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1.
Br J Hosp Med (Lond) ; 83(7): 1-10, 2022 Jul 02.
Article in English | MEDLINE | ID: covidwho-1988543

ABSTRACT

Mast cells are innate immune cells found in connective tissues throughout the body, most prevalent at tissue-environment interfaces. They possess multiple cell-surface receptors which react to various stimuli and, after activation, release many mediators including histamine, heparin, cytokines, prostaglandins, leukotrienes and proteases. In mast cell activation syndrome, excessive amounts of inflammatory mediators are released in response to triggers such as foods, fragrances, stress, exercise, medications or temperature changes. Diagnostic markers may be difficult to assess because of their rapid degradation; these include urinary N-methyl histamine, urinary prostaglandins D2, DM and F2α and serum tryptase (which is stable) in the UK. Self-management techniques, medications and avoiding triggers may improve quality of life. Treatments include mast cell mediator blockers, mast cell stabilisers and anti-inflammatory agents. 'Long COVID' describes post-COVID-19 syndrome when symptoms persist for more than 12 weeks after initial infection with no alternative diagnosis. Both mast cell activation syndrome and long COVID cause multiple symptoms. It is theorised that COVID-19 infection could lead to exaggeration of existing undiagnosed mast cell activation syndrome, or could activate normal mast cells owing to the persistence of viral particles. Other similarities include the relapse-remission cycle and improvements with similar treatments. Importantly, however, aside from mast cell disorders, long COVID could potentially be attributed to several other conditions.


Subject(s)
COVID-19 , Mast Cell Activation Syndrome , COVID-19/complications , Histamine/metabolism , Humans , Mast Cells/metabolism , Neoplasm Recurrence, Local , Quality of Life
2.
Handb Exp Pharmacol ; 276: 133-159, 2022.
Article in English | MEDLINE | ID: covidwho-1930203

ABSTRACT

Mast cells (MCs) distribute to interface tissues with environment, such as skin, airway, and gut mucosa, thereby functioning as the sentinel against invading allergens and pathogens. To respond to and exclude these external substances promptly, MCs possess granules containing inflammatory mediators, including heparin, proteases, tumor necrosis factor, and histamine, and produce these mediators as a consequence of degranulation within minutes of activation. As a delayed response to external substances, MCs de novo synthesize inflammatory mediators, such as cytokines and chemokines, by sensing pathogen- and damage-associated molecular patterns through their pattern recognition receptors, including Toll-like receptors (TLRs). A substantial number of studies have reported immune responses by MCs through surface TLR signaling, particularly TLR2 and TLR4. However, less attention has been paid to immune responses through nucleic acid-recognizing intracellular TLRs. Among intracellular TLRs, human and rodent MCs express TLR3, TLR7, and TLR9, but not TLR8. Some virus infections modulate intracellular TLR expression in MCs. MC-derived mediators, such as histamine, cysteinyl leukotrienes, LL-37, and the granulocyte-macrophage colony-stimulating factor, have also been reported to modulate intracellular TLR expression in an autocrine and/or paracrine fashion. Synthetic ligands for intracellular TLRs and some viruses are sensed by intracellular TLRs of MCs, leading to the production of inflammatory cytokines and chemokines including type I interferons. These MC responses initiate and facilitate innate responses and the subsequent recruitment of additional innate effector cells. MCs also associate with the regulation of adaptive immunity. In this overview, the expression of intracellular TLRs in MCs and the recognition of pathogens, including viruses, by intracellular TLRs in MCs were critically evaluated.


Subject(s)
Histamine , Mast Cells , Adaptive Immunity , Chemokines , Cytokines , Humans , Immunity, Innate/physiology , Mast Cells/metabolism , Toll-Like Receptors
3.
Inflamm Res ; 71(7-8): 995-998, 2022 Aug.
Article in English | MEDLINE | ID: covidwho-1872377

ABSTRACT

In the light of cancellation of the 50th Annual Meeting of the European Histamine Research Society (EHRS) due to continuing challenges and restrictions imposed by the coronavirus disease 2019 (COVID-19) outbreak, the EHRS Council decided to organize a series of online events spread in 2021 to allow dissemination of histamine research progress and advancement among the Society members and beyond. This report summarizes the outcomes of the EHRS Council initiative that comprised the organization of four webinars, each focusing on a highly relevant histamine research scientific area. These included insights into novel therapeutic targets related to the histaminergic system in the eye, histamine intolerance, and the role of histamine and the histaminergic system in the regulation of the nervous system, as well as an update on studies leading to the development of novel methods for histamine detection. The outcome of this series of virtual events conformed that histamine research continued to develop despite the pandemic, and we witnessed stimulating advancements in 2021. Importantly, the EHRS Council brought histaminologists together in this unprecedented time.


Subject(s)
COVID-19 , Pandemics , Histamine , Humans
4.
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
6.
Infect Disord Drug Targets ; 22(3): e070122200096, 2022.
Article in English | MEDLINE | ID: covidwho-1613451

ABSTRACT

The novel coronavirus, SARS-coV-2, which emerged in Wuhan in November 2019, has increasingly spread worldwide. More than 272 million cases of infection have been identified. COVID-19 has affected 223 countries and territories across the world. The principal target of the SARS-CoV-2 infection is the lower respiratory tract. Series of moderate to non-specific severe clinical signs and symptoms appear two to fourteen days after exposure to SARS-CoV-2 in patients with COVID-19 disease, including cough, breath deficiency, and at least two of these symptoms: headache, fever, chills, repeated rigor, myalgia, oropharyngitis, anosmia, and ageusia. No therapeutic agents have been validated to have substantial efficacy in the clinical care of COVID-19 patients in large-scale trials, despite worsening infected rates of COVID-19. Early clinical evidence from many sources suggests that treatment with famotidine may decrease COVID-19-related morbidity and mortality. The mechanism by which famotidine could improve the outcomes of COVID-19 is currently unknown. A more recent postulated mechanism is that the effect of famotidine is mediated by histamine-2 receptor antagonism or inverse agonism, inferring that the SARS-CoV-2, resulting in COVID-19 infection, at least partially leads to the abnormal release of histamine and perhaps dysfunction of mast cells.


Subject(s)
COVID-19 , COVID-19/drug therapy , Famotidine/therapeutic use , Fever , Histamine , Humans , SARS-CoV-2
8.
J Investig Med ; 70(1): 61-67, 2022 01.
Article in English | MEDLINE | ID: covidwho-1455731

ABSTRACT

Long COVID is characterized by the emergence of multiple debilitating symptoms following SARS-CoV-2 infection. Its etiology is unclear and it often follows a mild acute illness. Anecdotal reports of gradual clinical responses to histamine receptor antagonists (HRAs) suggest a histamine-dependent mechanism that is distinct from anaphylaxis, possibly mediated by T cells, which are also regulated by histamine. T cell perturbations have been previously reported in post-viral syndromes, but the T cell landscape in patients who have recovered from mild COVID-19 and its relationship to both long COVID symptoms and any symptomatic response to HRA remain underexplored. We addressed these questions in an observational study of 65 individuals who had recovered from mild COVID-19. Participants were surveyed between 87 and 408 days after the onset of acute symptoms; none had required hospitalization, 16 had recovered uneventfully, and 49 had developed long COVID. Symptoms were quantified using a structured questionnaire and T cell subsets enumerated in a standard diagnostic assay. Patients with long-COVID had reduced CD4+ and CD8+ effector memory (EM) cell numbers and increased PD-1 (programmed cell death protein 1) expression on central memory (CM) cells, whereas the asymptomatic participants had reduced CD8+ EM cells only and increased CD28 expression on CM cells. 72% of patients with long COVID who received HRA reported clinical improvement, although T cell profiling did not clearly distinguish those who responded to HRA. This study demonstrates that T cell perturbations persist for several months after mild COVID-19 and are associated with long COVID symptoms.


Subject(s)
COVID-19/complications , COVID-19/immunology , Histamine Antagonists/therapeutic use , T-Lymphocytes , Adult , Aged , COVID-19/diagnosis , Female , Histamine , Humans , Male , Middle Aged , SARS-CoV-2/immunology , T-Lymphocyte Subsets/immunology , Young Adult
9.
Skin Res Technol ; 28(1): 54-57, 2022 Jan.
Article in English | MEDLINE | ID: covidwho-1455654

ABSTRACT

BACKGROUND: A histamine skin prick test (SPT) generally evokes a wheal and a flare. The present study was initiated by an observation that histamine did not evoke a flare around a wheal in the skin of an 86-year-old man. Could that be of relevance to the findings that old men are prone to a more severe COVD-19 infection with a higher mortality than young ones? MATERIALS AND METHODS: Histamine SPT was performed on the forearm of six old men, all above the age of 80. The skin reactions were photographed from above and from the side. The photographs taken from above were treated in a computer with LYYN, a program that increases color differences. With the help of ImageJ (NIH), the size relation between flare and wheal was calculated. On the photographs, taken as side views, areas, heights, and diameters of wheals were measured. Controls consisted of three groups of younger people. RESULTS: Among the old men, no or only a small flare was seen. All the controls had prominent flares. Histamine SPT evoked small wheals in the group of old men as compared to young men. CONCLUSION: Reduced neurogenic inflammation evoked by histamine from mast cells in blood and tissue may reduce the defense against COVID-19 infection.


Subject(s)
COVID-19 , Neurogenic Inflammation , Aged, 80 and over , Histamine , Humans , Male , Reflex , SARS-CoV-2 , Skin , Skin Tests
10.
Nutrients ; 13(10)2021 Sep 29.
Article in English | MEDLINE | ID: covidwho-1444284

ABSTRACT

There is an ongoing need for new therapeutic modalities against SARS-CoV-2 infection. Mast cell histamine has been implicated in the pathophysiology of COVID-19 as a regulator of proinflammatory, fibrotic, and thrombogenic processes. Consequently, mast cell histamine and its receptors represent promising pharmacological targets. At the same time, nutritional modulation of immune system function has been proposed and is being investigated for the prevention of COVID-19 or as an adjunctive strategy combined with conventional therapy. Several studies indicate that several immunonutrients can regulate mast cell activity to reduce the de novo synthesis and/or release of histamine and other mediators that are considered to mediate, at least in part, the complex pathophysiology present in COVID-19. This review summarizes the effects on mast cell histamine of common immunonutrients that have been investigated for use in COVID-19.


Subject(s)
COVID-19/immunology , Histamine/immunology , Immune System/immunology , Mast Cells/immunology , Nutritional Physiological Phenomena/immunology , Signal Transduction/immunology , Humans , SARS-CoV-2
11.
Postgrad Med ; 133(7): 765-770, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1276020

ABSTRACT

A clinical vignette illustrates a typical presentation of a patient seeking help for acute angioedema. Despite the risks of SARS-CoV-2 (COVID-19) exposure, it is critical to evaluate patients with acute angioedema in person, because there is always the potential for angioedema to progress to the head, neck, or lungs, which can rapidly compromise the airways and require immediate intervention to avoid potential asphyxiation. There are three mediators of angioedema, histamine, leukotriene, or bradykinin, each requiring different management. This article provides clinicians essential information for differentiating between these types of angioedema, including an overview of the underlying pathogenies of angioedema, and the subjective and objective findings that are useful in differentiating between angioedema types. The article ends with the appropriate management for each type of acute angioedema, including the medications approved by the FDA for on-demand treatment of an HAE attack.


Subject(s)
Angioedema/diagnosis , COVID-19/epidemiology , Acute Disease , Angioedema/physiopathology , Angioedema/therapy , Anti-Allergic Agents/therapeutic use , Bradykinin/biosynthesis , Cyclooxygenase 2 Inhibitors/therapeutic use , Diagnosis, Differential , Histamine/biosynthesis , Histamine Antagonists/therapeutic use , Humans , Leukotrienes/biosynthesis , Omalizumab/therapeutic use , Otorhinolaryngologic Surgical Procedures/methods , Physical Examination , SARS-CoV-2
12.
Viruses ; 13(3)2021 02 27.
Article in English | MEDLINE | ID: covidwho-1190473

ABSTRACT

The immunological findings from autopsies, biopsies, and various studies in COVID-19 patients show that the major cause of morbidity and mortality in COVID-19 is excess immune response resulting in hyper-inflammation. With the objective to review various mechanisms of excess immune response in adult COVID-19 patients, Pubmed was searched for free full articles not related to therapeutics or co-morbid sub-groups, published in English until 27.10.2020, irrespective of type of article, country, or region. Joanna Briggs Institute's design-specific checklists were used to assess the risk of bias. Out of 122 records screened for eligibility, 42 articles were included in the final review. The review found that eventually, most mechanisms result in cytokine excess and up-regulation of Nuclear Factor-κB (NF-κB) signaling as a common pathway of excess immune response. Molecules blocking NF-κB or targeting downstream effectors like Tumour Necrosis Factor α (TNFα) are either undergoing clinical trials or lack specificity and cause unwanted side effects. Neutralization of upstream histamine by histamine-conjugated normal human immunoglobulin has been demonstrated to inhibit the nuclear translocation of NF-κB, thereby preventing the release of pro-inflammatory cytokines Interleukin (IL) 1ß, TNF-α, and IL-6 and IL-10 in a safer manner. The authors recommend repositioning it in COVID-19.


Subject(s)
COVID-19/immunology , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/immunology , Histamine/administration & dosage , Immunoglobulins/administration & dosage , NF-kappa B/antagonists & inhibitors , NF-kappa B/immunology , Cytokine Release Syndrome/prevention & control , Cytokine Release Syndrome/virology , Databases, Factual , Down-Regulation/drug effects , Drug Repositioning , Humans , Immunity , Orphan Drug Production , SARS-CoV-2/drug effects , Signal Transduction/drug effects
13.
J Biomol Struct Dyn ; 40(13): 5785-5802, 2022 Aug.
Article in English | MEDLINE | ID: covidwho-1045961

ABSTRACT

With the world threatened by a second surge in the number of Coronavirus cases, there is an urgent need for the development of effective treatment for the novel coronavirus (COVID-19). Recently, global attention has turned to preliminary reports on the promising anti-COVID-19 effect of histamine H2-receptor antagonists (H2RAs), most especially Famotidine. Therefore, this study was designed to exploit a possible molecular basis for the efficacy of H2RAs against coronavirus. Molecular docking was performed between four H2RAs, Cimetidine, Famotidine, Nizatidine, Ranitidine, and three non-structural proteins viz. NSP3, NSP7/8 complex, and NSP9. Thereafter, a 100 ns molecular dynamics simulation was carried out with the most outstanding ligands to determine the stability. Thereafter, Famotidine and Cimetidine were subjected to gene target prediction analysis using HitPickV2 and eXpression2Kinases server to determine the possible network of genes associated with their anti-COVID activities. Results obtained from molecular docking showed the superiority of Famotidine and Cimetidine compared to other H2RAs with a higher binding affinity to all selected targets. Molecular dynamic simulation and MMPBSA results revealed that Famotidine as well as Cimetidine bind to non-structural proteins more efficiently with high stability over 100 ns. Results obtained suggest that Famotidine and Cimetidine could be a viable option to treat COVID-19 with a mechanism of action that involves the inhibition of viral replication through the inhibition of non-structural proteins. Therefore, Famotidineand Cimetidine qualify for further study as a potential treatment for COVID-19.


Subject(s)
COVID-19 , Histamine H2 Antagonists , COVID-19/drug therapy , Cimetidine/pharmacology , Famotidine/pharmacology , Histamine , Histamine H2 Antagonists/pharmacology , Humans , Molecular Docking Simulation
14.
J Biol Regul Homeost Agents ; 34(5): 1629-1632, 2020.
Article in English | MEDLINE | ID: covidwho-782629

ABSTRACT

SARS-CoV-2 virus is an infectious agent commonly found in certain mammalian animal species and today also in humans. SARS-CoV-2, can cause a pandemic infection with severe acute lung injury respiratory distress syndrome in patients with COVID-19, that can lead to patient death across all ages. The pathology associated with pandemic infection is linked to an over-response of immune cells, including virus-activated macrophages and mast cells (MCs). The local inflammatory response in the lung that occurs after exposure to SARS-CoV-2 is due to a complex network of activated inflammatory innate immune cells and structural lung cells such as bronchial epithelial cells, endothelial cells and fibroblasts. Bronchial epithelial cells and fibroblasts activated by SARS-CoV-2 can result in the up-regulation of pro-inflammatory cytokines and induction of MC differentiation. In addition, endothelial cells which control leukocyte traffic through the expression of adhesion molecules are also able to amplify leukocyte activation by generating interleukin (IL)-1, IL-6 and CXC chemokines. In this pathologic environment, the activation of mast cells (MCs) causes the release of histamine, proteases, cytokines, chemokines and arachidonic acid compounds, such as prostaglandin D2 and leukotrienes, all of which are involved in the inflammatory network. Histamine is stored endogenously within the secretory granules of MCs and is released into the vessels after cell stimulation. Histamine is involved in the expression of chemokine IL-8 and cytokine IL-6, an effect that can be inhibited by histamine receptor antagonists. IL-1 is a pleiotropic cytokine that is mainly active in inflammation and immunity. Alveolar macrophages activated by SARS-CoV-2 through the TLR produce IL-1 which stimulates MCs to produce IL-6. IL-1 in combination with IL-6 leads to excessive inflammation which can be lethal. In an interesting study published several years ago (by E. Vannier et al., 1993), it was found that histamine as well as IL-1 are implicated in the pathogenesis of pulmonary inflammatory reaction, after micorganism immune cell activation. IL-1 in combination with histamine can cause a strong increase of IL-1 levels and, consequently, a higher degree of inflammation. However, it has been reported that histamine alone has no effect on IL-1 production. Furthermore, histamine enhances IL-1-induced IL-6 gene expression and protein synthesis via H2 receptors in peripheral monocytes. Therefore, since MCs are large producers of histamine in inflammatory reactions, this vasoactive amine, by increasing the production of IL-1, can amplify the inflammatory process in the lung infected with SARS-CoV-2. Here, we have proposed for the first time an emerging role for histamine released by MCs which in combination with IL-1 can cause an increase in lung inflammation induced by the viral infection SARS-CoV-2.


Subject(s)
Coronavirus Infections/immunology , Cytokine Release Syndrome/virology , Histamine/immunology , Interleukin-1/immunology , Mast Cells/virology , Pneumonia, Viral/immunology , Betacoronavirus , COVID-19 , Endothelial Cells/virology , Humans , Inflammation , Pandemics , SARS-CoV-2
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