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1.
Theranostics ; 11(1): 316-329, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33391477

RESUMO

Severe coronavirus disease 2019 (COVID-19) is characterized by systemic hyper-inflammation, acute respiratory distress syndrome, and multiple organ failure. Cytokine storm refers to a set of clinical conditions caused by excessive immune reactions and has been recognized as a leading cause of severe COVID-19. While comparisons have been made between COVID-19 cytokine storm and other kinds of cytokine storm such as hemophagocytic lymphohistiocytosis and cytokine release syndrome, the pathogenesis of cytokine storm has not been clearly elucidated yet. Recent studies have shown that impaired response of type-1 IFNs in early stage of COVID-19 infection played a major role in the development of cytokine storm, and various cytokines such as IL-6 and IL-1 were involved in severe COVID-19. Furthermore, many clinical evidences have indicated the importance of anti-inflammatory therapy in severe COVID-19. Several approaches are currently being used to treat the observed cytokine storm associated with COVID-19, and expectations are especially high for new cytokine-targeted therapies, such as tocilizumab, anakinra, and baricitinib. Although a number of studies have been conducted on anti-inflammatory treatments for severe COVID-19, no specific recommendations have been made on which drugs should be used for which patients and when. In this review, we provide an overview of cytokine storm in COVID-19 and treatments currently being used to address it. In addition, we discuss the potential therapeutic role of extracorporeal cytokine removal to treat the cytokine storm associated with COVID-19.


Assuntos
Anti-Inflamatórios/uso terapêutico , Síndrome da Liberação de Citocina/imunologia , Citocinas/metabolismo , Imunossupressores/uso terapêutico , Anti-Inflamatórios/farmacologia , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Azetidinas/farmacologia , Azetidinas/uso terapêutico , /imunologia , Ensaios Clínicos como Assunto , Síndrome da Liberação de Citocina/tratamento farmacológico , Citocinas/antagonistas & inibidores , Citocinas/imunologia , Humanos , Imunossupressores/farmacologia , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Janus Quinases/antagonistas & inibidores , Janus Quinases/metabolismo , Purinas/farmacologia , Purinas/uso terapêutico , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Fatores de Transcrição STAT/antagonistas & inibidores , Fatores de Transcrição STAT/metabolismo , Índice de Gravidade de Doença , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Resultado do Tratamento
2.
Biochim Biophys Acta Mol Basis Dis ; 1867(2): 166014, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33232817

RESUMO

The coronavirus disease 2019 (COVID-19) has been threatening the globe since the end of November 2019. The disease revealed cracks in the health care system as health care providers across the world were left without guidelines on definitive usage of pharmaceutical agents or vaccines. The World Health Organization (WHO) declared COVID-19 as a pandemic on the 11th of March 2020. Individuals with underlying systemic disorders have reported complications, such as cytokine storms, when infected with the virus. As the number of positive cases and the death toll across the globe continue to rise, various researchers have turned to cell based therapy using stem cells to combat COVID-19. The field of stem cells and regenerative medicine has provided a paradigm shift in treating a disease with minimally invasive techniques that provides maximal clinical and functional outcome for patients. With the available evidence of immunomodulatory and immune-privilege actions, mesenchymal stem cells (MSCs) can repair, regenerate and remodulate the native homeostasis of pulmonary parenchyma with improved pulmonary compliance. This article revolves around the usage of novel MSCs therapy for combating COVID-19.


Assuntos
/epidemiologia , Síndrome da Liberação de Citocina/terapia , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/imunologia , Pandemias , /imunologia , /imunologia , Síndrome da Liberação de Citocina/epidemiologia , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/patologia , Feminino , Humanos , Masculino , Células-Tronco Mesenquimais/patologia
3.
Respir Physiol Neurobiol ; 283: 103548, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32956843

RESUMO

BACKGROUND: Globally, the current medical emergency for novel coronavirus 2019 (COVID-19) leads to respiratory distress syndrome and death. PURPOSE: This review highlighted the effect of COVID-19 on systemic multiple organ failure syndromes. This review is intended to fill a gap in information about human physiological response to COVID-19 infections. This review may shed some light on other potential mechanisms and approaches in COVID -19 infections towards systemic multiorgan failure syndromes. FINDING: SARS-CoV-2 intervened mainly in the lung with progression to pneumonia and acute respiratory distress syndrome (ARDS) via the angiotensin-converting enzyme 2(ACE2) receptor. Depending on the viral load, infection spread through the ACE2 receptor further to various organs such as heart, liver, kidney, brain, endothelium, GIT, immune cell, and RBC (thromboembolism). This may be aggravated by cytokine storm with the extensive release of proinflammatory cytokines from the deregulating immune system. CONCLUSION: The widespread and vicious combinations of cytokines with organ crosstalk contribute to systemic hyper inflammation and ultimately lead to multiple organ dysfunction (Fig. 1). This comprehensive study comprises various manifestations of different organs in COVID-19 and may assist the clinicians and scientists pertaining to a broad approach to fight COVID 19.


Assuntos
Infecções por Coronavirus/imunologia , Síndrome da Liberação de Citocina/imunologia , Insuficiência de Múltiplos Órgãos/imunologia , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/imunologia , Glicoproteína da Espícula de Coronavírus/metabolismo , Lesão Renal Aguda/imunologia , Lesão Renal Aguda/fisiopatologia , Arritmias Cardíacas/imunologia , Arritmias Cardíacas/fisiopatologia , Betacoronavirus/metabolismo , Infecções por Coronavirus/fisiopatologia , Síndrome da Liberação de Citocina/fisiopatologia , Citocinas/imunologia , Endotélio Vascular/metabolismo , Eritrócitos/metabolismo , Gastroenteropatias/imunologia , Gastroenteropatias/fisiopatologia , Trato Gastrointestinal/metabolismo , Insuficiência Cardíaca/imunologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Inflamação/imunologia , Rim/metabolismo , Fígado/metabolismo , Hepatopatias/imunologia , Hepatopatias/fisiopatologia , Pulmão/metabolismo , Insuficiência de Múltiplos Órgãos/fisiopatologia , Miocárdio/metabolismo , Pandemias , Pneumonia Viral/fisiopatologia , Tromboembolia/imunologia , Tromboembolia/fisiopatologia , Carga Viral
4.
Cell ; 184(1): 149-168.e17, 2021 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-33278357

RESUMO

COVID-19 is characterized by excessive production of pro-inflammatory cytokines and acute lung damage associated with patient mortality. While multiple inflammatory cytokines are produced by innate immune cells during SARS-CoV-2 infection, we found that only the combination of TNF-α and IFN-γ induced inflammatory cell death characterized by inflammatory cell death, PANoptosis. Mechanistically, TNF-α and IFN-γ co-treatment activated the JAK/STAT1/IRF1 axis, inducing nitric oxide production and driving caspase-8/FADD-mediated PANoptosis. TNF-α and IFN-γ caused a lethal cytokine shock in mice that mirrors the tissue damage and inflammation of COVID-19, and inhibiting PANoptosis protected mice from this pathology and death. Furthermore, treating with neutralizing antibodies against TNF-α and IFN-γ protected mice from mortality during SARS-CoV-2 infection, sepsis, hemophagocytic lymphohistiocytosis, and cytokine shock. Collectively, our findings suggest that blocking the cytokine-mediated inflammatory cell death signaling pathway identified here may benefit patients with COVID-19 or other infectious and autoinflammatory diseases by limiting tissue damage/inflammation.


Assuntos
/imunologia , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/patologia , Interferon gama/imunologia , Fator de Necrose Tumoral alfa/imunologia , Animais , Anticorpos Neutralizantes/administração & dosagem , Morte Celular , Modelos Animais de Doenças , Feminino , Células Endoteliais da Veia Umbilical Humana , Humanos , Inflamação/imunologia , Inflamação/patologia , Linfo-Histiocitose Hemofagocítica/induzido quimicamente , Masculino , Camundongos , Camundongos Transgênicos , Células THP-1
5.
Lab Med ; 52(1): 24-35, 2021 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-32729620

RESUMO

The COVID-19 pandemic has led to a major setback in both the health and economic sectors across the globe. The scale of the problem is enormous because we still do not have any specific anti-SARS-CoV-2 antiviral agent or vaccine. The human immune system has never been exposed to this novel virus, so the viral interactions with the human immune system are completely naive. New approaches are being studied at various levels, including animal in vitro models and human-based studies, to contain the COVID-19 pandemic as soon as possible. Many drugs are being tested for repurposing, but so far only remdesivir has shown some positive benefits based on preliminary reports, but these results also need further confirmation via ongoing trials. Otherwise, no other agents have shown an impactful response against COVID-19. Recently, research exploring the therapeutic application of mesenchymal stem cells (MSCs) in critically ill patients suffering from COVID-19 has gained momentum. The patients belonging to this subset are most likely beyond the point where they could benefit from an antiviral therapy because most of their illness at this stage of disease is driven by inflammatory (over)response of the immune system. In this review, we discuss the potential of MSCs as a therapeutic option for patients with COVID-19, based on the encouraging results from the preliminary data showing improved outcomes in the progression of COVID-19 disease.


Assuntos
/patologia , Síndrome da Liberação de Citocina/prevenção & controle , Transplante de Células-Tronco Mesenquimais/métodos , /patogenicidade , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/virologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/virologia , /mortalidade , Estado Terminal , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/mortalidade , Síndrome da Liberação de Citocina/virologia , Citocinas/antagonistas & inibidores , Citocinas/genética , Citocinas/imunologia , Células Dendríticas/imunologia , Células Dendríticas/virologia , Progressão da Doença , Humanos , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/imunologia , Índice de Gravidade de Doença , Análise de Sobrevida , Resultado do Tratamento
6.
J Med Virol ; 93(2): 831-842, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32672860

RESUMO

Coronavirus disease 2019 (COVID-19) can lead to a massive cytokine release. The use of the anti-interleukin-6 receptor monoclonal antibody tocilizumab (TCZ) has been proposed in this hyperinflammatory phase, although supporting evidence is limited. We retrospectively analyzed 88 consecutive patients with COVID-19 pneumonia that received at least one dose of intravenous TCZ in our institution between 16 and 27 March 2020. Clinical status from day 0 (first TCZ dose) through day 14 was assessed by a 6-point ordinal scale. The primary outcome was clinical improvement (hospital discharge and/or a decrease of ≥2 points on the 6-point scale) by day 7. Secondary outcomes included clinical improvement by day 14 and dynamics of vital signs and laboratory values. Rates of clinical improvement by days 7 and 14 were 44.3% (39/88) and 73.9% (65/88). Previous or concomitant receipt of subcutaneous interferon-ß (adjusted odds ratio [aOR]: 0.23; 95% confidence interval [CI]: 0.06-0.94; P = .041) and serum lactate dehydrogenase more than 450 U/L at day 0 (aOR: 0.25; 95% CI: 0.06-0.99; P = .048) were negatively associated with clinical improvement by day 7. All-cause mortality was 6.8% (6/88). Body temperature and respiratory and cardiac rates significantly decreased by day 1 compared to day 0. Lymphocyte count and pulse oximetry oxygen saturation/FiO2 ratio increased by days 3 and 5, whereas C-reactive protein levels dropped by day 2. There were no TCZ-attributable adverse events. In this observational single-center study, TCZ appeared to be useful and safe as immunomodulatory therapy for severe COVID-19 pneumonia.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antivirais/uso terapêutico , Síndrome da Liberação de Citocina/prevenção & controle , Fatores Imunológicos/uso terapêutico , /patogenicidade , Administração Intravenosa , Adulto , Temperatura Corporal/efeitos dos fármacos , Proteína C-Reativa/metabolismo , /mortalidade , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/mortalidade , Síndrome da Liberação de Citocina/virologia , Feminino , Frequência Cardíaca/efeitos dos fármacos , Humanos , Interferon beta/efeitos adversos , L-Lactato Desidrogenase/sangue , Masculino , Pessoa de Meia-Idade , Receptores de Interleucina-6/antagonistas & inibidores , Receptores de Interleucina-6/genética , Receptores de Interleucina-6/imunologia , Taxa Respiratória/efeitos dos fármacos , Estudos Retrospectivos , Índice de Gravidade de Doença , Análise de Sobrevida
8.
Virus Res ; 292: 198235, 2021 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-33232783

RESUMO

The first incidence of COVID-19 was reported in the Wuhan city of Hubei province in China in late December 2019. Because of failure in timely closing of borders of the affected region, COVID-19 spread across like a wildfire through air travel initiating a pandemic. It is a serious lower respiratory track viral infection caused by highly contagious, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Coronavirus including COVID-19 causing SARS-CoV-2 causes zoonotic diseases and thought to be originated from bats. Since its first incidence, the virus has spread all across the world, causing serious human casualties, economic losses, and disrupting global supply chains. As with SARS-CoV, COVID-19 causing SARS-CoV-2 follows a similar path of airborne infection, but is less lethal and more infectious than SARS and MERS. This review focusses on the pathogenesis of SARS-CoV-2, especially on the dysfunctional immune responses following a cytokine storm in severely affected persons. The mode of entry of SARS-CoV-2 is via the angiotensin converting enzyme 2 (ACE-2) receptors present on the epithelial lining of lungs, gastrointestinal tract, and mucus membranes. Older persons with weaker immune system and associated co-morbidities are more vulnerable to have dysfunctional immune responses, as most of them concomitantly have severe hypovitaminosis D. Consequently, causing severe damage to key organs of the body including lungs and the cardiovascular system. Since, vast majority of persons enters to the intensive care units and died, had severe vitamin D deficiency, thus, this area must be investigated seriously. In addition, this article assesses the role of vitamin D in reducing the risk of COVID-19. Vitamin D is a key regulator of the renin-angiotensin system that is exploited by SARS-CoV-2 for entry into the host cells. Further, vitamin D modulates multiple mechanisms of the immune system to contain the virus that includes dampening the entry and replication of SARS-CoV-2, reduces concentration of pro-inflammatory cytokines and increases levels of anti-inflammatory cytokines, enhances the production of natural antimicrobial peptide and activates defensive cells such as macrophages that could destroy SARS-CoV-2. Thus, this article provides the urgency of needed evidences through large population based randomized controlled trials and ecological studies to evaluate the potential role of vitamin D in COVID-19.


Assuntos
/imunologia , Vitamina D/imunologia , Imunidade Adaptativa , Animais , Ensaios Clínicos como Assunto , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/prevenção & controle , Gerenciamento Clínico , Humanos , Imunidade Inata , Fatores Imunológicos , Inflamação/imunologia , Inflamação/prevenção & controle , Vitamina D/uso terapêutico , Zoonoses/imunologia
9.
Eur J Clin Invest ; 51(1): e13429, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33058143

RESUMO

INTRODUCTION: The coronavirus pandemic has affected more than 20 million people so far. Elevated cytokines and suppressed immune responses have been hypothesized to set off a cytokine storm, contributing to ARDS, multiple-organ failure and, in the most severe cases, death. We aimed to quantify the differences in the circulating levels of major inflammatory and immunological markers between severe and nonsevere COVID-19 patients. METHODS: Relevant studies were identified from PubMed, EMBASE, Web of Science, SCOPUS and preprint servers. Risk of bias was assessed for each study, using appropriate checklists. All studies were described qualitatively and a subset was included in the meta-analysis, using forest plots. RESULTS: Based on 23 studies, mean cytokine levels were significantly higher (IL-6: MD, 19.55 pg/mL; CI, 14.80, 24.30; IL-8: MD, 19.18 pg/mL; CI, 2.94, 35.43; IL-10: MD, 3.66 pg/mL; CI, 2.41, 4.92; IL-2R: MD, 521.36 U/mL; CI, 87.15, 955.57; and TNF-alpha: MD, 1.11 pg/mL; CI, 0.07, 2.15) and T-lymphocyte levels were significantly lower (CD4+ T cells: MD, -165.28 cells/µL; CI, -207.58, -122.97; CD8+ T cells: MD, -106.51 cells/µL; CI, -128.59, -84.43) among severe cases as compared to nonsevere ones. There was heterogeneity across studies due to small sample sizes and nonuniformity in outcome assessment and varied definitions of disease severity. The overall quality of studies was sub-optimal. CONCLUSION: Severe COVID-19 is characterized by significantly increased levels of pro-inflammatory cytokines and reduced T lymphocytes. Well-designed and adequately powered prospective studies are needed to amplify the current evidence and provide definitive answers to dilemmas regarding timing and type of anti-COVID-19 therapy particularly in severe patients.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Síndrome da Liberação de Citocina/imunologia , Citocinas/imunologia , Contagem de Linfócito CD4 , Humanos , Interleucina-10/imunologia , Interleucina-6/imunologia , Interleucina-8/imunologia , Contagem de Linfócitos , Receptores de Interleucina-2/imunologia , Índice de Gravidade de Doença , Fator de Necrose Tumoral alfa/imunologia
10.
Nutrition ; 81: 110900, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32738510

RESUMO

The new coronavirus associated with severe acute respiratory syndrome (SARS-CoV-2), surprisingly, does not affect only the lungs. The severe response to SARS-CoV-2 appears to include a "cytokine storm," which indicates a state of hyperinflammation and subsequent dysfunction of multiple organs and tissues in the most severe cases. This could be the reason why populations at the highest risk for death from the SARS-CoV-2 infection-induced disease (coronavirus disease 2019 [COVID-19]) are those suffering from chronic low-grade inflammation, but prone to hyperinflammation. This includes individuals of advanced age and those with obesity, type 2 diabetes, hypertension, and metabolic syndrome. Inflammation resolution is strongly dependent on lipid mediators, the specialized pro-resolution mediators (SPMs). ω-3 polyunsaturated fatty acids (ω-3 PUFAs) are precursors of very potent SPMs, including resolvins, protectins, and maresins. Additionally, they are associated with a less aggressive inflammatory initiation, after competing with ω-6 fatty acids for eicosanoid synthesis. Therefore, it makes sense to consider the use of ω-3 PUFAs for clinical management of COVID-19 patients. ω-3 PUFAs may be given by oral, enteral, or parenteral routes; however, the parenteral route favors faster incorporation into plasma phospholipids, blood cells, and tissues. Here, we discuss these aspects to propose the parenteral infusion of ω-3 PUFAs as adjuvant immunopharmacotherapy for hospitalized patients with COVID-19.


Assuntos
/tratamento farmacológico , Óleos de Peixe/administração & dosagem , /epidemiologia , Quimioterapia Adjuvante , Síndrome da Liberação de Citocina/tratamento farmacológico , Síndrome da Liberação de Citocina/imunologia , Ácidos Graxos Ômega-3/administração & dosagem , Humanos , Inflamação/dietoterapia , Inflamação/imunologia , Infusões Parenterais , Modelos Biológicos , Fenômenos Fisiológicos da Nutrição , Pandemias
11.
Probl Endokrinol (Mosk) ; 66(4): 9-15, 2020 09 01.
Artigo em Russo | MEDLINE | ID: mdl-33351354

RESUMO

Genes of HLA system (Human Leukocyte Antigen) play an essential role in the normal functioning of the immune system. There are three classes of genes: I, II, and III. The function of HLA molecules class I is to present antigens of peptides from the cytoplasm to T-lymphocytes on the cell surface, and class II - to present antigens of peptides from the extracellular space. In the classical view, the pathological activation of the immune system in patients with a genetic predisposition can result in the development of autoimmune diseases. However, the influence of this system on the development of non-autoimmune diseases, their severity and prognosis, has been recently considered. Besides, HLA molecules provide a presentation of various infectious agents. In this connection, the loci of the main histocompatibility complex can be considered candidates for determining the genetic predisposition to infectious diseases themselves and their course. This review hypothesizes that specific variants of HLA genes may cause the formation of a «cytokine storm¼ in patients with COVID-19. Identification of a group of patients with particular genetic variations that cause violation of immune tolerance and hyperresponse in the setting of viral infection will help to optimize the algorithm for disease prevention and treatment of such patients and, as a result, to reduce the severity of the epidemiological situation.


Assuntos
Doenças Autoimunes/imunologia , Síndrome da Liberação de Citocina/genética , Antígenos HLA/imunologia , Alelos , Doenças Autoimunes/epidemiologia , Doenças Autoimunes/genética , Doenças Autoimunes/virologia , /imunologia , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/virologia , Predisposição Genética para Doença , Antígenos HLA/genética , Humanos , /patogenicidade
12.
Eur Rev Med Pharmacol Sci ; 24(24): 13062-13064, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33378059

RESUMO

Cytokine storm in COVID-19 is linked to disease severity and mortality. 40% of patients with severe COVID-19 require mechanical ventilation. Analgesia and sedation are used for treatment of pain, facilitation of mechanical ventilation, or management of acute agitation. Herein, we present the immunomodulating actions of morphine that may either improve or worsen the clinical course of COVID-19 once cytokine storm develops. A literature search was performed to find articles on potential immunomodulatory effects of morphine. Taken together, the results of in vitro and in vivo models in non-COVID-19 conditions suggest that morphine could have a beneficial effect by mitigating the cytokine storm in the early stages of severe COVID-19. In contrast, it could be potentially harmful in late stages of severe COVID-19, especially in the presence of septic shock.


Assuntos
Analgésicos Opioides/efeitos adversos , Síndrome da Liberação de Citocina/imunologia , Imunomodulação , Morfina/efeitos adversos , Analgésicos Opioides/uso terapêutico , Citocinas/imunologia , Humanos , Morfina/uso terapêutico , Respiração Artificial , Choque Séptico/imunologia
13.
PLoS Pathog ; 16(12): e1009128, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33284859

RESUMO

Cytokine storm is suggested as one of the major pathological characteristics of SARS-CoV-2 infection, although the mechanism for initiation of a hyper-inflammatory response, and multi-organ damage from viral infection is poorly understood. In this virus-cell interaction study, we observed that SARS-CoV-2 infection or viral spike protein expression alone inhibited angiotensin converting enzyme-2 (ACE2) receptor protein expression. The spike protein promoted an angiotensin II type 1 receptor (AT1) mediated signaling cascade, induced the transcriptional regulatory molecules NF-κB and AP-1/c-Fos via MAPK activation, and increased IL-6 release. SARS-CoV-2 infected patient sera contained elevated levels of IL-6 and soluble IL-6R. Up-regulated AT1 receptor signaling also influenced the release of extracellular soluble IL-6R by the induction of the ADAM-17 protease. Use of the AT1 receptor antagonist, Candesartan cilexetil, resulted in down-regulation of IL-6/soluble IL-6R release in spike expressing cells. Phosphorylation of STAT3 at the Tyr705 residue plays an important role as a transcriptional inducer for SOCS3 and MCP-1 expression. Further study indicated that inhibition of STAT3 Tyr705 phosphorylation in SARS-CoV-2 infected and viral spike protein expressing epithelial cells did not induce SOCS3 and MCP-1 expression. Introduction of culture supernatant from SARS-CoV-2 spike expressing cells on a model human liver endothelial Cell line (TMNK-1), where transmembrane IL-6R is poorly expressed, resulted in the induction of STAT3 Tyr705 phosphorylation as well as MCP-1 expression. In conclusion, our results indicated that the presence of SARS-CoV-2 spike protein in epithelial cells promotes IL-6 trans-signaling by activation of the AT1 axis to initiate coordination of a hyper-inflammatory response.


Assuntos
/imunologia , Interleucina-6/imunologia , Receptores de Angiotensina/metabolismo , Glicoproteína da Espícula de Coronavírus/imunologia , /metabolismo , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/metabolismo , Síndrome da Liberação de Citocina/virologia , Células Epiteliais/imunologia , Células Epiteliais/metabolismo , Células Epiteliais/virologia , Humanos , Interleucina-6/metabolismo , Mucosa Respiratória/imunologia , Mucosa Respiratória/metabolismo , Mucosa Respiratória/virologia , Transdução de Sinais/fisiologia , Ativação Transcricional
15.
Front Immunol ; 11: 570993, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33329533

RESUMO

Corona virus disease 2019 (COVID-19) has caused a global outbreak and severely posed threat to people's health and social stability. Mounting evidence suggests that immunopathological changes, including diminished lymphocytes and elevated cytokines, are important drivers of disease progression and death in coronavirus infections. Cytokine storm not only limits further spread of virus in the body but also induces secondary tissue damage through the secretion of large amounts of active mediators and inflammatory factors. It has been determined that cytokine storm is a major cause of deaths in COVID-19; therefore, in order to reverse the deterioration of severe and critically ill patients from this disease, the cytokine storm has become a key therapeutic target. Although specific mechanisms of the occurrences of cytokine storms in COVID-19 have not been fully illuminated, hyper-activated innate immune responses, and dysregulation of ACE2 (angiotensin converting enzyme 2) expression and its downstream pathways might provide possibilities. Tailored immunoregulatory therapies have been applied to counteract cytokine storms, such as inhibition of cytokines, corticosteroids, blood purification therapy, and mesenchymal stem cell therapy. This review will summarize advances in the research of cytokine storms induced by COVID-19, as well as potential intervention strategies to control cytokine storms.


Assuntos
Síndrome da Liberação de Citocina , Surtos de Doenças , Imunoterapia , /imunologia , /imunologia , /epidemiologia , /terapia , Síndrome da Liberação de Citocina/epidemiologia , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/terapia , Humanos , Imunidade Inata/imunologia
16.
Front Immunol ; 11: 598404, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33329592

RESUMO

Background: Bacterial sepsis has been used as a prototype to understand the pathogenesis of severe coronavirus disease 2019 (COVID-19). In addition, some management programs for critically ill COVID-19 patients are also based on experience with bacterial sepsis. However, some differences may exist between these two types of sepsis. Methods: This retrospective study investigated whether there are differences in the immune system status of these two types of sepsis. A total of 64 bacterial sepsis patients and 43 patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sepsis were included in this study. Demographic data were obtained from medical records. Laboratory results within 24 h after the diagnosis of sepsis were provided by the clinical laboratory. Results: The results of blood routine (neutrophil, lymphocyte, and monocyte counts), infection biomarkers (C-reactive protein, ferritin, and procalcitonin levels), lymphocyte subset counts (total T lymphocyte, CD4+ T cell, CD8+ T cell, B cell, and NK cell counts), and lymphocyte subset functions (the proportions of PMA/ionomycin-stimulated IFN-γ positive cells in CD4+, CD8+ T cells, and NK cells) were similar in bacterial sepsis patients and SARS-CoV-2 sepsis patients. Cytokine storm was milder, and immunoglobulin and complement protein levels were higher in SARS-CoV-2 sepsis patients. Conclusions: There are both similarities and differences in the immune system status of bacterial sepsis and SARS-CoV-2 sepsis. Our findings do not support blocking the cytokine storm or supplementing immunoglobulins in SARS-CoV-2 sepsis, at least in the early stages of the disease. Treatments for overactivation of the complement system and lymphocyte depletion may be worth exploring further.


Assuntos
Infecções Bacterianas , Síndrome da Liberação de Citocina , Subpopulações de Linfócitos , Sepse , Adulto , Idoso , Infecções Bacterianas/sangue , Infecções Bacterianas/imunologia , /imunologia , Síndrome da Liberação de Citocina/sangue , Síndrome da Liberação de Citocina/imunologia , Feminino , Humanos , Contagem de Linfócitos , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , /metabolismo , Sepse/sangue , Sepse/imunologia
18.
Eur Rev Med Pharmacol Sci ; 24(23): 12500-12509, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33336769

RESUMO

OBJECTIVE: Since the emergence of coronavirus disease (COVID-19), the death toll has been increasing daily. Many risk factors are associated with a high mortality rate in COVID-19. Establishment of a common pathway among these risk factors could improve our understanding of COVID-19 severity and mortality. This review aims at establishing this common pathway and its possible effect on COVID-19 mortality. MATERIALS AND METHODS: The current review was executed in five consecutive stages starting from determining the risk factors of COVID-19 mortality and trying to find a common pathway among them depending on the available literature. This was followed by proposing a mechanism explaining how this common pathway could increase the mortality. Finally, its potential role in managing COVID-19 was proposed. RESULTS: This review identified this common pathway to be a low baseline of reduced glutathione (i.e., GSH) level. In particular, this review provided an in-depth discussion regarding the pathophysiology by which COVID-19 leads to GSH depletion, tissue damage, and acute respiratory distress syndrome. In addition, the current review demonstrated how GSH depletion could result in failure of the immune system and rendering the end organs vulnerable to damage from the oxidative stress. CONCLUSIONS: This preclinical study shows that GSH depletion may have a central role in COVID-19 mortality and pathophysiology. Therefore, elevating the GSH level in tissues may decrease the severity and mortality rates of COVID-19.


Assuntos
/mortalidade , Síndrome da Liberação de Citocina/imunologia , Glutationa/metabolismo , Lesão Pulmonar Aguda/metabolismo , Fatores Etários , Antioxidantes/metabolismo , Apoptose , /metabolismo , Síndrome da Liberação de Citocina/metabolismo , Diabetes Mellitus/epidemiologia , Diabetes Mellitus/metabolismo , Glutationa/imunologia , Humanos , Hipertensão/epidemiologia , Hipertensão/metabolismo , Macrófagos/imunologia , Isquemia Miocárdica/epidemiologia , Isquemia Miocárdica/metabolismo , Obesidade/epidemiologia , Obesidade/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Fatores de Risco , Fumar/epidemiologia , Fumar/metabolismo
19.
Eur Rev Med Pharmacol Sci ; 24(23): 12527-12535, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33336773

RESUMO

Since December 2019, an outbreak of a new coronavirus, COVID-19, infection has been taking place. At present, COVID-19 has spread to most countries worldwide. The latest evidence suggests that cytokine storm syndrome (CSS) is an important cause of the transition from mild to critical pneumonia and critically ill patients' death. The sudden exacerbation of COVID-19 may be related to a cytokine storm. Therefore, early identification and active treatment of CSS may play very important roles in improving the patients' prognosis, and these tasks are given attention in the current treatment of new Coronavirus pneumonia. However, there is still no specific medicine for this purpose. This article reviews cytokine storms and conducts an exploratory review of pharmacotherapy for cytokine storms to provide a reference for clinical treatment.


Assuntos
/imunologia , Síndrome da Liberação de Citocina/imunologia , Miocardite/imunologia , /metabolismo , Anticorpos Monoclonais Humanizados/uso terapêutico , Antioxidantes/uso terapêutico , Apoptose , Fator Natriurético Atrial/uso terapêutico , Azetidinas/uso terapêutico , Compostos de Benzil/uso terapêutico , Síndrome da Liberação de Citocina/tratamento farmacológico , Inibidores Enzimáticos/uso terapêutico , Glucocorticoides/uso terapêutico , Glicoproteínas/uso terapêutico , Humanos , Hipóxia/metabolismo , Hipóxia/terapia , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Isquemia Miocárdica/metabolismo , Miocardite/metabolismo , Miocardite/terapia , Miócitos Cardíacos/metabolismo , Estresse Oxidativo , Oxigenoterapia , Respiração Artificial , Moduladores do Receptor de Esfingosina 1 Fosfato/uso terapêutico , Inibidores da Tripsina/uso terapêutico , Inibidores do Fator de Necrose Tumoral/uso terapêutico , alfa-Metiltirosina/uso terapêutico
20.
J Immunother Cancer ; 8(2)2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33303577

RESUMO

The COVID-19 outbreak caused by SARS-CoV-2 challenges the medical system by interfering with routine therapies for many patients with chronic diseases. In patients with cancer receiving immune checkpoint inhibitors (ICIs), difficulties also arise from the incomplete understanding of the intricate interplay between their routine treatment and pathogenesis of the novel virus. By referring to previous ICI-based investigations, we speculate that ICIs themselves are not linked to high-infection risks of respiratory diseases or inflammation-related adverse effects in patients with cancer. Moreover, ICI treatment may even enhance coronavirus clearance in some patients with malignant tumor by boosting antiviral T-cell responsiveness. However, the 'explosive' inflammation during COVID-19 in some ICI-treated patients with cancer was illustrated as exuberant immunopathological damage or even death. In case of the COVID-19 immunopathogenesis fueled by ICIs, we propose a regular monitor of pathogenic T-cell subsets and their exhaustion marker expression (eg, Th17 and interleukin (IL)-6-producing Th1 subsets with surface programmed death 1 expression) to guide the usage of ICI. Here we aimed to address these considerations, based on available literature and experience from our practice, that may assist with the decision-making of ICI administration during the pandemic.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Síndrome da Liberação de Citocina/prevenção & controle , Neoplasias/tratamento farmacológico , /imunologia , Antineoplásicos Imunológicos/uso terapêutico , /diagnóstico , Tomada de Decisão Clínica , Síndrome da Liberação de Citocina/sangue , Síndrome da Liberação de Citocina/imunologia , Monitoramento de Medicamentos , Humanos , Pulmão/diagnóstico por imagem , Neoplasias/sangue , Neoplasias/imunologia , Pandemias , Seleção de Pacientes , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/metabolismo , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th1/metabolismo , Células Th17/efeitos dos fármacos , Células Th17/imunologia , Células Th17/metabolismo , Tomografia Computadorizada por Raios X
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