The α7 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

Sitapara, Ravikumar; Gauthier, Alex; Valdés‐Ferrer, Sergio Iván; Lin, Mo Jun; Patel, Vivek; Wang, Mao; Martino, Ashley T.; Perron, Jeanette C.; Ashby, Charles R.; Tracey, Kevin J.; Pavlov, Valentin A.; Mantell, Lin L.

doi:10.1186/s10020-020-00177-z

Cited by 35 publications

(32 citation statements)

References 80 publications

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“…GTS-21, is able to inhibit proinflammatory cytokines in vitro and in vivo and improve survival in murine endotoxemia and severe sepsis ( Pavlov et al, 2007 ). Hyperoxia-induced acute lung injury is attenuated by GTS-21 by inhibiting extracellular high mobility group box 1-mediated inflammatory responses ( Sitapara et al, 2020 ).…”

Section: How To Use the Anti-inflammatory Properties Of The Vagus Nermentioning

confidence: 99%

Therapeutic Potential of Vagus Nerve Stimulation for Inflammatory Bowel Diseases

2021

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The vagus nerve is a mixed nerve, comprising 80% afferent fibers and 20% efferent fibers. It allows a bidirectional communication between the central nervous system and the digestive tract. It has a dual anti-inflammatory properties via activation of the hypothalamic pituitary adrenal axis, by its afferents, but also through a vago-vagal inflammatory reflex involving an afferent (vagal) and an efferent (vagal) arm, called the cholinergic anti-inflammatory pathway. Indeed, the release of acetylcholine at the end of its efferent fibers is able to inhibit the release of tumor necrosis factor (TNF) alpha by macrophages via an interneuron of the enteric nervous system synapsing between the efferent vagal endings and the macrophages and releasing acetylcholine. The vagus nerve also synapses with the splenic sympathetic nerve to inhibit the release of TNF-alpha by splenic macrophages. It can also activate the spinal sympathetic system after central integration of its afferents. This anti-TNF-alpha effect of the vagus nerve can be used in the treatment of chronic inflammatory bowel diseases, represented by Crohn’s disease and ulcerative colitis where this cytokine plays a key role. Bioelectronic medicine, via vagus nerve stimulation, may have an interest in this non-drug therapeutic approach as an alternative to conventional anti-TNF-alpha drugs, which are not devoid of side effects feared by patients.

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Section: How To Use the Anti-inflammatory Properties Of The Vagus Nermentioning

confidence: 99%

Therapeutic Potential of Vagus Nerve Stimulation for Inflammatory Bowel Diseases

2021

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“…Recently, our lab has reported that in mice exposed to 72 h of hyperoxia, 4 mg/kg i.p. administration of GTS-21 significantly attenuates the accumulation of HMGB1 in the airways and the circulation and mitigates inflammatory lung injury by decreasing the infiltration of neutrophils and inflammatory monocytes into the lung and the airways (Sitapara et al 2020 ). Thus, these data suggest that the activation of the α7nAChR with agonists, such as GTS-21 or nicotine, may represent a pharmacological approach to combat Gram-negative bacterial infections in organisms subjected to oxidative stress (Entezari et al 2012 ; Wang 1999 ; Ogawa et al 2006 ; Rowe et al 2008 ).…”

Section: Discussionmentioning

confidence: 99%

“…Both nicotine (a non-selective α7nAChR agonist) and GTS-21 inhibit endotoxin-induced NF-κB activation in macrophages (Wang et al 2003 ; Pavlov et al 2007 ). We have reported that NF-κB activation plays a critical role in hyperoxia-induced HMGB1 release (Wang et al 2015 ) and GTS-21 significantly decreases HMGB1 accumulation in the airways and the circulation in mice subjected to hyperoxia (Sitapara et al 2020 ). Hyperoxia-induced NF-κB activation in cultured macrophages and mouse lung cells is inhibited by GTS-21, suggesting the possible involvement of NF-κB in mediating GTS-21’s decrease of hyperoxia-induced HMGB1 release (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…However, macrophage bacterial clearance functions impaired by hyperoxia can be attenuated by compounds that enhance antioxidant capacity (Patel et al 2016 , 2020 ), donate exogenous nitric oxide (Gore et al 2020 ), or inhibit NF-κB activation (Wang et al 2015 ). The resulting enhanced macrophage functions can mitigate hyperoxia-induced excessive pro-inflammatory response in the lungs of mice and decrease acute lung injury (Patel et al 2016 ; Entezari et al 2014 ; Sitapara et al 2020 ).…”

Section: Introductionmentioning

confidence: 99%

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GTS-21, an α7nAChR agonist, increases pulmonary bacterial clearance in mice by restoring hyperoxia-compromised macrophage function

Sitapara

Gauthier

Patel

et al. 2020

Mol Med

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Background Mechanical ventilation, in combination with supraphysiological concentrations of oxygen (i.e., hyperoxia), is routinely used to treat patients with respiratory distress, such as COVID-19. However, prolonged exposure to hyperoxia compromises the clearance of invading pathogens by impairing macrophage phagocytosis. Previously, we have shown that the exposure of mice to hyperoxia induces the release of the nuclear protein high mobility group box-1 (HMGB1) into the pulmonary airways. Furthermore, extracellular HMGB1 impairs macrophage phagocytosis and increases the mortality of mice infected with Pseudomonas aeruginosa (PA). The aim of this study was to determine whether GTS-21 (3-(2,4-dimethoxybenzylidene) anabaseine), an α7 nicotinic acetylcholine receptor (α7nAChR) agonist, could (1) inhibit hyperoxia-induced HMGB1 release into the airways; (2) enhance macrophage phagocytosis and (3) increase bacterial clearance from the lungs in a mouse model of ventilator-associated pneumonia. Method GTS-21 (0.04, 0.4, and 4 mg/kg) or saline were administered by intraperitoneal injection to mice that were exposed to hyperoxia (≥ 99% O2) and subsequently challenged with PA. Results The systemic administration of 4 mg/kg i.p. of GTS-21 significantly increased bacterial clearance, decreased acute lung injury and decreased accumulation of airway HMGB1 compared to the saline control. To determine the mechanism of action of GTS-21, RAW 264.7 cells, a macrophage-like cell line, were incubated with different concentrations of GTS-21 in the presence of 95% O2. The phagocytic activity of macrophages was significantly increased by GTS-21 in a dose-dependent manner. In addition, GTS-21 significantly inhibited the cytoplasmic translocation and release of HMGB1 from RAW 264.7 cells and attenuated hyperoxia-induced NF-κB activation in macrophages and mouse lungs exposed to hyperoxia and infected with PA. Conclusions Our results indicate that GTS-21 is efficacious in improving bacterial clearance and reducing acute lung injury via enhancing macrophage function by inhibiting the release of nuclear HMGB1. Therefore, the α7nAChR represents a possible pharmacological target to improve the clinical outcome of patients on ventilators by augmenting host defense against bacterial infections.

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“…In severe COVID-19 cases an additional stimulation of α7-nAChR would be essential to restore the integrity of the immune system. A combination of α7-nAChR agonists along with the proposed antibody will definitely help regulate the proinflammatory cytokine concentrations, but whether that alone would suffice to restore the ability of the body to generate sufficient quantities of antibodies for a long term immunity requires further evaluation ( Sitapara et al, 2020 ; Andersson, 2020 ; Alexandris et al, 2021 ).…”

Section: Implications For Clinical Therapymentioning

confidence: 99%

Is SARS-CoV-2 Spike glycoprotein impairing macrophage function via α7-nicotinic acetylcholine receptors?

Saraiya

Labrou

Farsalinos

et al. 2021

Food and Chemical Toxicology

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The innate immune cells play an important role in handling early infections, and can eliminate them completely up to a certain threshold. Beyond that threshold they take up their role in “The Resolution of Inflammation”. The recognition of the SARS-CoV-2 antigen triggers an eicosanoid storm and initiates a robust inflammatory response. This establishes a positive feedback loop which develops into a sustained cytokine storm which interferes with the activation of adaptive immune cells. The mechanism of this interaction, and hence the pathogenesis of the virus with the immune system, is yet to be determined. In silico studies predict a direct SARS-CoV-2 spike glycoprotein interaction with nicotinic acetylcholine receptors, which could impair macrophage function and initiate the cascade of events in severe infections. We here, add to the hypothesis that immune dysregulation can be caused by the interaction of the SARS-CoV-2 spike glycoprotein via a cryptic epitope with the α7-nAChR in Type-1 macrophages, discuss its implications for the treatment of COVID-19 patients, and present better prospects for the design and dissemination of more effective vaccines and their importance.

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The α7 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

Cited by 35 publications

References 80 publications

Therapeutic Potential of Vagus Nerve Stimulation for Inflammatory Bowel Diseases

Therapeutic Potential of Vagus Nerve Stimulation for Inflammatory Bowel Diseases

GTS-21, an α7nAChR agonist, increases pulmonary bacterial clearance in mice by restoring hyperoxia-compromised macrophage function

Is SARS-CoV-2 Spike glycoprotein impairing macrophage function via α7-nicotinic acetylcholine receptors?

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