-to-moderate COVID-19 symptoms include coughing, fever, myalgia, shortness of breath, and acute inflammatory lung injury (ALI). In contrast, acute respiratory distress syndrome (ARDS) and respiratory failure occur in patients diagnosed with severe COVID-19. ARDS is mediated, at least in part, by a dysregulated inflammatory response due to excessive levels of circulating cytokines, a condition known as the "cytokine-storm syndrome." Currently, there are FDA-approved therapies that attenuate the dysregulated inflammation that occurs in COVID-19 patients, such as dexamethasone or other corticosteroids and IL-6 inhibitors, including sarilumab, tocilizumab, and siltuximab. However, the efficacy of these treatments have been shown to be inconsistent. Compounds that activate the vagus nerve-mediated cholinergic anti-inflammatory reflex, such as the α7 nicotinic acetylcholine receptor agonist, GTS-21, attenuate ARDS/inflammatory lung injury by decreasing the extracellular levels of high mobility group box-1 (HMGB1) in the airways and the circulation. It is possible that HMGB1 may be an important mediator of the "cytokine-storm syndrome." Notably, high plasma levels of HMGB1 have been reported in patients diagnosed with severe COVID-19, and there is a significant negative correlation between HMGB1 plasma levels and clinical outcomes. Nicotine can activate the cholinergic anti-inflammatory reflex, which attenuates the up-regulation and the excessive release of pro-inflammatory cytokines/chemokines. Therefore, we hypothesize that low molecular weight compounds that activate the cholinergic anti-inflammatory reflex, such as nicotine or GTS-21, may represent a potential therapeutic approach to attenuate the dysregulated inflammatory responses in patients with severe COVID-19.

Benzylidene Compounds/pharmacology , COVID-19/drug therapy , Cholinergic Agents/pharmacology , Inflammation/drug therapy , Nicotine/metabolism , Pyridines/pharmacology , SARS-CoV-2/physiology , Tobacco Use Disorder/drug therapy , Antibodies, Monoclonal, Humanized/therapeutic use , Cigarette Smoking/adverse effects , Dexamethasone/therapeutic use , HMGB1 Protein/blood , Humans , Pandemics , alpha7 Nicotinic Acetylcholine Receptor/agonists
J Pharmacol Exp Ther ; 375(3): 498-509, 2020 12.
Article in English | MEDLINE | ID: covidwho-842063


Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 virus, is turning out to be one of the most devastating global pandemics in the history of humankind. There is a shortage of effective therapeutic strategies or preventative vaccines for this disease to date. A rigorous investigation is needed for identifying and developing more effective therapeutic strategies for COVID-19. Angiotensin-converting enzyme 2 (ACE2), a crucial factor in COVID-19 pathogenesis, has been identified as a potential target for COVID-19 treatment. Smoking and vaping are potential risk factors for COVID-19 that are also shown to upregulate ACE2 expression. In this review, we have discussed the pathobiology of COVID-19 in the lungs and brain and the role of ACE2 in the transmission and pathobiology of this disease. Furthermore, we have shown possible interactions between nicotine/smoking and ACE2 in the lungs and brain, which could aggravate the transmission and pathobiology of COVID-19, resulting in a poor disease outcome. SIGNIFICANCE STATEMENT: This review addresses the present global pandemic of coronavirus disease 2019 (COVID-19) with respect to its pathobiology in the lungs and brain. It focuses on the potential negative impact of tobacco and nicotine exposure on the outcomes of this disease by interaction with the angiotensin-converting enzyme 2 receptor. It adds to the time-sensitive and critically important growing knowledge about the risk factors, transmission, pathobiology, and prognosis of COVID-19.

COVID-19/epidemiology , Smoking/epidemiology , Angiotensin-Converting Enzyme 2/metabolism , Animals , Brain/drug effects , Brain/metabolism , Brain/virology , COVID-19/etiology , COVID-19/transmission , Humans , Lung/drug effects , Lung/metabolism , Lung/virology , Nicotine/metabolism , Nicotine/toxicity , SARS-CoV-2/pathogenicity , Smoking/adverse effects
Med Hypotheses ; 143: 109871, 2020 Oct.
Article in English | MEDLINE | ID: covidwho-343478


recent studies have provided novel evidence regarding the effect of nicotine agonists on the prevention or modulation of cytokines storm and reduction of infection. In this study we tried to attempt to address these issues from a therapeutic perspective of nicotine agonists in this manner and we describe one of the most challenging theories of immunotherapy in coronavirus-19 (COVID-19). The analysis of the proposed mechanism goes beyond the physiological consequences of a way to design new strategies to provide anti-inflammatory drugs.

Anti-Inflammatory Agents/administration & dosage , Coronavirus Infections/drug therapy , Coronavirus Infections/immunology , Immune System/drug effects , Immune System/virology , Nicotinic Agonists/administration & dosage , Pneumonia, Viral/drug therapy , Pneumonia, Viral/immunology , Anti-Inflammatory Agents/therapeutic use , Betacoronavirus , Biomarkers/metabolism , COVID-19 , Cholinergic Agents/therapeutic use , Coronavirus Infections/mortality , Cytokines/metabolism , Humans , Immunotherapy , Inflammation , Nicotine/metabolism , Pandemics , Pneumonia, Viral/mortality , Receptors, Nicotinic/metabolism , SARS-CoV-2 , Survivors , Treatment Outcome