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1.
J Clin Med ; 10(8)2021 Apr 09.
Статья в английский | MEDLINE | ID: covidwho-1526827

Реферат

Despite direct viral effect, the pathogenesis of coronavirus disease 2019 (COVID-19) includes an overproduction of cytokines including interleukin 6 (IL-6). Therefore, tocilizumab (TOC), a monoclonal antibody against IL-6 receptors, was considered as a possible therapeutic option. Patients were selected from the SARSTer database, containing 2332 individuals with COVID-19. Current study included 825 adult patients with moderate to severe course. Analysis was performed in 170 patients treated with TOC and 655 with an alternative medication. The end-points of treatment effectiveness were death rate, need for mechanical ventilation, and clinical improvement. Patients treated with TOC were balanced compared to non-TOC regarding gender, age, BMI, and prevalence of coexisting conditions. Significant effect of TOC on death was demonstrated in patients with baseline IL-6 > 100 pg/mL (hazard ratio [HR]: 0.21, 95% confidence interval [CI]: 0.08-0.57). The best effectiveness of TOC was achieved in patients with a combination of baseline IL-6 > 100 pg/mL and either SpO2 ≤ 90% (HR: 0.07) or requiring oxygen supplementation (HR: 0.18). Tocilizumab administration in COVID-19 reduces mortality and speeds up clinical improvement in patients with a baseline concentration of IL-6 > 100 pg/mL, particularly if they need oxygen supplementation owing to the lower value of SpO2 ≤ 90%.

3.
Commun Biol ; 4(1): 631, 2021 05 27.
Статья в английский | MEDLINE | ID: covidwho-1283664

Реферат

IL22 is an important cytokine involved in the intestinal defense mechanisms against microbiome. By using ileum-derived organoids, we show that the expression of anti-microbial peptides (AMPs) and anti-viral peptides (AVPs) can be induced by IL22. In addition, we identified a bacterial and a viral route, both leading to IL22 production by T cells, but via different pathways. Bacterial products, such as LPS, induce enterocyte-secreted SAA1, which triggers the secretion of IL6 in fibroblasts, and subsequently IL22 in T cells. This IL22 induction can then be enhanced by macrophage-derived TNFα in two ways: by enhancing the responsiveness of T cells to IL6 and by increasing the expression of IL6 by fibroblasts. Viral infections of intestinal cells induce IFNß1 and subsequently IL7. IFNß1 can induce the expression of IL6 in fibroblasts and the combined activity of IL6 and IL7 can then induce IL22 expression in T cells. We also show that IL22 reduces the expression of viral entry receptors (e.g. ACE2, TMPRSS2, DPP4, CD46 and TNFRSF14), increases the expression of anti-viral proteins (e.g. RSAD2, AOS, ISG20 and Mx1) and, consequently, reduces the viral infection of neighboring cells. Overall, our data indicates that IL22 contributes to the innate responses against both bacteria and viruses.


Тема - темы
Interleukins/biosynthesis , Interleukins/metabolism , Animals , Anti-Bacterial Agents/metabolism , Antiviral Agents/metabolism , Cell Culture Techniques , Cytokines/immunology , Cytokines/metabolism , Disease Models, Animal , Enterocytes/immunology , Enterocytes/metabolism , Female , Fibroblasts/immunology , Fibroblasts/metabolism , Interleukins/immunology , Intestinal Mucosa/metabolism , Intestines/physiology , Mice , Mice, Inbred C57BL , Myeloid Cells/immunology , Myeloid Cells/metabolism , Organoids/metabolism , Pore Forming Cytotoxic Proteins/genetics , Pore Forming Cytotoxic Proteins/metabolism
4.
Mol Med Rep ; 24(2)2021 Aug.
Статья в английский | MEDLINE | ID: covidwho-1271003

Реферат

Coronavirus disease 2019 (COVID­19), caused by the severe acute respiratory syndrome coronavirus­2 (SARS­CoV­2), led to an outbreak of viral pneumonia in December 2019. The present study aimed to investigate the host inflammatory response signature­caused by SARS­CoV­2 in human corneal epithelial cells (HCECs). The expression level of angiotensin­converting enzyme 2 (ACE2) in the human cornea was determined via immunofluorescence. In vitro experiments were performed in HCECs stimulated with the SARS­CoV­2 spike protein. Moreover, the expression levels of ACE2, IL­8, TNF­α, IL­6, gasdermin D (GSDMD) and IL­1ß in HCECs were detected using reverse transcription­quantitative PCR and/or western blotting. It was identified that ACE2 was expressed in normal human corneal epithelium and HCECs cultured in vitro. Furthermore, the expression levels of IL­8, TNF­α and IL­6 in HCECs were decreased following SARS­CoV­2 spike protein stimulation, while the expression levels of GSDMD and IL­1ß were increased. In conclusion, the present results demonstrated that the SARS­CoV­2 spike protein suppressed the host inflammatory response and induced pyroptosis in HCECs. Therefore, blocking the ACE2 receptor in HCECs may reduce the infection rate of COVID­19.


Тема - темы
Epithelium, Corneal/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Adult , Aged , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Cells, Cultured , Cornea/cytology , Epithelial Cells/cytology , Epithelial Cells/metabolism , Epithelial Cells/virology , Epithelium, Corneal/virology , Female , Humans , Interleukin-1beta/genetics , Interleukin-1beta/metabolism , Interleukin-6/genetics , Interleukin-6/metabolism , Intracellular Signaling Peptides and Proteins/genetics , Intracellular Signaling Peptides and Proteins/metabolism , Male , Middle Aged , Phosphate-Binding Proteins/genetics , Phosphate-Binding Proteins/metabolism , Pyroptosis , Spike Glycoprotein, Coronavirus/genetics , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/metabolism , Up-Regulation
5.
Br J Haematol ; 194(3): 518-529, 2021 08.
Статья в английский | MEDLINE | ID: covidwho-1266318

Реферат

The COVID-19 pandemic has been the most significant health crisis in recent global history. Early studies from Wuhan highlighted COVID-19-associated coagulopathy and a significant association with mortality was soon recognised. As research continues across the world, more evidence is emerging of the cross-talk between the innate immune system, coagulation activation and inflammation. Immunothrombosis has been demonstrated to play a key role in the pathophysiology of severe COVID-19, with extracellular histones and neutrophil extracellular traps detected in the plasma and cardiopulmonary tissues of critically ill patients. Targeting the components of immunothrombosis is becoming an important factor in the treatment of patients with COVID-19 infection. Recent studies report outcomes of intermediate and therapeutic anticoagulation in hospitalised patients with varying severities of COVID-19 disease, including optimal dosing and associated bleeding risks. Immunomodulatory therapies, including corticosteroids and IL-6 receptor antagonists, have been demonstrated to significantly reduce mortality in COVID-19 patients. As the pandemic continues, more studies are required to understand the driving factors and upstream mechanisms for coagulopathy and immunothrombosis in COVID-19, and thus potentially develop more targeted therapies for SARS-CoV-2 infection, both in the acute phase and in those who develop longer-term symptom burden.


Тема - темы
COVID-19/complications , Thrombosis/etiology , Animals , Blood Coagulation , COVID-19/blood , COVID-19/immunology , COVID-19/therapy , Disease Management , Humans , Immunogenic Cell Death , Inflammation/blood , Inflammation/etiology , Inflammation/immunology , Inflammation/therapy , SARS-CoV-2/immunology , Thrombosis/blood , Thrombosis/immunology , Thrombosis/therapy
6.
Brief Bioinform ; 22(6)2021 11 05.
Статья в английский | MEDLINE | ID: covidwho-1266105

Реферат

Recent studies have demonstrated that the excessive inflammatory response is an important factor of death in coronavirus disease 2019 (COVID-19) patients. In this study, we propose a deep representation on heterogeneous drug networks, termed DeepR2cov, to discover potential agents for treating the excessive inflammatory response in COVID-19 patients. This work explores the multi-hub characteristic of a heterogeneous drug network integrating eight unique networks. Inspired by the multi-hub characteristic, we design 3 billion special meta paths to train a deep representation model for learning low-dimensional vectors that integrate long-range structure dependency and complex semantic relation among network nodes. Based on the representation vectors and transcriptomics data, we predict 22 drugs that bind to tumor necrosis factor-α or interleukin-6, whose therapeutic associations with the inflammation storm in COVID-19 patients, and molecular binding model are further validated via data from PubMed publications, ongoing clinical trials and a docking program. In addition, the results on five biomedical applications suggest that DeepR2cov significantly outperforms five existing representation approaches. In summary, DeepR2cov is a powerful network representation approach and holds the potential to accelerate treatment of the inflammatory responses in COVID-19 patients. The source code and data can be downloaded from https://github.com/pengsl-lab/DeepR2cov.git.


Тема - темы
COVID-19/drug therapy , Drug Repositioning , Inflammation/drug therapy , SARS-CoV-2/drug effects , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/therapeutic use , COVID-19/complications , COVID-19/genetics , COVID-19/virology , Computational Biology , Deep Learning , Humans , Inflammation/complications , Inflammation/genetics , Inflammation/virology , Neural Networks, Computer , SARS-CoV-2/pathogenicity , Software , Transcriptome/drug effects , Transcriptome/genetics
7.
Cytokine ; 148: 155618, 2021 12.
Статья в английский | MEDLINE | ID: covidwho-1260707

Реферат

BACKGROUND: Coronavirus disease 2019 (COVID-19) is an acute respiratory disease; approximately 5% of patients developing severe COVID-19. It is known that cytokine release is associated with disease severity, but the relationship between the different clinical phenotypes and inflammatory endotypes is not well understood. OBJECTIVE: This study investigated the association between inflammatory biomarker-based endotypes and severe COVID-19 phenotypes. METHODS: Interleukin (IL) -6, C-reactive protein (CRP), C-X-C motif chemokine (CXCL) 9, IL-18, C-C motif chemokine (CCL) 3, CCL17, IL-10, and vascular endothelial growth factor (VEGF) were measured in 57 COVID-19 patients, and their association with clinical characteristics was examined using a cluster analysis. RESULTS: Significantly higher blood levels of the eight inflammatory markers were noted in patients who developed acute respiratory distress syndrome (ARDS) than in those who did not develop ARDS (non-ARDS). Using a cluster analysis, the patient groups were classified into four clusters, of which two had patients with high IL-6 and CRP levels. In the cluster with high levels of Type 1 (T1) inflammatory markers such as CXCL9 and IL-18, 85% of the patients had ARDS, 65% of the patients developed acute kidney injury (AKI), and 78% of the patients developed pulmonary fibrosis. CONCLUSIONS: In the cluster with high levels of T1 inflammatory markers, the patients frequently suffered from tissue damage, manifested as ARDS and AKI. Our findings identified distinct T1 inflammatory endotypes of COVID-19 and suggest the importance of controlling inflammation by monitoring T1 biomarkers and treating accordingly to limit the severity of the disease.


Тема - темы
COVID-19/complications , COVID-19/physiopathology , Inflammation/pathology , Pulmonary Fibrosis/complications , Pulmonary Fibrosis/physiopathology , Aged , Biomarkers/blood , COVID-19/blood , COVID-19/virology , Cluster Analysis , Disease Progression , Female , Humans , Inflammation/blood , Inflammation/complications , Lung Compliance , Male , Middle Aged , Pulmonary Fibrosis/blood , Respiratory Distress Syndrome/blood , Respiratory Distress Syndrome/complications , SARS-CoV-2/physiology
8.
Minerva Med ; 113(2): 300-308, 2022 Apr.
Статья в английский | MEDLINE | ID: covidwho-1249753

Реферат

BACKGROUND: The aim of this open supplement study was to evaluate the effects of Pycnogenol® in comparison with controls on symptoms of post-COVID-19 syndrome and in improving endothelial function, microcirculation, inflammatory markers and oxidative stress over 3 months in symptomatic subjects recovering from COVID-19. METHODS: Sixty subjects recovering from symptomatic COVID-19 were included. One group of 30 followed a standard recovery management while 30 comparable subjects received a supplement of 150 mg Pycnogenol® daily (in 3 doses of 50 mg) in addition to standard management. RESULTS: Two groups of selected subjects were comparable at baseline. The groups progressively improved both with the SM (standard management) and with the SM in combination with the supplement. Patients, supplemented with Pycnogenol® showed significantly better improvement compared to the control group patients. No side effects from the supplementation were observed; tolerability was optimal. The progressive evolution over time was visible in all target measurements. Physiological tests: endothelial function, low in all subjects at inclusion was assessed by flow mediated dilation (FMD) and finger reactive hyperemia in the microcirculation (laser Doppler measurements) after the release of an occluding suprasystolic cuff. It was significantly improved in the Pycnogenol® group after one month and after 3 months (P<0.05 vs. controls). The rate of ankle swelling (RAS) by strain gauge decreased significantly in the supplemented group (P<0.05) in comparison with controls showing an improvement of the capillary filtration rate. At inclusion, the kidney cortical flow velocity indicated a decrease in perfusion (lower systolic and diastolic flow velocity) in all patients. Kidney cortical flow velocity increased significantly with the supplement (P<0.05) in comparison with controls with improvement in systolic velocity and in diastolic component. High sensitivity CRP (hs-CRP) and Il-6 plasma levels decreased progressively over 3 months with a significant more pronounced decrease in the supplement group (P<0.05). The number of patients with normal plasma IL-6 levels at the end of the study was higher (P<0.05) with the supplement. ESR followed the same pattern with a progressive and a more significant decrease in the supplemented subjects (P<0.02). Oxidative stress decreased significantly in the supplemented group (P<0.05) compared with the control group. Systolic blood pressure was significantly lower in the supplemented group (P<0.05) at the end of the study. Finally, the scores of Quality-of-life, mood and fatigue questionnaire and the Karnofsky Scale Performance Index significantly improved in the supplement group (P<0.05) compared to controls after 1 and 3 months. All other blood parameters (including platelets and clotting factors) were within normal values at the end of the study. CONCLUSIONS: In conclusion, Pycnogenol® may offer a significant option for managing some of the signs and symptoms associated with post-COVID-19 syndrome. This pilot evaluation offers some potential rationale for the use of Pycnogenol® in this condition that will have significant importance in the coming years.


Тема - темы
COVID-19 , Cardiovascular Diseases , COVID-19/complications , COVID-19/drug therapy , Cardiovascular Diseases/chemically induced , Dietary Supplements , Flavonoids/pharmacology , Flavonoids/therapeutic use , Heart Disease Risk Factors , Humans , Interleukin-6 , Microcirculation , Oxidative Stress , Plant Extracts/pharmacology , Plant Extracts/therapeutic use , Registries , Risk Factors
9.
Front Immunol ; 12: 666223, 2021.
Статья в английский | MEDLINE | ID: covidwho-1247864

Реферат

BACKGROUND: SARS, MERS, and COVID-19 share similar characteristics. For instance, the genetic homology of SARS-CoV-2 compared to SARS-CoV and MERS-CoV is 80% and 50%, respectively, which may cause similar clinical features. Moreover, uncontrolled release of proinflammatory mediators (also called a cytokine storm) by activated immune cells in SARS, MERS, and COVID-19 patients leads to severe phenotype development. AIM: This systematic review and meta-analysis aimed to evaluate the inflammatory cytokine profile associated with three strains of severe human coronavirus diseases (MERS-CoV, SARS-CoV, and SARS-CoV-2). METHOD: The PubMed, Embase, and Cochrane Library databases were searched for studies published until July 2020. Randomized and observational studies reporting the inflammatory cytokines associated with severe and non-severe human coronavirus diseases, including MERS-CoV, SARS-CoV, and SARS-CoV-2, were included. Two reviewers independently screened articles, extracted data, and assessed the quality of the included studies. Meta-analysis was performed using a random-effects model with a 95% confidence interval to estimate the pooled mean of inflammatory biomarkers. RESULTS: A high level of circulating IL-6 could be associated with the severity of infection of the three coronavirus strains. TNF, IL-10, and IL-8 are associated with the severity of COVID-19. Increased circulating levels of CXCL10/IP10 and CCL2/MCP-1 might also be related to the severity of MERS. CONCLUSION: This study suggests that the immune response and immunopathology in the three severe human coronavirus strains are somewhat similar. The findings highlight that nearly all studies reporting severe cases of SARS, MERS, and COVID-19 have been associated with elevated levels of IL-6. This could be used as a potential therapeutic target to improve patients' outcomes in severe cases. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration 94 number: CRD42020209931.


Тема - темы
Coronavirus Infections/immunology , Coronavirus/physiology , Cytokine Release Syndrome/immunology , Inflammation/immunology , Animals , Blood Circulation , Chemokines/metabolism , Cytokines/metabolism , Humans , Randomized Controlled Trials as Topic
10.
Neurol Res Pract ; 3(1): 24, 2021 Jun 01.
Статья в английский | MEDLINE | ID: covidwho-1247614

Реферат

BACKGROUND: The report of a patient with blepharospasm during the COVID-19 pandemic suggested a potential ameliorating effect of wearing a face mask. OBJECTIVE: We prospectively evaluated a possible symptom change through wearing a face mask in all consecutive patients with craniofacial hyperkinesias in our botulinum toxin outpatient treatment cohort. METHODS: Patients with craniofacial hyperkinesia were asked to rate changes of symptoms between - 2 (markedly worsened), - 1 (slightly worsened), 0 (no change), + 1 (slightly improved) and + 2 (markedly improved). RESULTS: Of 101 patients (19 with blepharospasm [BSP], 54 with cervical dystonia [CD], 6 with oromandibular dystonia [OMD], and 22 with hemifacial spasm [HFS]) 81 (80%) rated no symptom change, 11 (11%) symptom improvement, and 9 (9%) symptom worsening. Improvements in 9 of the 82 dystonia patients (BSP, CD, OMD) consisted of a perceived decrease in dystonic activity. 33% of dystonia patients had previously noticed or used a sensory trick. Its presence turned out to be a significant predictor of improvement during mask wearing. Deteriorations were attributed from all patients to disturbing effects of the mask interacting with facial muscle overactivity. Improvements in HSF patients were attributed to the symptom-hiding nature of the mask and not to an effect on the spasm activity itself. CONCLUSIONS: Wearing a face mask did not affect self-perceived symptoms in 80% of patients with craniofacial hyperkinesis. 11% of patients reported an improvement, which occurred as sensory trick in dystonia patients and as a concealment of a stigmatizing facial expression in patients with HSF.

11.
Exp Ther Med ; 22(1): 756, 2021 Jul.
Статья в английский | MEDLINE | ID: covidwho-1244180

Реферат

In patients who were not previously diagnosed with any thyroid conditions, the scenario of COVID-19-related anomalies of the hypothalamus-pituitary-thyroid axes may include either: A process of central thyroid stimulating hormone (TSH) disturbances via virus-related hypophysitis; an atypical type of subacute thyroiditis which is connected to the virus spread or to excessive cytokine production including a destructive process with irreversible damage of the gland or low T3 (triiodothyronine) syndrome (so called non-thyroid illness syndrome) which is not specifically related to the COVID-19 infection, but which is associated with a very severe illness status. Our objective here was to briefly review thyroid changes due to the COVID-19 infection. Ongoing assessment of the effects of the COVID-19 pandemic will reveal more information on coronavirus-induced thyroid conditions. Routine thyroid assays performed in patients with severe infection/at acute phase of COVID-19 are encouraged in order to detect thyrotoxicosis. After recovery, thyroid function should be assessed to identify potential hypothyroidism. There remain unanswered questions related to the prognostic value of interleukin-6 in infected patients, especially in cases with cytokine storm, and the necessity of thyroid hormone replacement in subjects with hypophysitis-related central hypothyroidism.

12.
Front Immunol ; 12: 641295, 2021.
Статья в английский | MEDLINE | ID: covidwho-1241168

Реферат

Although millions of patients with underlining conditions are treated primarily with anti-TNF-α agents, little is known about the safety of this standard therapy during the coronavirus disease-2019 (COVID-19) pandemic. In this study, we investigated the effect of anti-TNF-α monoclonal antibodies on the cellular entry mechanism of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and increasing the risk of COVID-19 development. We focused on the expression of angiotensin-converting enzyme II (ACE2), type II transmembrane serine proteases (TMPRSS2)/TNF-α converting enzyme (TACE) ratio. We also investigated the involvement of Notch-1 signaling and its downstream influence on IL-6, myeloid cell leukemia sequence-1(MCL-1) in the anti-TNF-α mode of action and increased the susceptibility to Mycobacterium avium subspecies paratuberculosis (MAP) infection. Surprisingly, anti-TNF-α downregulated ACE2 expression by 0.46-fold and increased TMPRSS2/TACE ratio by 44% in THP-1 macrophages. Treatment of macrophages with rIL-6 also downregulated ACE2 and increased TMPRSS2/TACE ratio by 54%. Interestingly, anti-TNF-α treatment upregulated Notch-1, IL-6, and MCL-1 by 1.3, 1.2, and 1.9-fold, respectively, and increased viability and burden of MAP infection in macrophages. Blocking Notch signaling doubled ACE2 expression, decreased TMPRSS2/TACE ratio by 38%, and reduced MAP viability by 56%. In a small group of patients, ACE2 level was significantly lower in the plasma from rheumatoid arthritis (RA) patients on anti-TNF-α treatment compared to healthy control. The data in this critical study demonstrated that through Notch-1/IL-6 signaling, anti-TNF-α agents decreased ACE2 expression and shedding through TMPRSS2/TACE modulation and increased the susceptibility to infection. Overall, this study warns against anti-TNF-α therapy in some patients with underlining inflammatory conditions during the COVID-19 pandemic. The findings should impact current guidelines regarding treatment decisions of patients on anti-TNF-α during the COVID-19 pandemic.


Тема - темы
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/immunology , Macrophages/immunology , Mycobacterium avium/physiology , Receptor, Notch1/metabolism , SARS-CoV-2/physiology , Tuberculosis, Avian/immunology , Tumor Necrosis Factor-alpha/antagonists & inhibitors , ADAM17 Protein/metabolism , Animals , COVID-19/transmission , COVID-19/virology , Disease Susceptibility , Disease Transmission, Infectious , Humans , Interleukin-6/metabolism , Risk , Serine Endopeptidases/metabolism , Signal Transduction , THP-1 Cells
13.
Clin Respir J ; 15(8): 915-924, 2021 Aug.
Статья в английский | MEDLINE | ID: covidwho-1238374

Реферат

BACKGROUND: Coronavirus disease 2019 (COVID-19) is an emerging, rapidly evolving pandemic, hypertension is one of the most common co-existing chronic conditions and a risk factor for mortality. Nearly one-third of the adult population is hypertensive worldwide, it is urgent to identify the factors that determine the clinical course and outcomes of COVID-19 patients with hypertension. METHODS AND RESULTS: 148 COVID-19 patients with pre-existing hypertension with clarified outcomes (discharge or deceased) from a national cohort in China were included in this study, of whom 103 were discharged and 45 died in hospital. Multivariate regression showed higher odds of in-hospital death associated with high-sensitivity cardiac troponin (hs-cTn) > 28 pg/ml (hazard ratio [HR]: 3.27, 95% confidence interval [CI]: 1.55-6.91) and interleukin-6 (IL-6) > 7 pg/ml (HR: 3.63, 95% CI:1.54-8.55) at admission. Patients with uncontrolled blood pressure (BP) (n = 52) which were defined as systolic BP ≥140 mm Hg or diastolic BP ≥90 mm Hg for more than once (≥2 times) during hospitalization, were more likely to have ICU admission (p = 0.037), invasive mechanical ventilation (p = 0.028), and renal injury (p = 0.005). A stricter BP control with the threshold of 130/80 mm Hg was associated with lower mortality. Treatment with renin-angiotensin-aldosterone system (RAAS) suppressors, including angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARB), and spironolactone, was associated with a lower rate of ICU admission compared to other types of anti-hypertensive medications (8 (22.9%) vs. 25 (43.1%), p = 0.048). CONCLUSION: Among COVID-19 patients with pre-existing hypertension, elevated hs-cTn and IL-6 could help clinicians to identify patients with fatal outcomes at an early stage, blood pressure control is associated with better clinical outcomes, and RAAS suppressors do not increase mortality and may decrease the need for ICU admission.


Тема - темы
COVID-19 , Hypertension , Angiotensin Receptor Antagonists , Angiotensin-Converting Enzyme Inhibitors , China/epidemiology , Hospital Mortality , Humans , Hypertension/epidemiology , Retrospective Studies , SARS-CoV-2
14.
Am J Respir Cell Mol Biol ; 65(4): 403-412, 2021 10.
Статья в английский | MEDLINE | ID: covidwho-1237350

Реферат

Mechanical ventilation is a known risk factor for delirium, a cognitive impairment characterized by dysfunction of the frontal cortex and hippocampus. Although IL-6 is upregulated in mechanical ventilation-induced lung injury (VILI) and may contribute to delirium, it is not known whether the inhibition of systemic IL-6 mitigates delirium-relevant neuropathology. To histologically define neuropathological effects of IL-6 inhibition in an experimental VILI model, VILI was simulated in anesthetized adult mice using a 35 cc/kg tidal volume mechanical ventilation model. There were two control groups, as follow: 1) spontaneously breathing or 2) anesthetized and mechanically ventilated with 10 cc/kg tidal volume to distinguish effects of anesthesia from VILI. Two hours before inducing VILI, mice were treated with either anti-IL-6 antibody, anti-IL-6 receptor antibody, or saline. Neuronal injury, stress, and inflammation were assessed using immunohistochemistry. CC3 (cleaved caspase-3), a neuronal apoptosis marker, was significantly increased in the frontal (P < 0.001) and hippocampal (P < 0.0001) brain regions and accompanied by significant increases in c-Fos and heat shock protein-90 in the frontal cortices of VILI mice compared with control mice (P < 0.001). These findings were not related to cerebral hypoxia, and there was no evidence of irreversible neuronal death. Frontal and hippocampal neuronal CC3 were significantly reduced with anti-IL-6 antibody (P < 0.01 and P < 0.0001, respectively) and anti-IL-6 receptor antibody (P < 0.05 and P < 0.0001, respectively) compared with saline VILI mice. In summary, VILI induces potentially reversible neuronal injury and inflammation in the frontal cortex and hippocampus, which is mitigated with systemic IL-6 inhibition. These data suggest a potentially novel neuroprotective role of systemic IL-6 inhibition that justifies further investigation.


Тема - темы
Antibodies/pharmacology , Apoptosis/drug effects , Delirium/metabolism , Interleukin-6/antagonists & inhibitors , Neurons/metabolism , Ventilator-Induced Lung Injury/metabolism , Animals , Delirium/drug therapy , Delirium/pathology , Disease Models, Animal , Female , Frontal Lobe/injuries , Frontal Lobe/metabolism , Frontal Lobe/pathology , HSP90 Heat-Shock Proteins/metabolism , Hippocampus/injuries , Hippocampus/metabolism , Hippocampus/pathology , Inflammation/drug therapy , Inflammation/metabolism , Inflammation/pathology , Interleukin-6/metabolism , Mice , Neurons/pathology , Proto-Oncogene Proteins c-fos/metabolism , Repressor Proteins/metabolism , Tumor Suppressor Proteins/metabolism , Ventilator-Induced Lung Injury/drug therapy , Ventilator-Induced Lung Injury/pathology
15.
J Inflamm Res ; 14: 1677-1687, 2021.
Статья в английский | MEDLINE | ID: covidwho-1231284

Реферат

BACKGROUND: Whether COVID-19 comorbidities and risk factors such as old age, male gender, smoking, obesity, eosinophils and blood types have direct contact with expression of ACE2 and pro-inflammation cytokines in human lung tissues were still unclear. PATIENTS AND METHODS: Sixty-four patients with normal FEV1 and FEV1/FVC underwent thoracotomy for pulmonary nodules were included. Blinded histological assessments were performed by two pathologists. Clinical features and results of the immunohistochemical staining of ACE2 were collected and analyzed. RESULTS: ACE2 expressed in alveolar macrophages (most obvious), alveolar epithelia and vascular endothelia, but not in small-airway epithelia. ACE2 expressions are positively related to age (r =0.26, P =0.040), weight (r =0.43, P<0.001), as well as BMI (r = 0.38, P =0.002), and male patients show higher expressions of ACE2 in lungs (P <0.05). ACE2 expressions are negatively related to peripheral eosinophils (r = -0.30, P =0.017). There was no correlation between ABO blood types and ACE2 expression in normal lung tissues (P > 0.05). IL-13 and IL-6R expression in lung tissue increased with age (r =0.26, P <0.05, for both). CONCLUSION: Our pathological evidences showed that the alveolar epithelia, vascular endothelia, and alveolar macrophages are susceptible in human lungs for SARS-CoV-2 infection. The risk factors such as high body weight/BMI, old age, male gender, and eosinopenia may be related to ACE2 expression in human lungs, and associated with more chance to develop the severe cases. IL-6R expression in lung tissue also increased with age. Therefore, weight control and smoking cessation are essential to reduce the susceptibility of SARS-CoV-2 infection, especially in obesity, old or male patients. Peripheral eosinophils monitor is also quite necessary to detect severe tendency in COVID-19 patients.

16.
Front Immunol ; 12: 661052, 2021.
Статья в английский | MEDLINE | ID: covidwho-1229177

Реферат

While lymphocytopenia is a common characteristic of coronavirus disease 2019 (COVID-19), the mechanisms responsible for this lymphocyte depletion are unclear. Here, we retrospectively reviewed the clinical and immunological data from 18 fatal COVID-19 cases, results showed that these patients had severe lymphocytopenia, together with high serum levels of inflammatory cytokines (IL-6, IL-8 and IL-10), and elevation of many other mediators in routine laboratory tests, including C-reactive protein, lactate dehydrogenase, α-hydroxybutyrate dehydrogenase and natriuretic peptide type B. The spleens and hilar lymph nodes (LNs) from six additional COVID-19 patients with post-mortem examinations were also collected, histopathologic detection showed that both organs manifested severe tissue damage and lymphocyte apoptosis in these six cases. In situ hybridization assays illustrated that SARS-CoV-2 viral RNA accumulates in these tissues, and transmission electronic microscopy confirmed that coronavirus-like particles were visible in the LNs. SARS-CoV-2 Spike and Nucleocapsid protein (NP) accumulated in the spleens and LNs, and the NP antigen restricted in angiotensin-converting enzyme 2 (ACE2) positive macrophages and dendritic cells (DCs). Furthermore, SARS-CoV-2 triggered the transcription of Il6, Il8 and Il1b genes in infected primary macrophages and DCs in vitro, and SARS-CoV-2-NP+ macrophages and DCs also manifested high levels of IL-6 and IL-1ß, which might directly decimate human spleens and LNs and subsequently lead to lymphocytopenia in vivo. Collectively, these results demonstrated that SARS-CoV-2 induced lymphocytopenia by promoting systemic inflammation and direct neutralization in human spleen and LNs.


Тема - темы
COVID-19/immunology , Lymph Nodes/immunology , Lymphopenia/immunology , SARS-CoV-2/immunology , Spleen/immunology , Angiotensin-Converting Enzyme 2/immunology , COVID-19/complications , COVID-19/pathology , Coronavirus Nucleocapsid Proteins/immunology , Cytokines/immunology , Female , Humans , Inflammation/immunology , Inflammation/pathology , Lymph Nodes/ultrastructure , Lymphopenia/etiology , Lymphopenia/pathology , Middle Aged , Phosphoproteins/immunology , RNA, Messenger/immunology , Retrospective Studies , SARS-CoV-2/pathogenicity , SARS-CoV-2/ultrastructure , Spleen/ultrastructure
17.
J Hepatol ; 75(3): 647-658, 2021 09.
Статья в английский | MEDLINE | ID: covidwho-1228069

Реферат

BACKGROUND AND AIMS: COVID-19 is associated with liver injury and elevated interleukin-6 (IL-6). We hypothesized that IL-6 trans-signaling in liver sinusoidal endothelial cells (LSECs) leads to endotheliopathy (a proinflammatory and procoagulant state) and liver injury in COVID-19. METHODS: Coagulopathy, endotheliopathy, and alanine aminotransferase (ALT) were retrospectively analyzed in a subset (n = 68), followed by a larger cohort (n = 3,780) of patients with COVID-19. Liver histology from 43 patients with COVID-19 was analyzed for endotheliopathy and its relationship to liver injury. Primary human LSECs were used to establish the IL-6 trans-signaling mechanism. RESULTS: Factor VIII, fibrinogen, D-dimer, von Willebrand factor (vWF) activity/antigen (biomarkers of coagulopathy/endotheliopathy) were significantly elevated in patients with COVID-19 and liver injury (elevated ALT). IL-6 positively correlated with vWF antigen (p = 0.02), factor VIII activity (p = 0.02), and D-dimer (p <0.0001). On liver histology, patients with COVID-19 and elevated ALT had significantly increased vWF and platelet staining, supporting a link between liver injury, coagulopathy, and endotheliopathy. Intralobular neutrophils positively correlated with platelet (p <0.0001) and vWF (p <0.01) staining, and IL-6 levels positively correlated with vWF staining (p <0.01). IL-6 trans-signaling leads to increased expression of procoagulant (factor VIII, vWF) and proinflammatory factors, increased cell surface vWF (p <0.01), and increased platelet attachment in LSECs. These effects were blocked by soluble glycoprotein 130 (IL-6 trans-signaling inhibitor), the JAK inhibitor ruxolitinib, and STAT1/3 small-interfering RNA knockdown. Hepatocyte fibrinogen expression was increased by the supernatant of LSECs subjected to IL-6 trans-signaling. CONCLUSION: IL-6 trans-signaling drives the coagulopathy and hepatic endotheliopathy associated with COVID-19 and could be a possible mechanism behind liver injury in these patients. LAY SUMMARY: Patients with SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection often have liver injury, but why this occurs remains unknown. High levels of interleukin-6 (IL-6) and its circulating receptor, which form a complex to induce inflammatory signals, have been observed in patients with COVID-19. This paper demonstrates that the IL-6 signaling complex causes harmful changes to liver sinusoidal endothelial cells and may promote blood clotting and contribute to liver injury.


Тема - темы
COVID-19/complications , Endothelial Cells/pathology , Interleukin-6/physiology , Liver Diseases/etiology , SARS-CoV-2 , Adult , Blood Coagulation Disorders/etiology , Fibrinogen/analysis , Humans , Interleukin-6/blood , Janus Kinase 1/metabolism , Nitriles , Pyrazoles/pharmacology , Pyrimidines , Retrospective Studies , STAT3 Transcription Factor/metabolism , Signal Transduction/physiology , von Willebrand Factor/analysis
18.
Mol Ther ; 29(8): 2424-2440, 2021 08 04.
Статья в английский | MEDLINE | ID: covidwho-1225433

Реферат

Lung inflammation is a hallmark of coronavirus disease 2019 (COVID-19). In this study, we show that mice develop inflamed lung tissue after being administered exosomes released from the lung epithelial cells exposed to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Nsp12 and Nsp13 (exosomesNsp12Nsp13). Mechanistically, we show that exosomesNsp12Nsp13 are taken up by lung macrophages, leading to activation of nuclear factor κB (NF-κB) and the subsequent induction of an array of inflammatory cytokines. Induction of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1ß from exosomesNsp12Nsp13-activated lung macrophages contributes to inducing apoptosis in lung epithelial cells. Induction of exosomesNsp12Nsp13-mediated lung inflammation was abolished with ginger exosome-like nanoparticle (GELN) microRNA (miRNA aly-miR396a-5p. The role of GELNs in inhibition of the SARS-CoV-2-induced cytopathic effect (CPE) was further demonstrated via GELN aly-miR396a-5p- and rlcv-miR-rL1-28-3p-mediated inhibition of expression of Nsp12 and spike genes, respectively. Taken together, our results reveal exosomesNsp12Nsp13 as potentially important contributors to the development of lung inflammation, and GELNs are a potential therapeutic agent to treat COVID-19.


Тема - темы
COVID-19/metabolism , Exosomes/metabolism , MicroRNAs/metabolism , Plants/metabolism , Pneumonia/metabolism , A549 Cells , Animals , Cell Line , Cell Line, Tumor , Chlorocebus aethiops , Cytokines/metabolism , Epithelial Cells/metabolism , Humans , Interleukin-6/metabolism , Macrophages, Alveolar/metabolism , Male , Mice , Mice, Inbred C57BL , NF-kappa B/metabolism , SARS-CoV-2/pathogenicity , Tumor Necrosis Factor-alpha/metabolism , U937 Cells , Vero Cells
19.
J Infect Chemother ; 27(9): 1329-1335, 2021 Sep.
Статья в английский | MEDLINE | ID: covidwho-1225294

Реферат

BACKGROUND: Cytokine release syndrome (CRS), characterized by overproduction of proinflammatory cytokines in the course of severe coronavirus disease 2019 (COVID-19), has been suggested as the major cause of mortality. Tocilizumab, a recombinant humanized monoclonal antibody against human IL-6 receptor, poses a therapeutic option for the treatment of CRS leading to severe acute respiratory syndrome in coronavirus-2 (SARS-CoV-2) infection. METHODS: We performed a single-center retrospective study to reveal the outcome of COVID-19 patients on tocilizumab and proposed "the Cerrahpasa-PREDICT score", a new clinical scoring system using clinical and laboratory parameters that would help predicting the 28-day mortality of COVID-19 patients receiving tocilizumab. RESULTS: Eighty-seven patients (median age: 59 years) were included of whom 75.8% were male. Tocilizumab use significantly improved clinical and laboratory parameters. The 28-day mortality rate on tocilizumab was 16.1%. The Cerrahpasa-PREDICT score, consisting of platelet counts, procalcitonin, D-dimer levels, SO2R and the time from symptom onset to tocilizumab administration had a positive predictive value of 94.5% and negative predictive value of 92.9% for anticipating 28-day mortality. CONCLUSIONS: Severe COVID-19 should closely be monitored for the signs of hyperinflammation. We showed that administration of tocilizumab early in the course of the disease (prior to ICU admission) resulted in a favorable outcome. Close monitoring usually aids identifying patients who would benefit from tocilizumab. In this regard, the Cerrahpasa-PREDICT score might serve as a practical tool for estimating the 28-day mortality in COVID-19 patients who received tocilizumab and would facilitate timely recognition of fatal cases to be evaluated for other therapeutic options.


Тема - темы
COVID-19 , Antibodies, Monoclonal, Humanized , COVID-19/drug therapy , Humans , Male , Middle Aged , Retrospective Studies , SARS-CoV-2 , Treatment Outcome
20.
Vaccines (Basel) ; 9(5)2021 Apr 29.
Статья в английский | MEDLINE | ID: covidwho-1217123

Реферат

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a severe pandemic of the current century. The vicious tentacles of the disease have been disseminated worldwide with unknown complications and repercussions. Advanced COVID-19 syndrome is characterized by the uncontrolled and elevated release of pro-inflammatory cytokines and suppressed immunity, leading to the cytokine storm. The uncontrolled and dysregulated secretion of inflammatory and pro-inflammatory cytokines is positively associated with the severity of the viral infection and mortality rate. The secretion of various pro-inflammatory cytokines such as TNF-α, IL-1, and IL-6 leads to a hyperinflammatory response by recruiting macrophages, T and B cells in the lung alveolar cells. Moreover, it has been hypothesized that immune cells such as macrophages recruit inflammatory monocytes in the alveolar cells and allow the production of large amounts of cytokines in the alveoli, leading to a hyperinflammatory response in severely ill patients with COVID-19. This cascade of events may lead to multiple organ failure, acute respiratory distress, or pneumonia. Although the disease has a higher survival rate than other chronic diseases, the incidence of complications in the geriatric population are considerably high, with more systemic complications. This review sheds light on the pivotal roles played by various inflammatory markers in COVID-19-related complications. Different molecular pathways, such as the activation of JAK and JAK/STAT signaling are crucial in the progression of cytokine storm; hence, various mechanisms, immunological pathways, and functions of cytokines and other inflammatory markers have been discussed. A thorough understanding of cytokines' molecular pathways and their activation procedures will add more insight into understanding immunopathology and designing appropriate drugs, therapies, and control measures to counter COVID-19. Recently, anti-inflammatory drugs and several antiviral drugs have been reported as effective therapeutic drug candidates to control hypercytokinemia or cytokine storm. Hence, the present review also discussed prospective anti-inflammatory and relevant immunomodulatory drugs currently in various trial phases and their possible implications.

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