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1.
Free Radic Biol Med ; 190: 247-263, 2022 09.
Article in English | MEDLINE | ID: covidwho-2036015

ABSTRACT

Clinical studies have shown a significant positive correlation between age and the likelihood of being infected with SARS-CoV-2. This increased susceptibility is positively correlated with chronic inflammation and compromised neurocognitive functions. Postmortem analyses suggest that acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), with systemic and lung hyperinflammation, can cause significant morbidity and mortality in COVID-19 patients. Supraphysiological supplemental oxygen, also known as hyperoxia, is commonly used to treat decreased blood oxygen saturation in COVID-19 patients. However, prolonged exposure to hyperoxia alone can cause oxygen toxicity, due to an excessive increase in the levels of reactive oxygen species (ROS), which can overwhelm the cellular antioxidant capacity. Subsequently, this causes oxidative cellular damage and increased levels of aging biomarkers, such as telomere shortening and inflammaging. The oxidative stress in the lungs and brain can compromise innate immunity, resulting in an increased susceptibility to secondary lung infections, impaired neurocognitive functions, and dysregulated hyperinflammation, which can lead to ALI/ARDS, and even death. Studies indicate that lung inflammation is regulated by the central nervous system, notably, the cholinergic anti-inflammatory pathway (CAIP), which is innervated by the vagus nerve and α7 nicotinic acetylcholine receptors (α7nAChRs) on lung cells, particularly lung macrophages. The activation of α7nAChRs attenuates oxygen toxicity in the lungs and improves clinical outcomes by restoring hyperoxia-compromised innate immunity. Mechanistically, α7nAChR agonist (e.g., GAT 107 and GTS-21) can regulate redox signaling by 1) activating Nrf2, a master regulator of the antioxidant response and a cytoprotective defense system, which can decrease cellular damage caused by ROS and 2) inhibiting the activation of the NF-κB-mediated inflammatory response. Notably, GTS-21 has been shown to be safe and it improves neurocognitive functions in humans. Therefore, targeting the α7nAChR may represent a viable therapeutic approach for attenuating dysregulated hyperinflammation-mediated ARDS and sepsis in COVID-19 patients receiving prolonged oxygen therapy.


Subject(s)
Acute Lung Injury , COVID-19 , Hyperoxia , Pneumonia , Respiratory Distress Syndrome , Acute Lung Injury/metabolism , Aging , Antioxidants/metabolism , COVID-19/therapy , Humans , Hyperoxia/complications , Hyperoxia/metabolism , Lung/metabolism , Oxygen/metabolism , Pneumonia/metabolism , Reactive Oxygen Species/metabolism , SARS-CoV-2 , alpha7 Nicotinic Acetylcholine Receptor/metabolism
2.
World J Crit Care Med ; 11(4): 228-235, 2022 Jul 09.
Article in English | MEDLINE | ID: covidwho-2025160

ABSTRACT

The cholinergic anti-inflammatory pathway (CAP) refers to the anti-inflammatory effects mediated by the parasympathetic nervous system. Existence of this pathway was first demonstrated when acetylcholinesterase inhibitors showed benefits in animal models of sepsis. CAP functions via the vagus nerve. The systemic anti-inflammatory effects of CAP converges on the α7 nicotinic acetylcholine receptor on splenic macrophages, leading to suppression of pro-inflammatory cytokines and simultaneous stimulation of anti-inflammatory cytokines, including interleukin 10. CAP offers a novel mechanism to mitigate inflammation. Electrical vagal nerve stimulation has shown benefits in patients suffering from rheumatoid arthritis. Direct agonists like nicotine and GTS-1 have also demonstrated anti-inflammatory properties in models of sepsis and acute respiratory distress syndrome, as have acetylcholinesterase inhibitors like Galantamine and Physostigmine. Experience with coronavirus disease 2019 (COVID-19) induced acute respiratory distress syndrome indicates that immunomodulators have a protective role in patient outcomes. Dexamethasone is the only medication currently in use that has shown to improve clinical outcomes. This is likely due to the suppression of what is referred to as a cytokine storm, which is implicated in the lethality of viral pneumonia. Nicotine transdermal patch activates CAP and harvests its anti-inflammatory potential by means of an easily administered depot delivery mechanism. It could prove to be a promising, safe and inexpensive additional tool in the currently limited armamentarium at our disposal for management of COVID-19 induced acute hypoxic respiratory failure.

3.
Mol Med ; 28(1): 57, 2022 05 16.
Article in English | MEDLINE | ID: covidwho-1846786

ABSTRACT

BACKGROUND: Severe COVID-19 is characterized by pro-inflammatory cytokine release syndrome (cytokine storm) which causes high morbidity and mortality. Recent observational and clinical studies suggest famotidine, a histamine 2 receptor (H2R) antagonist widely used to treat gastroesophageal reflux disease, attenuates the clinical course of COVID-19. Because evidence is lacking for a direct antiviral activity of famotidine, a proposed mechanism of action is blocking the effects of histamine released by mast cells. Here we hypothesized that famotidine activates the inflammatory reflex, a brain-integrated vagus nerve mechanism which inhibits inflammation via alpha 7 nicotinic acetylcholine receptor (α7nAChR) signal transduction, to prevent cytokine storm. METHODS: The potential anti-inflammatory effects of famotidine and other H2R antagonists were assessed in mice exposed to lipopolysaccharide (LPS)-induced cytokine storm. As the inflammatory reflex is integrated and can be stimulated in the brain, and H2R antagonists penetrate the blood brain barrier poorly, famotidine was administered by intracerebroventricular (ICV) or intraperitoneal (IP) routes. RESULTS: Famotidine administered IP significantly reduced serum and splenic LPS-stimulated tumor necrosis factor (TNF) and IL-6 concentrations, significantly improving survival. The effects of ICV famotidine were significantly more potent as compared to the peripheral route. Mice lacking mast cells by genetic deletion also responded to famotidine, indicating the anti-inflammatory effects are not mast cell-dependent. Either bilateral sub-diaphragmatic vagotomy or genetic knock-out of α7nAChR abolished the anti-inflammatory effects of famotidine, indicating the inflammatory reflex as famotidine's mechanism of action. While the structurally similar H2R antagonist tiotidine displayed equivalent anti-inflammatory activity, the H2R antagonists cimetidine or ranitidine were ineffective even at very high dosages. CONCLUSIONS: These observations reveal a previously unidentified vagus nerve-dependent anti-inflammatory effect of famotidine in the setting of cytokine storm which is not replicated by high dosages of other H2R antagonists in clinical use. Because famotidine is more potent when administered intrathecally, these findings are also consistent with a primarily central nervous system mechanism of action.


Subject(s)
COVID-19 , Famotidine , Animals , Anti-Inflammatory Agents , Cytokine Release Syndrome , Famotidine/pharmacology , Histamine , Histamine H2 Antagonists , Lipopolysaccharides , Mice , Reflex , Vagus Nerve , alpha7 Nicotinic Acetylcholine Receptor
4.
Clin Exp Neuroimmunol ; 2022 Apr 29.
Article in English | MEDLINE | ID: covidwho-1819880

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified in Wuhan, China, in late 2019 and caused coronavirus disease 2019 (COVID-19), which is still a global pandemic. In most infected people, SARS-CoV-2 can only cause moderate symptoms, while in other patients, it leads to severe illness and eventually death. Although the main clinical manifestation of COVID-19 is often seen in the lungs, this disease affects almost all body organs. The excessive and prolonged release of inflammatory cytokines that may occur in COVID-19 patients, known as cytokine storms, stimulates undesired immune responses and can cause various tissues damage. In the current review article, we focus on the potential advantages of the intrinsic cholinergic anti-inflammatory pathway (CAP) as the efferent arm of inflammatory reflex in COVID-19 management. Considering this endogenous protective mechanism against chronic inflammation, we focused on the effects of SARS-CoV-2 in the destruction of this anti-inflammatory system. Several studies indicated the interaction of SARS-CoV-2 with the alpha7 subtype of the nicotinic acetylcholine receptor as the effector molecule of the inflammatory reflex. On the other hand, neurological manifestations have increasingly been identified as significant extrapulmonary manifestations of COVID-19. The rational connection between these findings and COVID-19 pathogenesis may be an important issue in both our understanding and dealing with this disease. COVID-19 is deeply rooted in our daily life and requires an urgent need for the establishment of effective therapeutic options, and all the possible treatments must be considered for the control of such inflammatory conditions.

5.
Bioimpacts ; 12(2): 171-174, 2022.
Article in English | MEDLINE | ID: covidwho-1668071

ABSTRACT

The cholinergic anti-inflammatory pathway (CAP) first described by Wang et al, 2003 has contemporary interest arising from the COVID-19 pandemic. While tobacco smoking has been considered an aggravating factor in the severity of COVID-19 infections, it has been suggested by some that the nicotine derived from tobacco could lessen the severity of COVID-19 infections. This spotlight briefly describes the CAP and its potential role as a therapeutic target for the treatment of COVID-19 infections using vagus nerve stimulation or selective alpha7 nicotinic acetylcholine receptor agonists.

6.
J Proteome Res ; 21(3): 599-611, 2022 03 04.
Article in English | MEDLINE | ID: covidwho-1510548

ABSTRACT

Acylcholines are comprised of an acyl chain esterified to a choline moiety; acetylcholine is the best-characterized member of this class, functioning as a neurotransmitter in the central and peripheral nervous systems as well as an inhibitor of cytokine production by macrophages and other innate immune cells. Acylcholines are metabolized by a class of cholinesterases, including acetylcholinesterase (a specific regulator of acetylcholine levels) and butyrylcholinesterase (BChE, an enigmatic enzyme whose function has not been resolved by genetic knockout models). BChE provides reserve capacity to hydrolyze acetylcholine, but its importance is arguable given acetylcholinesterase is the most catalytically efficient enzyme characterized to date. While known to be substrates of BChE in vitro, endogenous production of long-chain acylcholines is a recent discovery enabled by untargeted metabolomics. Compared to acetylcholine, long-chain acylcholines show greater stability in circulation with homeostatic levels-dictated by synthesis and clearance-suggested to impact cholinergic receptor sensitivity of acetylcholine with varying levels of antagonism. Acylcholines then provide a link between BChE and non-neuronal acetylcholine signaling, filling a gap in understanding around how imbalances between acylcholines and BChE could modulate inflammatory disease, such as the "cytokine storm" identified in severe COVID-19. Areas for further research, development, and clinical testing are outlined.


Subject(s)
Butyrylcholinesterase , COVID-19 , Acetylcholinesterase/genetics , Acetylcholinesterase/metabolism , Butyrylcholinesterase/genetics , Butyrylcholinesterase/metabolism , Cholinergic Agents , Humans , SARS-CoV-2
7.
Front Physiol ; 12: 704599, 2021.
Article in English | MEDLINE | ID: covidwho-1365574

ABSTRACT

Importance: An exacerbated inflammatory response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is believed to be one of the major causes of the morbidity and mortality of the coronavirus disease 2019 (COVID-19). Neuromodulation therapy, based on vagus nerve stimulation, was recently hypothesized to control both the SARS-CoV-2 replication and the ensuing inflammation likely through the inhibition of the nuclear factor kappa-light-chain-enhancer of activated B cells pathway and could improve the clinical outcomes as an adjunct treatment. We proposed to test it by the stimulation of the auricular branch of the vagus nerve, i.e., auricular neuromodulation (AN), a non-invasive procedure through the insertion of semipermanent needles on the ears. Objective: The aim of this study was to assess the effect of AN on the clinical outcomes in patients affected by COVID-19. Design, Setting, and Participants: A multicenter, randomized, placebo-controlled, double-blind clinical trial included 31 patients with respiratory failure due to COVID-19 requiring hospitalization. Within 72 h after admission, patients received either AN (n = 14) or sham neuromodulation (SN, n = 15) in addition to the conventional treatments. Main Outcome and Measures: The primary endpoint of the study was the rate of a clinical benefit conferred by AN at Day 14 (D14) as assessed by a 7-point Clinical Progression Scale. The secondary endpoint of the study was the impact of AN on the rate of transfer to the intensive care unit (ICU) and on the survival rate at D14. Results: The AN procedure was well-tolerated without any reported side effects but with no significant improvement for the measures of both primary (p > 0.3) and secondary (p > 0.05) endpoints at the interim analysis. None of the AN-treated patients died but one in the SN group did (81 years). Two AN-treated patients (73 and 79 years, respectively) and one SN-treated patient (59 years) were transferred to ICU. Remarkably, AN-treated patients were older with more representation by males than in the SN arm (i.e., the median age of 75 vs. 65 years, 79% male vs. 47%). Conclusion: The AN procedure, which was used within 72 h after the admission of patients with COVID-19, was safe and could be successfully implemented during the first two waves of COVID-19 in France. Nevertheless, AN did not significantly improve the outcome of the patients in our small preliminary study. It is pertinent to explore further to validate AN as the non-invasive mass vagal stimulation solution for the forthcoming pandemics. Clinical Trial Registration: [https://clinicaltrials.gov/], identifier [NCT04341415].

8.
Front Psychol ; 12: 624655, 2021.
Article in English | MEDLINE | ID: covidwho-1247906

ABSTRACT

The coronavirus disease 2019 (COVID-19) has been causing major disruptions in the sporting world. Negative physiological and psychological effects on athletes have been reported, such as respiratory issues and increased stress. Therefore, it is timely to support this population by presenting cost-effective and accessible intervention techniques to reduce this impact. Slow-paced breathing (SPB) has the potential to counteract many of the detrimental effects of COVID-19 that can directly affect sports performance. In this article, we present and justify the use of SPB in athletes by focusing on three key outcomes, namely aerobic endurance performance, emotional well-being, and sleep quality. We examine the physiological mechanisms that underpin these three outcomes and review literature showing that SPB can activate anti-inflammatory pathways, increase lung capacity and, in turn, improve aerobic endurance, emotional well-being, and sleep quality. We conclude that interventions using SPB can have preventive and rehabilitative properties for athletes. Future studies should empirically test the potential of SPB to help this specific population.

9.
Front Psychol ; 12: 614451, 2021.
Article in English | MEDLINE | ID: covidwho-1191717

ABSTRACT

The emergent Coronavirus Disease 2019 (COVID-19) caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) could produce a maternal immune activation (MIA) via the inflammatory response during gestation that may impair fetal neurodevelopment and lead to postnatal and adulthood mental illness and behavioral dysfunctions. However, so far, limited evidence exists regarding long-term physiological, immunological, and neurodevelopmental modifications produced by the SARS-CoV-2 in the human maternal-fetal binomial and, particularly, in the offspring. Relevant findings derived from epidemiological and preclinical models show that a MIA is indeed linked to an increased risk of neurodevelopmental disorders in the offspring. We hypothesize that a gestational infection triggered by SARS-CoV-2 increases the risks leading to neurodevelopmental disorders of the newborn, which can affect childhood and the long-term quality of life. In particular, disruption of either the maternal or the fetal cholinergic anti-inflammatory pathway (CAP) could cause or exacerbate the severity of COVID-19 in the maternal-fetal binomial. From a translational perspective, in this paper, we discuss the possible manifestation of a MIA by SARS-CoV-2 and the subsequent neurodevelopmental disorders considering the role of the fetal-maternal cytokine cross-talk and the CAP. Specifically, we highlight the urgent need of preclinical studies as well as multicenter and international databanks of maternal-fetal psychophysiological data obtained pre-, during, and post-infection by SARS-CoV-2 from pregnant women and their offspring.

10.
Front Immunol ; 11: 595342, 2020.
Article in English | MEDLINE | ID: covidwho-1106024

ABSTRACT

The outbreak of coronavirus disease 2019 (COVID-19) underlined the urgent need for alleviating cytokine storm. We propose here that activating the cholinergic anti-inflammatory pathway (CAP) is a potential therapeutic strategy. However, there is currently no approved drugs targeting the regulatory pathway. It is evident that nicotine, anisodamine and some herb medicine, activate the CAP and exert anti-inflammation action in vitro and in vivo. As the vagus nerve affects both inflammation and specific immune response, we propose that vagus nerve stimulation by invasive or non-invasive devices and acupuncture at ST36, PC6, or GV20, are also feasible approaches to activate the CAP and control COVID-19. It is worth to investigate the efficacy and safety of the strategy in patients with COVID-19.


Subject(s)
COVID-19/therapy , Cytokine Release Syndrome/therapy , Neuroimmunomodulation/immunology , Vagus Nerve Stimulation/methods , Vagus Nerve/immunology , Acupuncture , Anti-Inflammatory Agents/pharmacology , Cytokines/blood , Drugs, Chinese Herbal/pharmacology , Humans , Inflammation/therapy , Nicotine/pharmacology , SARS-CoV-2 , Solanaceous Alkaloids/pharmacology
11.
Int J Environ Res Public Health ; 17(20)2020 10 11.
Article in English | MEDLINE | ID: covidwho-983009

ABSTRACT

SARS-CoV-2 is a new coronavirus that has caused a worldwide pandemic. It produces severe acute respiratory disease (COVID-19), which is fatal in many cases, characterised by the cytokine release syndrome (CRS). According to the World Health Organization, those who smoke are likely to be more vulnerable to infection. Here, in order to clarify the epidemiologic relationship between smoking and COVID-19, we present a systematic literature review until 28th April 2020 and a meta-analysis. We included 18 recent COVID-19 clinical and epidemiological studies based on smoking patient status from 720 initial studies in China, the USA, and Italy. The percentage of hospitalised current smokers was 7.7% (95% CI: 6.9-8.4) in China, 2.3% (95% CI: 1.7-2.9) in the USA and 7.6% (95% CI: 4.2-11.0) in Italy. These percentages were compared to the smoking prevalence of each country and statistically significant differences were found in them all (p < 0.0001). By means of the meta-analysis, we offer epidemiological evidence showing that smokers were statistically less likely to be hospitalised (OR = 0.18, 95% CI: 0.14-0.23, p < 0.01). In conclusion, the analysis of data from 18 studies shows a much lower percentage of hospitalised current smokers than expected. As more studies become available, this trend should be checked to obtain conclusive results and to explore, where appropriate, the underlying mechanism of the severe progression and adverse outcomes of COVID-19.


Subject(s)
Coronavirus Infections/therapy , Hospitalization/statistics & numerical data , Pneumonia, Viral/therapy , Smokers/statistics & numerical data , COVID-19 , China/epidemiology , Coronavirus Infections/epidemiology , Humans , Italy/epidemiology , Pandemics , Pneumonia, Viral/epidemiology , United States/epidemiology
12.
Bioelectron Med ; 6(1): 22, 2020 Nov 24.
Article in English | MEDLINE | ID: covidwho-967706

ABSTRACT

COVID-19 has left mankind desperately seeking how to manage dramatically rising infection rates associated with severe disease progressions. COVID-19 courses range from mild symptoms up to multiple organ failure and death, triggered by excessively high serum cytokine levels (IL 1ß, IL 6, TNF α, IL 8). The vagally driven cholinergic anti-inflammatory pathway (CAP) stops the action of nuclear factor κB (NF-κB), the transcriptional factor of pro-inflammatory cytokines. Thus, well-balanced cytokine release depends on adequate vagal signaling. Coronaviruses replicate using NF-κB transcriptional factor as well. By degrading the cytoplasmatic inhibitor of NF-κB subunits (IκB), coronaviruses induce unrestricted NF-κB expression accelerating both, virus replication and cytokine transcription.We hypothesize that CAP detriment due to depressed vagal tone critically determines the severity of COVID-19.

13.
Hellenic J Cardiol ; 62(4): 265-269, 2021.
Article in English | MEDLINE | ID: covidwho-967843

ABSTRACT

Coronavirus disease-2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2, is currently in a pandemic outbreak and has become a global health issue. In addition to the primarily involvement of the respiratory system, myocarditis is considered an important and fatal lesion in patients with COVID-19. However, effective therapeutic methods are currently lacking. The cholinergic anti-inflammatory pathway (CAP) has been demonstrated to suppress pro-inflammatory cytokine production and control inflammation in sepsis and other medical conditions. Therefore, the CAP may be a potential and effective therapeutic method for COVID-19-related myocarditis. This article reviews the relationship between COVID-19-related myocarditis and the CAP and discusses the CAP as a potential therapeutic modality in the treatment of COVID-19-related myocarditis.


Subject(s)
COVID-19 , Myocarditis , Humans , Myocarditis/drug therapy , Myocarditis/etiology , Neuroimmunomodulation , Pandemics , SARS-CoV-2
14.
Cureus ; 12(10): e11220, 2020 Oct 28.
Article in English | MEDLINE | ID: covidwho-955228

ABSTRACT

COVID-19 has a benign outcome in most cases, yet it can also be fatal and no specific treatment is available as of yet. Older age and several medical comorbidities are risk factors for COVID-19 complications. We report on an elderly man with a longstanding history of bipolar affective disorder associated with heavy smoking, alcohol abuse and multiple comorbidities, including severe chronic obstructive pulmonary disease and recurrent pulmonary sepsis, who contracted COVID-19 during his inpatient treatment of a manic episode, and who fully recovered from COVID-19 without any need for respiratory support. We discuss how his excessive use of nicotine replacement therapy may have contributed to his emerging unscathed from COVID-19. Nicotine, an α7-nACh receptor agonist, may boost the cholinergic anti-inflammatory pathway and hinder the uncontrolled overproduction of pro-inflammatory cytokines triggered by the SARS-CoV-2 virus, which is understood to be the main pathway to poor outcomes and death in severe COVID-19.

16.
Front Physiol ; 11: 890, 2020.
Article in English | MEDLINE | ID: covidwho-719750

ABSTRACT

Background: Covid-19 is an infectious disease caused by an invasion of the alveolar epithelial cells by coronavirus 19. The most severe outcome of the disease is the Acute Respiratory Distress Syndrome (ARDS) combined with hypoxemia and cardiovascular damage. ARDS and co-morbidities are associated with inflammatory cytokine storms, sympathetic hyperactivity, and respiratory dysfunction. Hypothesis: In the present paper, we present and justify a novel potential treatment for Covid19-originated ARDS and associated co-morbidities, based on the non-invasive stimulation of the auricular branch of the vagus nerve. Methods: Auricular vagus nerve stimulation activates the parasympathetic system including anti-inflammatory pathways (the cholinergic anti-inflammatory pathway and the hypothalamic pituitary adrenal axis) while regulating the abnormal sympatho-vagal balance and improving respiratory control. Results: Along the paper (1) we expose the role of the parasympathetic system and the vagus nerve in the control of inflammatory processes (2) we formulate our physiological and methodological hypotheses (3) we provide a large body of clinical and preclinical data that support the favorable effects of auricular vagus nerve stimulation in inflammation, sympatho-vagal balance as well as in respiratory and cardiac ailments, and (4) we list the (few) possible collateral effects of the treatment. Finally, we discuss auricular vagus nerve stimulation protective potential, especially in the elderly and co-morbid population with already reduced parasympathetic response. Conclusions: Auricular vagus nerve stimulation is a safe clinical procedure and it could be either an effective treatment for ARDS originated by Covid-19 and similar viruses or a supplementary treatment to actual ARDS therapeutic approaches.

17.
Bioelectron Med ; 6: 15, 2020.
Article in English | MEDLINE | ID: covidwho-679597

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), at the origin of the worldwide COVID-19 pandemic, is characterized by a dramatic cytokine storm in some critical patients with COVID-19. This storm is due to the release of high levels of pro-inflammatory cytokines such as interleukin (IL)-1 ß, IL-6, tumor necrosis factor (TNF), and chemokines by respiratory epithelial and dendritic cells, and macrophages. We hypothesize that this cytokine storm and the worsening of patients' health status can be dampened or even prevented by specifically targeting the vagal-driven cholinergic anti-inflammatory pathway (CAP). The CAP is a concept that involves an anti-inflammatory effect of vagal efferents by the release of acetylcholine (ACh). Nicotinic acetylcholine receptor alpha7 subunit (α7nAChRs) is required for ACh inhibition of macrophage-TNF release and cytokine modulation. Hence, targeting the α7nAChRs through vagus nerve stimulation (VNS) could be of interest in the management of patients with SARS-CoV-2 infection. Indeed, through the wide innervation of the organism by the vagus nerve, especially the lungs and gastrointestinal tract, VNS appears as a serious candidate for a few side effect treatment that could dampen or prevent the cytokine storm observed in COVID-19 patients with severe symptoms. Finally, a continuous vagal tone monitoring in patients with COVID-19 could be used as a predictive marker of COVID-19 illness course but also as a predictive marker of response to COVID-19 treatment such as VNS or others.

18.
Mol Med ; 26(1): 63, 2020 06 29.
Article in English | MEDLINE | ID: covidwho-617382

ABSTRACT

BACKGROUND: Oxygen therapy, using supraphysiological concentrations of oxygen (hyperoxia), is routinely administered to patients who require respiratory support including mechanical ventilation (MV). However, prolonged exposure to hyperoxia results in acute lung injury (ALI) and accumulation of high mobility group box 1 (HMGB1) in the airways. We previously showed that airway HMGB1 mediates hyperoxia-induced lung injury in a mouse model of ALI. Cholinergic signaling through the α7 nicotinic acetylcholine receptor (α7nAChR) attenuates several inflammatory conditions. The aim of this study was to determine whether 3-(2,4 dimethoxy-benzylidene)-anabaseine dihydrochloride, GTS-21, an α7nAChR partial agonist, inhibits hyperoxia-induced HMGB1 accumulation in the airways and circulation, and consequently attenuates inflammatory lung injury. METHODS: Mice were exposed to hyperoxia (≥99% O2) for 3 days and treated concurrently with GTS-21 (0.04, 0.4 and 4 mg/kg, i.p.) or the control vehicle, saline. RESULTS: The systemic administration of GTS-21 (4 mg/kg) significantly decreased levels of HMGB1 in the airways and the serum. Moreover, GTS-21 (4 mg/kg) significantly reduced hyperoxia-induced acute inflammatory lung injury, as indicated by the decreased total protein content in the airways, reduced infiltration of inflammatory monocytes/macrophages and neutrophils into the lung tissue and airways, and improved lung injury histopathology. CONCLUSIONS: Our results indicate that GTS-21 can attenuate hyperoxia-induced ALI by inhibiting extracellular HMGB1-mediated inflammatory responses. This suggests that the α7nAChR represents a potential pharmacological target for the treatment regimen of oxidative inflammatory lung injury in patients receiving oxygen therapy.


Subject(s)
Acute Lung Injury/etiology , Acute Lung Injury/metabolism , Benzylidene Compounds/pharmacology , HMGB1 Protein/metabolism , Hyperoxia/complications , Nicotinic Agonists/pharmacology , Pyridines/pharmacology , Acute Lung Injury/drug therapy , Acute Lung Injury/pathology , Animals , Biomarkers , Disease Susceptibility , HMGB1 Protein/blood , HMGB1 Protein/genetics , Immunohistochemistry , Male , Mice , Models, Biological
19.
ACS Chem Neurosci ; 11(13): 1868-1870, 2020 07 01.
Article in English | MEDLINE | ID: covidwho-606648

ABSTRACT

Cytokine storm in COVID-19 is characterized by an excessive inflammatory response to SARS-CoV-2 that is caused by a dysregulated immune system of the host. We are proposing a new hypothesis that SARS-CoV-2 mediated inflammation of nucleus tractus solitarius (NTS) may be responsible for the cytokine storm in COVID 19. The inflamed NTS may result in a dysregulated cholinergic anti-inflammatory pathway and hypothalamic-pituitary-adrenal axis.


Subject(s)
Betacoronavirus/metabolism , Coronavirus Infections/metabolism , Cytokines/metabolism , Pneumonia, Viral/metabolism , Solitary Nucleus/metabolism , Axons/immunology , Axons/metabolism , Axons/virology , Betacoronavirus/immunology , COVID-19 , Coronavirus Infections/immunology , Cranial Nerves/immunology , Cranial Nerves/metabolism , Cranial Nerves/virology , Cytokines/immunology , Humans , Hypothalamo-Hypophyseal System/immunology , Hypothalamo-Hypophyseal System/metabolism , Hypothalamo-Hypophyseal System/virology , Inflammation Mediators/immunology , Inflammation Mediators/metabolism , Pandemics , Pituitary-Adrenal System/immunology , Pituitary-Adrenal System/metabolism , Pituitary-Adrenal System/virology , Pneumonia, Viral/immunology , SARS-CoV-2 , Solitary Nucleus/immunology , Solitary Nucleus/virology
20.
Front Immunol ; 11: 1359, 2020.
Article in English | MEDLINE | ID: covidwho-619393

ABSTRACT

SARS-CoV-2 is a new coronavirus that has caused a worldwide pandemic. It causes severe acute respiratory syndrome (COVID-19), which is fatal in many cases, and is characterized by a cytokine release syndrome (CRS). Great efforts are currently being made to block the signal transduction pathway of pro-inflammatory cytokines in order to control this "cytokine storm" and rescue severely affected patients. Consequently, possible treatments for cytokine-mediated hyperinflammation, preferably within approved safe therapies, are urgently being researched to reduce rising mortality. One approach to inhibit proinflammatory cytokine release is to activate the cholinergic anti-inflammatory pathway through nicotinic acetylcholine receptors (α7nAchR). Nicotine, an exogenous α7nAchR agonist, is clinically used in ulcerative colitis to counteract inflammation. We have found epidemiological evidence, based on recent clinical SARS-CoV-2 studies in China, that suggest that smokers are statistically less likely to be hospitalized. In conclusion, our hypothesis proposes that nicotine could constitute a novel potential CRS therapy in severe SARS-CoV-2 patients.


Subject(s)
Coronavirus Infections/immunology , Cytokine Release Syndrome/drug therapy , Nicotine/therapeutic use , Pneumonia, Viral/immunology , COVID-19 , China/epidemiology , Cigarette Smoking , Coronavirus Infections/drug therapy , Coronavirus Infections/epidemiology , Coronavirus Infections/pathology , Humans , Pandemics , Pneumonia, Viral/drug therapy , Pneumonia, Viral/epidemiology , Pneumonia, Viral/pathology , Severity of Illness Index , alpha7 Nicotinic Acetylcholine Receptor/agonists
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