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

ABSTRACT

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.


Subject(s)
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
2.
J Infect Dis ; 224(9): 1473-1488, 2021 11 16.
Article in English | MEDLINE | ID: covidwho-1522215

ABSTRACT

BACKGROUND: Postdischarge immunity and its correlation with clinical features among patients recovered from coronavirus disease 2019(COVID-19) are poorly described. This prospective cross-sectional study explored the inflammatory profiles and clinical recovery of patients with COVID-19 at 3 months after hospital discharge. METHODS: Patients with COVID-19 discharged from 4 hospitals in Wuhan, recovered asymptomatic patients (APs) from an isolation hotel, and uninfected healthy controls (HCs) were recruited. Viral nucleic acid and antibody detection, laboratory examination, computed tomography, pulmonary function assessment, multiplex cytokine assay, and flow cytometry were performed. RESULTS: The72 age-, sex- and body mass index-matched participants included 19 patients with severe/critical COVID-19 (SPs), 20 patients with mild/moderate COVID-19 (MPs), 16 APs, and 17 HCs. At 3 months after discharge, levels of proinflammatory cytokines and factors related to vascular injury/repair in patients recovered from COVID-19 had not returned to those of the HCs, especially among recovered SPs compared with recovered MPs and APs. These cytokines were significantly correlated with impaired pulmonary function and chest computed tomographic abnormalities. However, levels of immune cells had returned to nearly normal levels and were not significantly correlated with abnormal clinical features. CONCLUSION: Vascular injury, inflammation, and chemotaxis persisted in patients with COVID-19 and were correlated with abnormal clinical features 3 months after discharge, especially in recovered SPs.


Subject(s)
COVID-19/diagnosis , COVID-19/immunology , Cytokines/immunology , Survivors/psychology , Aftercare , Anti-Bacterial Agents/therapeutic use , Antiviral Agents/therapeutic use , COVID-19/epidemiology , COVID-19/therapy , China/epidemiology , Cross-Sectional Studies , Humans , Patient Discharge , Prospective Studies , Retrospective Studies , SARS-CoV-2 , Treatment Outcome , Vascular System Injuries
3.
Front Physiol ; 12: 634839, 2021.
Article in English | MEDLINE | ID: covidwho-1526786

ABSTRACT

Though the current preponderance of evidence indicates the toxicity associated with the smoking of tobacco products through conventional means, less is known about the role of "vaping" in respiratory disease. "Vaping" is described as the use of electronic cigarettes (E-Cigarettes or E-Cigs), which has only more recently been available to the public (∼10 years) but has quickly emerged as a popular means of tobacco consumption worldwide. The World Health Organization (WHO) declared the SARS-CoV-2 outbreak as a global pandemic in March 2020. SARS-CoV-2 can easily be transmitted between people in close proximity through direct contact or respiratory droplets to develop coronavirus infectious disease 2019 (COVID-19). Symptoms of COVID-19 range from a mild flu-like illness with high fever to severe respiratory distress syndrome and death. The risk factors for increased disease severity remain unclear. Herein, we utilize a murine-tropic coronavirus (beta coronavirus) MHV-A59 along with a mouse model and measures of pathology (lung weight/dry ratios and histopathology) and inflammation (ELISAs and cytokine array panels) to examine whether vaping may exacerbate the pulmonary disease severity of coronavirus disease. While vaping alone did result in some noted pathology, mice exposed with intranasal vaped e-liquid suffered more severe mortality due to pulmonary inflammation than controls when exposed to coronavirus infection. Our data suggest a role for vaping in increased coronavirus pulmonary disease in a mouse model. Furthermore, our data indicate that disease exacerbation may involve calcium (Ca2+) dysregulation, identifying a potential therapeutic intervention.

4.
Pharmacol Res ; 169: 105689, 2021 07.
Article in English | MEDLINE | ID: covidwho-1525917

ABSTRACT

Genome wide association, epidemiological, and clinical studies have established high lipoprotein(a) [Lp(a)] as a causal risk factor for atherosclerotic cardiovascular disease (ASCVD). Lp(a) is an apoB100 containing lipoprotein covalently bound to apolipoprotein(a) [apo(a)], a glycoprotein. Plasma Lp(a) levels are to a large extent determined by genetics. Its link to cardiovascular disease (CVD) may be driven by its pro-inflammatory effects, of which its association with oxidized phospholipids (oxPL) bound to Lp(a) is the most studied. Various inflammatory conditions, such as rheumatoid arthritis (RA), systemic lupus erythematosus, acquired immunodeficiency syndrome, and chronic renal failure are associated with high Lp(a) levels. In cases of RA, high Lp(a) levels are reversed by interleukin-6 receptor (IL-6R) blockade by tocilizumab, suggesting a potential role for IL-6 in regulating Lp(a) plasma levels. Elevated levels of IL-6 and IL-6R polymorphisms are associated with CVD. Therapies aimed at lowering apo(a) and thereby reducing plasma Lp(a) levels are in clinical trials. Their results will determine if reductions in apo(a) and Lp(a) decrease cardiovascular outcomes. As we enter this new arena of available treatments, there is a need to improve our understanding of mechanisms. This review will focus on the role of Lp(a) in inflammation and CVD.


Subject(s)
Inflammation/metabolism , Lipoprotein(a)/blood , Animals , Cardiovascular Diseases/blood , Cardiovascular Diseases/etiology , Cardiovascular Diseases/metabolism , Humans , Inflammation/blood , Inflammation/etiology , Lipoprotein(a)/metabolism , Lipoprotein(a)/physiology
5.
Calcif Tissue Int ; 108(4): 452-460, 2021 04.
Article in English | MEDLINE | ID: covidwho-1509222

ABSTRACT

Bone is not only a mineralized and apparently non-vital structure that provides support for locomotion and protection to inner organs. An increasing number of studies are unveiling new biologic functions and connections to other systems, giving the rise to new fields of research, such as osteoimmunology. The bone marrow niche, a new entity in bone physiology, seems to represent the site where a complex crosstalk between bone and immune/inflammatory responses takes place. An impressive interplay with the immune system is realized in bone marrow, with reciprocal influences between bone cells and haematopoietic cells. In this way, systemic chronic inflammatory diseases realize a crosstalk with bone, resulting in bone disease. Thus, pathogenetic links between chronic kidney disease-mineral bone disorders and osteoporosis, cardiovascular disease, and ageing are common. The aim of this narrative review is to provide a general view of the progresses in the field of bone research and their potential clinical implications, with emphasis on the links with inflammation and the connections to osteoimmunology and chemokines.


Subject(s)
Bone and Bones , Renal Insufficiency, Chronic , Bone Marrow , Humans , Inflammation , Oxidative Stress
6.
Arthritis Rheumatol ; 73(10): 1791-1799, 2021 10.
Article in English | MEDLINE | ID: covidwho-1391545

ABSTRACT

OBJECTIVE: Infection with the novel coronavirus SARS-CoV-2 triggers severe illness with high mortality in a subgroup of patients. Such a critical course of COVID-19 is thought to be associated with the development of cytokine storm, a condition seen in macrophage activation syndrome (MAS) and secondary hemophagocytic lymphohistiocytosis (HLH). However, specific data demonstrating a clear association of cytokine storm with severe COVID-19 are still lacking. The aim of this study was to directly address whether immune activation in COVID-19 does indeed mimic the conditions found in these classic cytokine storm syndromes. METHODS: Levels of 22 biomarkers were quantified in serum samples from patients with COVID-19 (n = 30 patients, n = 83 longitudinal samples in total), patients with secondary HLH/MAS (n = 50), and healthy controls (n = 9). Measurements were performed using bead array assays and single-marker enzyme-linked immunosorbent assay. Serum biomarker levels were assessed for correlations with disease outcome. RESULTS: In patients with secondary HLH/MAS, we observed pronounced activation of the interleukin-18 (IL-18)-interferon-γ axis, increased serum levels of IL-1 receptor antagonist, intercellular adhesion molecule 1, and IL-8, and strongly reduced levels of soluble Fas ligand in the course of SARS-CoV-2 infection. These observations appeared to discriminate immune dysregulation in critical COVID-19 from the well-recognized characteristics of other cytokine storm syndromes. CONCLUSION: Serum biomarker profiles clearly separate COVID-19 from MAS or secondary HLH in terms of distinguishing the severe systemic hyperinflammation that occurs following SARS-CoV-2 infection. These findings could be useful in determining the efficacy of drugs targeting key molecules and pathways specifically associated with systemic cytokine storm conditions in the treatment of COVID-19.


Subject(s)
COVID-19/diagnosis , Cytokine Release Syndrome/etiology , Interleukin-18/blood , Interleukin-8/blood , Lymphohistiocytosis, Hemophagocytic/diagnosis , Macrophage Activation Syndrome/diagnosis , Adolescent , Adult , Aged , Aged, 80 and over , Biomarkers/blood , COVID-19/blood , COVID-19/complications , Cytokine Release Syndrome/blood , Diagnosis, Differential , Female , Humans , Lymphohistiocytosis, Hemophagocytic/blood , Lymphohistiocytosis, Hemophagocytic/complications , Macrophage Activation Syndrome/blood , Macrophage Activation Syndrome/complications , Male , Middle Aged , Young Adult
7.
Int J Mol Sci ; 22(5)2021 Mar 04.
Article in English | MEDLINE | ID: covidwho-1389392

ABSTRACT

Alveolar type II (ATII) cells are a key structure of the distal lung epithelium, where they exert their innate immune response and serve as progenitors of alveolar type I (ATI) cells, contributing to alveolar epithelial repair and regeneration. In the healthy lung, ATII cells coordinate the host defense mechanisms, not only generating a restrictive alveolar epithelial barrier, but also orchestrating host defense mechanisms and secreting surfactant proteins, which are important in lung protection against pathogen exposure. Moreover, surfactant proteins help to maintain homeostasis in the distal lung and reduce surface tension at the pulmonary air-liquid interface, thereby preventing atelectasis and reducing the work of breathing. ATII cells may also contribute to the fibroproliferative reaction by secreting growth factors and proinflammatory molecules after damage. Indeed, various acute and chronic diseases are associated with intensive inflammation. These include oedema, acute respiratory distress syndrome, fibrosis and numerous interstitial lung diseases, and are characterized by hyperplastic ATII cells which are considered an essential part of the epithelialization process and, consequently, wound healing. The aim of this review is that of revising the physiologic and pathologic role ATII cells play in pulmonary diseases, as, despite what has been learnt in the last few decades of research, the origin, phenotypic regulation and crosstalk of these cells still remain, in part, a mystery.


Subject(s)
Alveolar Epithelial Cells/pathology , Alveolar Epithelial Cells/physiology , Lung Diseases/physiopathology , Lung/physiology , Alveolar Epithelial Cells/cytology , Animals , COVID-19/physiopathology , Humans , Immunity, Innate , Ions/metabolism , Lung/anatomy & histology , Lung Diseases/etiology , Lung Diseases/pathology , Pulmonary Surfactant-Associated Proteins/metabolism , Regeneration
8.
Curr Med Chem ; 28(22): 4499-4530, 2021.
Article in English | MEDLINE | ID: covidwho-1374185

ABSTRACT

BACKGROUND: The identification of vulnerable subgroups and risk factors associated with the susceptibility to severe acute respiratory syndrome coronavirus 2 (SARS-CoV- 2) infection and coronavirus disease 2019 (COVID-19) is of utmost importance in a pandemic scenario. Potential interactions between renin-angiotensin system (RAS), immune markers and COVID-19 play a role in disease outcome in specific groups of patients. OBJECTIVE: This review aimed to describe the particularities of the RAS and the immune system profile of particular subgroups of patients. METHODS: This non-systematic review summarizes evidence on SARS-CoV-2 infection in specific subgroups of patients and possible relationships between immune system, RAS and the pathophysiology of COVID-19. RESULTS: The RAS and the immune system exert a role in the pathogenesis and prognosis of COVID-19, mainly in cases of hypertension, diabetes, obesity and other chronic diseases. The overactivation of the ACE/Ang II/AT1R axis and the enhancement of inflammation contribute to deleterious effects of COVID-19. Likewise, pregnant women and elderly patients usually display immune responses that are less effective in withstanding exposition to viruses, while children are relatively protected against severe complications of COVID-19. Women, conversely, exhibit stronger antiviral responses and are less sensitive to the effects of increased Ang II. Future Perspectives: The recognition of vulnerable subgroups and risk factors for disease severity is essential to better understand the pandemic. Precision medicine tools, including proteomics and metabolomics approaches, identified metabolic patterns of the severe form of disease and might be the alternative to diagnose, evaluate and predict the prognosis and the efficiency of therapies.


Subject(s)
COVID-19 , Renin-Angiotensin System , Aged , Angiotensin-Converting Enzyme Inhibitors , Child , Female , Humans , Immune System/metabolism , Peptidyl-Dipeptidase A/metabolism , Pregnancy , SARS-CoV-2
9.
J Biol Chem ; 296: 100630, 2021.
Article in English | MEDLINE | ID: covidwho-1333548

ABSTRACT

Unchecked inflammation can result in severe diseases with high mortality, such as macrophage activation syndrome (MAS). MAS and associated cytokine storms have been observed in COVID-19 patients exhibiting systemic hyperinflammation. Interleukin-18 (IL-18), a proinflammatory cytokine belonging to the IL-1 family, is elevated in both MAS and COVID-19 patients, and its level is known to correlate with the severity of COVID-19 symptoms. IL-18 binds its specific receptor IL-1 receptor 5 (IL-1R5, also known as IL-18 receptor alpha chain), leading to the recruitment of the coreceptor, IL-1 receptor 7 (IL-1R7, also known as IL-18 receptor beta chain). This heterotrimeric complex then initiates downstream signaling, resulting in systemic and local inflammation. Here, we developed a novel humanized monoclonal anti-IL-1R7 antibody to specifically block the activity of IL-18 and its inflammatory signaling. We characterized the function of this antibody in human cell lines, in freshly obtained peripheral blood mononuclear cells (PBMCs) and in human whole blood cultures. We found that the anti-IL-1R7 antibody significantly suppressed IL-18-mediated NFκB activation, reduced IL-18-stimulated IFNγ and IL-6 production in human cell lines, and reduced IL-18-induced IFNγ, IL-6, and TNFα production in PBMCs. Moreover, the anti-IL-1R7 antibody significantly inhibited LPS- and Candida albicans-induced IFNγ production in PBMCs, as well as LPS-induced IFNγ production in whole blood cultures. Our data suggest that blocking IL-1R7 could represent a potential therapeutic strategy to specifically modulate IL-18 signaling and may warrant further investigation into its clinical potential for treating IL-18-mediated diseases, including MAS and COVID-19.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Antibodies, Monoclonal/pharmacology , Antibodies, Neutralizing/pharmacology , Immunologic Factors/pharmacology , Interleukin-18/genetics , Receptors, Interleukin-18/genetics , Anti-Inflammatory Agents/metabolism , Antibodies, Monoclonal/biosynthesis , Antibodies, Neutralizing/biosynthesis , COVID-19/drug therapy , Candida albicans/growth & development , Candida albicans/pathogenicity , Gene Expression Regulation , HEK293 Cells , Humans , Immunologic Factors/biosynthesis , Inflammation , Interferon-gamma/genetics , Interferon-gamma/immunology , Interleukin-18/immunology , Interleukin-6/genetics , Interleukin-6/immunology , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/immunology , Leukocytes, Mononuclear/microbiology , Lipopolysaccharides/antagonists & inhibitors , Lipopolysaccharides/pharmacology , Macrophage Activation Syndrome/drug therapy , NF-kappa B/genetics , NF-kappa B/immunology , Primary Cell Culture , Receptors, Interleukin-18/antagonists & inhibitors , Receptors, Interleukin-18/immunology , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity , Signal Transduction/drug effects , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/immunology
10.
Biochimie ; 179: 281-284, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-1326920

ABSTRACT

Poxytrins (Pufa Oxygenated Trienes) are dihydroxy derivatives from polyunsaturated fatty acids (PUFA) with adjacent hydroxyl groups to a conjugated triene having the specific E,Z,E geometry. They are made by the double action of one lipoxygenase or the combined actions of two lipoxygenases, followed by reduction of the resulting hydroperoxides with glutathione peroxidase. Because of their E,Z,E conjugated triene, poxytrins may inhibit inflammation associated with cyclooxygenase (COX) activities, and reactive oxygen species (ROS) formation. In addition of inhibiting COX activities, at least one poxytrin, namely protectin DX (PDX) from docosahexaenoic acid (DHA), has also been reported as able to inhibit influenza virus replication by targeting its RNA metabolism.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Antiviral Agents/pharmacology , Docosahexaenoic Acids/pharmacology , Fatty Acids, Unsaturated/pharmacology , Animals , Anti-Inflammatory Agents/chemistry , Antiviral Agents/chemistry , Brain/drug effects , Brain/metabolism , Docosahexaenoic Acids/chemistry , Fatty Acids, Unsaturated/chemistry , Humans , Prostaglandin-Endoperoxide Synthases/drug effects , Reactive Oxygen Species/metabolism , Virus Replication/drug effects
11.
Exp Clin Transplant ; 19(7): 744-748, 2021 07.
Article in English | MEDLINE | ID: covidwho-1323413

ABSTRACT

Acute respiratory distress syndrome remains the main cause of death among people with COVID-19. Although many immunomodulatory and antiviral drug therapies have been tested, the only effective therapy against severe COVID-19 pneumonia among the general population is a regimen of high-dose corticosteroids for cases of severe associated inflammation. In solid-organ transplant recipients with long-term immunosuppression, data on disease presentation and evolution are scarce, and the benefit of high-dose corticosteroids remains uncertain for cases of severe COVID-19 pneumonia. Here, we report 2 cases of COVID-19-related acute respiratory distress syndrome that occurred in lung transplant recipients in March and April 2020, respectively. Both cases of acute respiratory distress syndrome occurred in patients with long-term azithromycin treatment prescribed to prevent chronic allograft dysfunction. Acute respiratory distress syndrome was associated with severe inflammation and was cured after early administration of high-dose corticosteroids in both cases, with progressive and complete resolution of lung lesions evidenced on thoracic computed tomography scan. Our findings support the benefit of early high-dose corticosteroids in COVID-19-related acute respiratory distress syndrome with hyperinflammation in patients with long-term immunosuppression such as lung transplant recipients.


Subject(s)
COVID-19/drug therapy , Lung Transplantation , Methylprednisolone/therapeutic use , Postoperative Complications/drug therapy , Respiratory Distress Syndrome/drug therapy , COVID-19/complications , Female , Humans , Male , Middle Aged , Postoperative Complications/virology , Remission Induction , Respiratory Distress Syndrome/virology
12.
J Biol Regul Homeost Agents ; 35(2): 423-427, 2021.
Article in English | MEDLINE | ID: covidwho-1298274

ABSTRACT

Acute severe respiratory syndrome coronavirus-2 (SARS-CoV-2) infection causes coronavirus disease-2019 (COVID-19) which is associated with inflammation, thrombosis edema, hemorrhage, intra-alveolar fibrin deposition, and vascular and pulmonary damage. In COVID-19, the coronavirus activates macrophages by inducing the generation of pro-inflammatory cytokines [interleukin (IL)-1, IL-6, IL-18 and TNF] that can damage endothelial cells, activate platelets and neutrophils to produce thromboxane A2 (TxA2), and mediate thrombus generation. In severe cases, all these phenomena can lead to patient death. The binding of SARS-CoV-2 to the Toll Like Receptor (TLR) results in the release of pro-IL-1ß that is cleaved by caspase-1, followed by the production of active mature IL-1ß which is the most important cytokine in causing fever and inflammation. Its activation in COVID-19 can cause a "cytokine storm" with serious biological and clinical consequences. Blockade of IL-1 with inhibitory and anti-inflammatory cytokines represents a new therapeutic strategy also for COVID-19. Recently, very rare allergic reactions to vaccines have been reported, with phenomena of pulmonary thrombosis. These side effects have raised substantial concern in the population. Highly allergic subjects should therefore be vaccinated under strict medical supervision. COVID-19 has accelerated vaccine therapy but also the use of drugs and monoclonal antibodies (mABs) which have been used in COVID-19 therapy. They are primarily adopted to treat high-risk mild-to-moderate non-hospitalized patients, and it has been noted that the administration of two mABs gave better results. mABs, other than polyclonal plasma antibodies from infected subjects with SARS-CoV-2, are produced in the laboratory and are intended to fight SARS-CoV-2. They bind specifically to the antigenic determinant of the spike protein, inhibiting the pathogenicity of the virus. The most suitable individuals for mAB therapy are people at particular risk, such as the elderly and those with serious chronic diseases including diabetics, hypertension and obesity, including subjects suffering from cardiovascular diseases. These antibodies have a well-predetermined target, they bind mainly to the protein S (formed by the S1A, B, C and D subtypes), located on the viral surface, and to the S2 protein that acts as a fuser between the virus and the cell membrane. Since mABs are derived from a single splenic immune cell, they are identical and form a cell clone which can neutralize SARS-CoV-2 by binding to the epitope of the virus. However, this COVID-19 therapy may cause several side effects such as mild pain, bleeding, bruising of the skin, soreness, swelling, thrombotic-type episodes, arterial hypertension, changes in heart activity, slowed bone marrow activity, impaired renal function, diarrhea, fatigue, nausea, vomiting, allergic reaction, fever, and possible subsequent infection may occur at the site of injection. In conclusion, the studies promoting mAB therapy in COVID-19 are very promising but the results are not yet definitive and more investigations are needed to certify both their good neutralizing effects of SARS-CoV-2, and to eliminate, or at least mitigate, the harmful side effects.


Subject(s)
COVID-19 , SARS-CoV-2 , Aged , Antibodies, Monoclonal , Cytokine Release Syndrome , Endothelial Cells , Humans
13.
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
14.
Heliyon ; 6(8): e04696, 2020 Aug.
Article in English | MEDLINE | ID: covidwho-1269279

ABSTRACT

Obesity is a risk factor for SARS-CoV-2 infected patients to develop respiratory failure. Leptin produced in visceral fat might play a role in the deterioration to mechanical ventilation. A cross sectional study was performed. The mean BMI was 31 kg/m2 (range 24.8-48.4) for the 31 SARS-CoV-2 ventilated patients and 26 kg/m2 (range 22.4-33.5) for 8 critically ill non-infected control patients. SARS-CoV-2 infected patients with a similar BMI as control patients appear to have significantly higher levels of serum leptin. The mean leptin level was 21.2 (6.0-85.2) vs 5.6 (2.4-8.2) ug/L for SARS-CoV-2 and controls respectively (p = 0.0007). With these findings we describe a clinical and biological framework that may explain these clinical observations. The ACE2 utilization by the virus leads to local pulmonary inflammation due to ACE2-ATII disbalance. This might be enhanced by an increase in leptin production induced by SARS-CoV-2 infection of visceral fat. Leptin receptors in the lungs are now more activated to enhance local pulmonary inflammation. This adds to the pre-existent chronic inflammation in obese patients. Visceral fat, lung tissue and leptin production play an interconnecting role. This insight can lead the way to further research and treatment.

15.
Neurobiol Dis ; 156: 105422, 2021 08.
Article in English | MEDLINE | ID: covidwho-1267874

ABSTRACT

Synthetic glucocorticoids (sGCs) such as dexamethasone (DEX), while used to mitigate inflammation and disease progression in premature infants with severe bronchopulmonary dysplasia (BPD), are also associated with significant adverse neurologic effects such as reductions in myelination and abnormalities in neuroanatomical development. Ciclesonide (CIC) is a sGC prodrug approved for asthma treatment that exhibits limited systemic side effects. Carboxylesterases enriched in the lower airways convert CIC to the glucocorticoid receptor (GR) agonist des-CIC. We therefore examined whether CIC would likewise activate GR in neonatal lung but have limited adverse extra-pulmonary effects, particularly in the developing brain. Neonatal rats were administered subcutaneous injections of CIC, DEX or vehicle from postnatal days 1-5 (PND1-PND5). Systemic effects linked to DEX exposure, including reduced body and brain weight, were not observed in CIC treated neonates. Furthermore, CIC did not trigger the long-lasting reduction in myelin basic protein expression in the cerebral cortex nor cerebellar size caused by neonatal DEX exposure. Conversely, DEX and CIC were both effective at inducing the expression of select GR target genes in neonatal lung, including those implicated in lung-protective and anti-inflammatory effects. Thus, CIC is a promising, novel candidate drug to treat or prevent BPD in neonates given its activation of GR in neonatal lung and limited adverse neurodevelopmental effects. Furthermore, since sGCs such as DEX administered to pregnant women in pre-term labor can adversely affect fetal brain development, the neurological-sparing properties of CIC, make it an attractive alternative for DEX to treat pregnant women severely ill with respiratory illness, such as with asthma exacerbations or COVID-19 infections.


Subject(s)
Cerebellum/drug effects , Cerebral Cortex/drug effects , Glucocorticoids , Lung/drug effects , Pregnenediones/pharmacology , Prodrugs/pharmacology , Signal Transduction/drug effects , Animals , Animals, Newborn , Anti-Inflammatory Agents/pharmacology , Body Weight/drug effects , Brain/drug effects , Brain/growth & development , COVID-19/drug therapy , Dexamethasone/pharmacology , Female , Mice , Mice, Inbred C57BL , Myelin Basic Protein/biosynthesis , Organ Size/drug effects , Pregnancy , Rats , Rats, Sprague-Dawley , Receptors, Glucocorticoid/drug effects
16.
Crit Care ; 25(1): 202, 2021 06 10.
Article in English | MEDLINE | ID: covidwho-1266500

ABSTRACT

BACKGROUND: The mechanisms driving acute kidney injury (AKI) in critically ill COVID-19 patients are unclear. We collected kidney biopsies from COVID-19 AKI patients within 30 min after death in order to examine the histopathology and perform mRNA expression analysis of genes associated with renal injury. METHODS: This study involved histopathology and mRNA analyses of postmortem kidney biopsies collected from patients with COVID-19 (n = 6) and bacterial sepsis (n = 27). Normal control renal tissue was obtained from patients undergoing total nephrectomy (n = 12). The mean length of ICU admission-to-biopsy was 30 days for COVID-19 and 3-4 days for bacterial sepsis patients. RESULTS: We did not detect SARS-CoV-2 RNA in kidney biopsies from COVID-19-AKI patients yet lung tissue from the same patients was PCR positive. Extensive acute tubular necrosis (ATN) and peritubular thrombi were distinct histopathology features of COVID-19-AKI compared to bacterial sepsis-AKI. ACE2 mRNA levels in both COVID-19 (fold change 0.42, p = 0.0002) and bacterial sepsis patients (fold change 0.24, p < 0.0001) were low compared to control. The mRNA levels of injury markers NGAL and KIM-1 were unaltered compared to control tissue but increased in sepsis-AKI patients. Markers for inflammation and endothelial activation were unaltered in COVID-19 suggesting a lack of renal inflammation. Renal mRNA levels of endothelial integrity markers CD31, PV-1 and VE-Cadherin did not differ from control individuals yet were increased in bacterial sepsis patients (CD31 fold change 2.3, p = 0.0006, PV-1 fold change 1.5, p = 0.008). Angiopoietin-1 mRNA levels were downregulated in renal tissue from both COVID-19 (fold change 0.27, p < 0.0001) and bacterial sepsis patients (fold change 0.67, p < 0.0001) compared to controls. Moreover, low Tie2 mRNA expression (fold change 0.33, p = 0.037) and a disturbed VEGFR2/VEGFR3 ratio (fold change 0.09, p < 0.0001) suggest decreased microvascular flow in COVID-19. CONCLUSIONS: In a small cohort of postmortem kidney biopsies from COVID-19 patients, we observed distinct histopathological and gene expression profiles between COVID-19-AKI and bacterial sepsis-AKI. COVID-19 was associated with more severe ATN and microvascular thrombosis coupled with decreased microvascular flow, yet minimal inflammation. Further studies are required to determine whether these observations are a result of true pathophysiological differences or related to the timing of biopsy after disease onset.


Subject(s)
COVID-19/pathology , Gene Expression/genetics , Kidney/pathology , Kidney/physiopathology , Sepsis/pathology , Acute Kidney Injury/etiology , Acute Kidney Injury/physiopathology , Adult , Aged , Aged, 80 and over , Analysis of Variance , COVID-19/genetics , COVID-19/physiopathology , Critical Illness/therapy , Female , Humans , Intensive Care Units/organization & administration , Intensive Care Units/statistics & numerical data , Male , Middle Aged , Sepsis/genetics , Sepsis/physiopathology , Simplified Acute Physiology Score
17.
Autoimmun Rev ; 20(8): 102865, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-1263223

ABSTRACT

BACKGROUND AND AIMS: The novel SARS-CoV-2 has been rattling the world since its outbreak in December 2019, leading to the COVID-19 pandemic. The learning curve of this new virus has been steep, with a global scientific community desperate to learn how the virus is transmitted, how it replicates, why it causes such a wide spectrum of disease manifestations, resulting in none or few symptoms in some. Others are burdened by an intense immune response that resembles the cytokine storm syndrome (CSS), which leads to severe disease manifestations, often complicated by fatal acute respiratory distress syndrome and death. Research efforts have been focusing on finding effective cures and vaccinations for this virus. The presence of SARS-CoV-2 in the gastrointestinal (GI) tract, represented by several GI manifestations, has led to its investigation as a target for the virus and as an indicator of disease severity. The response of the microbiome (which is heavily linked to immunity) to the novel SARS-CoV-2 virus, and its role in igniting the exaggerated immune response has therefore become a focus of interest. The objective of our study was to gather the data connecting between the microbiome, the GI tract and COVID-19 and to investigate whether these reported alterations in the gut microbiome bear any resemblance to those seen in lupus, the prototypical autoimmune disease. Confirming such changes may become the steppingstone to potential therapies that may prevent transmission, progression and immune related manifestations of COVID-19, via manipulation of the gut microbiota. METHODS: We performed an extensive literature review, utilizing the Pubmed search engine and Google Scholar for studies evaluating the microbiome in COVID-19 patients and compared results with studies evaluating the microbiome in lupus. We searched for the terms: microbiome, dysbiosis, COVID-19, SARS-CoV-2, gastrointestinal as well as lupus and autoimmune. While there were hundreds of articles which referred to gastrointestinal manifestations in COVID-19, to date only 4 studies investigated the gastrointestinal microbiome in this setting. We compared the similarities between microbiome of COVID-19 patients and lupus patients. RESULTS: We found that there are several similar processes of immune dysregulation in patients with COVID-19 and in those with lupus, with several other alterations seen in other pathological states. Some of these similarities include loss of microbiota biodiversity, increased representation of pathobionts, which are microbes associated with inflammation and disease (i.e Proteobacteria) and a relative decrease of symbionts, which are protective microbes, associated with anti-inflammatory properties (i.e Lactobacillus). Compromise to the intestinal barrier has also been reported in both. CONCLUSIONS: We conclude that the gastrointestinal tract contributes to the disease manifestations in COVID-19. Whether gastrointestinal dysbiosis is the cause or effect of gastrointestinal manifestations and several severe systemic manifestations, which may be the response to an increased pro-inflammatory environment, is still debatable and warrants further investigation. Given the resemblance of the microbiome in COVID-19 patients to that seen in lupus patients, it becomes clearer why several therapies used in autoimmune conditions are currently under investigation for the treatment of COVID-19 patients. Moreover, these findings should promote further investigating the utility of manipulation of the microbiome, via nutritional supplementation or even fecal transplantations, interventions that may alter the course of the disease, and potentially prevent disease transmission at low cost and low risk.


Subject(s)
COVID-19 , Autoimmunity , Dysbiosis , Humans , Pandemics , SARS-CoV-2
18.
PLoS One ; 16(6): e0252758, 2021.
Article in English | MEDLINE | ID: covidwho-1261297

ABSTRACT

BACKGROUND: Angiotensin-converting enzyme 2 (ACE2) has been implicated in the pathogenesis of experimental kidney disease. ACE2 is on the X chromosome, and in mice, deletion of ACE2 leads to the development of focal segmental glomerulosclerosis (FSGS). The relationship between sex and renal ACE2 expression in humans with kidney disease is a gap in current knowledge. METHODS: We studied renal tubulointerstitial microarray data and clinical variables from subjects with FSGS enrolled in the Nephrotic Syndrome Study Network (NEPTUNE) study. We compared relationships between ACE2 expression and age, estimated glomerular filtration rate (eGFR), urinary albumin to creatinine ratio (UACR), interstitial fibrosis, tubular atrophy, and genes implicated in inflammation and fibrosis in male and female subjects. RESULTS: ACE2 mRNA expression was lower in the tubulointerstitium of males compared to females (P = 0.0026). Multiple linear regression analysis showed that ACE2 expression was related to sex and eGFR but not to age or treatment with renin angiotensin system blockade. ACE2 expression is also related to interstitial fibrosis, and tubular atrophy, in males but not in females. Genes involved in inflammation (CCL2 and TNF) correlated with ACE2 expression in males (TNF: r = -0.65, P < 0.0001; CCL2: r = -0.60, P < 0.0001) but not in females. TGFB1, a gene implicated in fibrosis correlated with ACE2 in both sexes. CONCLUSIONS: Sex is an important determinant of ACE2 expression in the tubulointerstitium of the kidney in FSGS. Sex also influences the relationships between ACE2, kidney fibrosis, and expression of genes involved in kidney inflammation.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Glomerulosclerosis, Focal Segmental/metabolism , Adolescent , Adult , Angiotensin-Converting Enzyme 2/genetics , Chemokine CCL2/genetics , Chemokine CCL2/metabolism , Child , Female , Glomerulosclerosis, Focal Segmental/genetics , Glomerulosclerosis, Focal Segmental/pathology , Humans , Kidney/metabolism , Male , Middle Aged , Sex Factors , Transforming Growth Factor beta1/genetics , Transforming Growth Factor beta1/metabolism , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/metabolism
19.
Sci Rep ; 11(1): 11636, 2021 06 02.
Article in English | MEDLINE | ID: covidwho-1253991

ABSTRACT

The elevated level of D-dimer and its relationship with poor outcomes in SARS-COV-2 pneumonia patients have been demonstrated. In addition to a hypercoagulable state, D-dimer is also a biomarker of inflammation. We investigated the relationship between D-dimer level and chest computed tomography (CT) severity score, which could reflect the severity of inflammation in SARS-COV-2 pneumonia patients. We retrospectively enrolled 86 consecutive SARS-COV-2 pneumonia patients. CT severity scores were computed to quantify the overall lung involvement. The D-dimer level among CT score tertiles and the association of the D-dimer level with CT score were analyzed. Our results showed that the median D-dimer level was 0.70 mg/L (IQR 0.35-1.76). 42 patients (48.8%) had D-dimer levels above the median level. The D-dimer levels were significantly different across CT score tertiles (0.37 mg/l [IQR 0.31-0.87], 0.66 mg/l [IQR 0.39-1.43], 1.83 mg/l [IQR 0.85-4.41], P < 0.001). The natural logarithm of the D-dimer level was significantly associated with the CT score (rs = 0.586, P < 0.001). In conclusion, the D-dimer level may be associated with the severity of inflammation of SARS-COV-2 pneumonia prior to coagulopathy/thrombosis. This could be an additional explanation for the mechanism of the relationship between elevated D-dimer level and higher mortality.


Subject(s)
COVID-19/diagnostic imaging , COVID-19/etiology , Fibrin Fibrinogen Degradation Products/analysis , Adult , Aged , COVID-19/blood , Female , Humans , Lung/diagnostic imaging , Lung/pathology , Lung/virology , Male , Middle Aged , Pulmonary Embolism/diagnostic imaging , Pulmonary Embolism/virology , Respiration, Artificial , Retrospective Studies , Tomography, X-Ray Computed/methods
20.
Med Sci Monit ; 27: e933369, 2021 May 31.
Article in English | MEDLINE | ID: covidwho-1257129

ABSTRACT

In early 2020, at the beginning of the coronavirus disease 2019 (COVID-19) pandemic due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), rare cases were reported in children and adolescents of multisystem inflammatory syndrome in children (MIS-C). MIS-C is characterized by fever, systemic inflammation, and multiorgan dysfunction and usually presents late in SARS-CoV-2 infection. Since May 2020, the Centers for Disease Control and Prevention (CDC) has recorded all reported cases of COVID-19 and MIS-C in children and adolescents in the USA. In April 2021, the American College of Rheumatology (ACR) revised its clinical guidelines for diagnosing and managing hyperinflammation and MIS-C. There are several challenges ahead for preventing, diagnosing, and managing MIS-C, particularly following the rapid emergence of new strains of SARS-CoV-2. This Editorial aims to present an update on the current status of the clinical presentation, diagnosis, and management of MIS-C and includes some updates from population studies and clinical guidelines.


Subject(s)
COVID-19/diagnosis , COVID-19/therapy , Systemic Inflammatory Response Syndrome/diagnosis , Systemic Inflammatory Response Syndrome/therapy , Adolescent , COVID-19 Testing , Child , Disease Management , Humans , SARS-CoV-2/isolation & purification
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