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1.
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
2.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-333131

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 was 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 α and interleukin-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.

3.
Res Sq ; 2022 Apr 11.
Article in English | MEDLINE | ID: covidwho-1786501

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 was 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 α and interleukin-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.

4.
Cells ; 10(12)2021 11 26.
Article in English | MEDLINE | ID: covidwho-1551567

ABSTRACT

High mobility group box 1 protein (HMGB1), a highly conserved nuclear DNA-binding protein, is a "damage-associated molecular pattern" molecule (DAMP) implicated in both stimulating and inhibiting innate immunity. As reviewed here, HMGB1 is an oxidation-reduction sensitive DAMP bearing three cysteines, and the post-translational modification of these residues establishes its proinflammatory and anti-inflammatory activities by binding to different extracellular cell surface receptors. The redox-sensitive signaling mechanisms of HMGB1 also occupy an important niche in innate immunity because HMGB1 may carry other DAMPs and pathogen-associated molecular pattern molecules (PAMPs). HMGB1 with DAMP/PAMP cofactors bind to the receptor for advanced glycation end products (RAGE) which internalizes the HMGB1 complexes by endocytosis for incorporation in lysosomal compartments. Intra-lysosomal HMGB1 disrupts lysosomal membranes thereby releasing the HMGB1-transported molecules to stimulate cytosolic sensors that mediate inflammation. This HMGB1-DAMP/PAMP cofactor pathway slowed the development of HMGB1-binding antagonists for diagnostic or therapeutic use. However, recent discoveries that HMGB1 released from neurons mediates inflammation via the TLR4 receptor system, and that cancer cells express fully oxidized HMGB1 as an immunosuppressive mechanism, offer new paths to targeting HMGB1 for inflammation, pain, and cancer.


Subject(s)
Disulfides/metabolism , HMGB1 Protein/metabolism , Inflammation/metabolism , Protein Processing, Post-Translational , Animals , COVID-19/metabolism , Humans , Sensory Receptor Cells/metabolism
5.
Mol Med ; 27(1): 48, 2021 05 11.
Article in English | MEDLINE | ID: covidwho-1224858

ABSTRACT

BACKGROUND: Macrophage activation syndrome (MAS) is a potentially fatal complication of systemic inflammation. HMGB1 is a nuclear protein released extracellularly during proinflammatory lytic cell death or secreted by activated macrophages, NK cells, and additional cell types during infection or sterile injury. Extracellular HMGB1 orchestrates central events in inflammation as a prototype alarmin. TLR4 and the receptor for advanced glycation end products operate as key HMGB1 receptors to mediate inflammation. METHODS: Standard ELISA and cytometric bead array-based methods were used to examine the kinetic pattern for systemic release of HMGB1, ferritin, IL-18, IFN-γ, and MCP-1 before and during treatment of four children with critical MAS. Three of the patients with severe underlying systemic rheumatic diseases were treated with biologics including tocilizumab or anakinra when MAS developed. All patients required intensive care therapy due to life-threatening illness. Add-on etoposide therapy was administered due to insufficient clinical response with standard treatment. Etoposide promotes apoptotic rather than proinflammatory lytic cell death, conceivably ameliorating subsequent systemic inflammation. RESULTS: This therapeutic intervention brought disease control coinciding with a decline of the increased systemic HMGB1, IFN-γ, IL-18, and ferritin levels whereas MCP-1 levels evolved independently. CONCLUSION: Systemic HMGB1 levels in MAS have not been reported before. Our results suggest that the molecule is not merely a biomarker of inflammation, but most likely also contributes to the pathogenesis of MAS. These observations encourage further studies of HMGB1 antagonists. They also advocate therapeutic etoposide administration in severe MAS and provide a possible biological explanation for its mode of action.


Subject(s)
Biomarkers , Etoposide/administration & dosage , HMGB1 Protein/blood , Macrophage Activation Syndrome/blood , Macrophage Activation Syndrome/drug therapy , Adolescent , Antineoplastic Agents, Phytogenic/administration & dosage , Child , Child, Preschool , Cytokines/blood , Female , Humans , Immunosuppressive Agents/administration & dosage , Inflammation Mediators/blood , Macrophage Activation Syndrome/etiology , Male , Treatment Outcome
6.
The FASEB Journal ; 35(S1), 2021.
Article in English | Wiley | ID: covidwho-1234051

ABSTRACT

The pandemic COVID-19 disease with severe acute respiratory syndrome (SARS) is mediated by the coronavirus SARS-CoV-2. The highly conserved surface spike glycoprotein of the SARS-coronavirus is critical for viral entry into cells, a central step in pathogenesis. To further understand and characterize viral spike proteins in host cell immune responses, we generated two species of spike proteins: a recombinant receptor binding domain (RBD) and a truncated part of RBD, the receptor binding motif (RBM). In cell cultures with murine macrophage-like RAW 264.7 cells or with thioglycollate-elicited peritoneal primary mouse macrophages, recombinant RBD and RBM dose-dependently induced the release of TNF and HMGB1, pro-inflammatory molecules observed in increased systemic levels in COVID-19 patients (Chen R et al, Heliyon 6, 2020, e05672). Intratracheal administration of RBD (100 µg/mouse) or RBM (100 µg/mouse) also induced HMGB1 release in bronchoalveolar lung (BAL) fluid at 24 hours post-instillation (HMGB1 levels = 71 ± 30 ng/mL in PBS group vs. 253 ± 19* ng/mL in RBD group and 284 ± 42* ng/mL in RBM group;n=3-4 mice/group;*: p<0.05 vs. vehicle PBS group). Furthermore, intratracheal administration of recombinant RBM induced TNF, IL-6 and IL-1? release in bronchoalveolar lavage fluid at 24 hours post-instillation (n=13 per group, p<0.05 vs.PBS group). Taken together, our studies reveal that recombinant RBD and RBM induce pro-inflammatory cytokine release in vivo and in cultured murine macrophages.

7.
The FASEB Journal ; 35(S1), 2021.
Article in English | Wiley | ID: covidwho-1234045

ABSTRACT

The COVID-19 pandemic in the U.S. currently exceeds 21.1 million cases and 350,000 deaths. Consumption of famotidine, a histamine H2 receptor antagonist widely used to treat acid reflux and gastritis, is associated with improved survival and attenuated COVID-19 disease severity (Mather JF et al. Am J Gastroenterol. 115:1617,2020;Freedberg DE, et al. Gastroenterology 159: 1129, 2020;Janowitz T et al. Gut, 69:1592, 2020). However, the mode of action for these beneficial effects is unknown. Here we studied famotidine in mice exposed to bacterial endotoxin (lipopolysaccharide, LPS). LPS (6 mg/kg) was administered intraperitoneally in male C57BL/6 mice followed by intraperitoneal injection of famotidine (100 µg/mouse) or vehicle (PBS) twice daily for 3 days. Two-week survival was 100% in the famotidine-treated group vs. 70% in the PBS-control group (n=30/group, p < 0.05). Furthermore, famotidine administration significantly reduced serum and splenic TNF levels and serum IL-6 levels in the endotoxemic mice (p<0.05, famotidine vs. PBS). Human peripheral blood mononuclear cells co-cultured with famotidine and LPS also express significantly reduced amounts of pro-inflammatory cytokines (TNF, IL-6, HMGB1, IP-10, GM-CSF). Together these results indicate famotidine inhibits endotoxin induced cytokine storm and attenuates lethality in mice exposed to lethal endotoxemia.

9.
Transnational Corporations ; 27(2):127, 2020.
Article in English | ProQuest Central | ID: covidwho-896332

ABSTRACT

This paper explores the rising tensions between efficiency and resilience in global value chains (GVCs) in the post-COVID-19 world and discusses their potential implications for managing and coordinating GVCs. It considers efficiency and resilience in GVCs in relation to each other and explores the possibility of tensions between the two concepts. Particularly, it is argued that, while efficiency and resilience in GVCs may be at odds with each other in the short-term, they are not necessarily mutually exclusive in the long run. The paper adds to the discussions of trade-offs involved in managing contemporary GVCs and offers a new perspective on the interplay between efficiency and resilience. Embedded in the discussion of resilience vis-à-vis efficiency, we also provide a long-term perspective to prepare for and deal with global pandemics – or other risks – in an increasingly interconnected world. We lay out decisions and steps involved in finding the balance between efficiency and resilience, as both need to be maintained concurrently over longer periods.

10.
Mol Med ; 26(1): 64, 2020 06 29.
Article in English | MEDLINE | ID: covidwho-617273

ABSTRACT

The ubiquiotous nuclear protein HMGB1 is extracellularly released by dying cells or activated innate immunity cells to promote inflammation. Extracellular HMGB1 plays a prominent role in the pathogenesis of acute lung injury of infectious as well as sterile origin including hyperoxia. Excessive amounts of systemic HMGB1 and HMGB1-partner molecule complexes can be retained in the pulmonary circulation indicated by a substantial reduction of HMGB1 plasma levels in arterial versus venous blood. The cholinergic antiinflammatory mechanism ameliorates pulmonary inflammation by inhibiting HMGB1 release and HMGB1 receptor expression. This comprehension was recently reinforced by results reported in Molecular Medicine by Sitapara and coworkers demonstrating that administration of an α7 nicotinic acetylcholine receptor agonist attenuated hyperoxia-induced acute inflammatory lung injury by alleviating the accumulation of HMGB1 in the airways and the circulation. Activating the cholinergic antiinflammatory path might be considered to alleviate severe COVID-19 with or without concurrent oxygen-induced lung injury.


Subject(s)
Acute Lung Injury/prevention & control , Coronavirus Infections/prevention & control , HMGB1 Protein/antagonists & inhibitors , Neuroimmunomodulation/drug effects , Nicotinic Agonists/therapeutic use , Pandemics/prevention & control , Pneumonia, Viral/prevention & control , Acute Lung Injury/immunology , Acute Lung Injury/pathology , Animals , Betacoronavirus/immunology , COVID-19 , Coronavirus Infections/immunology , Coronavirus Infections/pathology , Coronavirus Infections/virology , Humans , Pneumonia, Viral/immunology , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , SARS-CoV-2
11.
Mol Med ; 26(1): 42, 2020 05 07.
Article in English | MEDLINE | ID: covidwho-197895

ABSTRACT

BACKGROUND: The 2019 novel coronavirus disease (COVID-19) causes for unresolved reasons acute respiratory distress syndrome in vulnerable individuals. There is a need to identify key pathogenic molecules in COVID-19-associated inflammation attainable to target with existing therapeutic compounds. The endogenous damage-associated molecular pattern (DAMP) molecule HMGB1 initiates inflammation via two separate pathways. Disulfide-HMGB1 triggers TLR4 receptors generating pro-inflammatory cytokine release. Extracellular HMGB1, released from dying cells or secreted by activated innate immunity cells, forms complexes with extracellular DNA, RNA and other DAMP or pathogen-associated molecular (DAMP) molecules released after lytic cell death. These complexes are endocytosed via RAGE, constitutively expressed at high levels in the lungs only, and transported to the endolysosomal system, which is disrupted by HMGB1 at high concentrations. Danger molecules thus get access to cytosolic proinflammatory receptors instigating inflammasome activation. It is conceivable that extracellular SARS-CoV-2 RNA may reach the cellular cytosol via HMGB1-assisted transfer combined with lysosome leakage. Extracellular HMGB1 generally exists in vivo bound to other molecules, including PAMPs and DAMPs. It is plausible that these complexes are specifically removed in the lungs revealed by a 40% reduction of HMGB1 plasma levels in arterial versus venous blood. Abundant pulmonary RAGE expression enables endocytosis of danger molecules to be destroyed in the lysosomes at physiological HMGB1 levels, but causing detrimental inflammasome activation at high levels. Stress induces apoptosis in pulmonary endothelial cells from females but necrosis in cells from males. CONCLUSION: Based on these observations we propose extracellular HMGB1 to be considered as a therapeutic target for COVID-19.


Subject(s)
Betacoronavirus , Coronavirus Infections , HMGB1 Protein/metabolism , Pandemics , Pneumonia, Viral , COVID-19 , Coronavirus Infections/drug therapy , Coronavirus Infections/metabolism , Coronavirus Infections/physiopathology , Humans , Inflammation/metabolism , Inflammation/prevention & control , Lung/metabolism , Lung/physiopathology , Molecular Targeted Therapy , Pneumonia, Viral/drug therapy , Pneumonia, Viral/metabolism , Pneumonia, Viral/physiopathology , RNA, Viral/metabolism , SARS-CoV-2 , Toll-Like Receptor 4/metabolism
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