Cytokine storm syndrome(CSS)is a life-threatening systemic inflammatory syndrome involving innate immune hyperactivity triggered by various therapies,infections,and autoimmune conditions.However,the potential interpla...Cytokine storm syndrome(CSS)is a life-threatening systemic inflammatory syndrome involving innate immune hyperactivity triggered by various therapies,infections,and autoimmune conditions.However,the potential interplay between innate immune cells is not fully understood.Here,using poly I:C and lipopolysaccharide(LPS)-induced cytokine storm models,a protective role of neutrophils through the modulation of macrophage activation was identified in a CSS model.Intravital imaging revealed neutrophil-derived extracellular vesicles(NDEVs)in the liver and spleen,which were captured by macrophages.NDEVs suppressed proinflammatory cytokine production by macrophages when cocultured in vitro or infused into CSS models.Metabolic profiling of macrophages treated with NDEV revealed elevated levels of the anti-inflammatory metabolite,itaconate,which is produced from cis-aconitate in the Krebs cycle by cis-aconitate decarboxylase(Acod1,encoded by Irg1).Irg1 in macrophages,but not in neutrophils,was critical for the NDEV-mediated anti-inflammatory effects.Mechanistically,NDEVs delivered miR-27a-3p,which suppressed the expression of Suclg1,the gene encoding the enzyme that metabolizes itaconate,thereby resulting in the accumulation of itaconate in macrophages.These findings demonstrated that neutrophil-to-macrophage communication mediated by extracellular vesicles is critical for promoting the anti-inflammatory reprogramming of macrophages in CSS and may have potential implications for the treatment of this fatal condition.展开更多
Theoretically, mesenchymal stem cells (MSCs) are very promising as adjuvanttherapy to alleviate coronavirus disease 2019 (COVID-19)-associated acute lunginjury and cytokine storm. Several published studies, which used...Theoretically, mesenchymal stem cells (MSCs) are very promising as adjuvanttherapy to alleviate coronavirus disease 2019 (COVID-19)-associated acute lunginjury and cytokine storm. Several published studies, which used MSCs toalleviate COVID-19-associated acute lung injury and cytokine storm, reportedpromising results. However, the evidence came from a case report, case series,and clinical trials with a limited number of participants. Therefore, more studiesare needed to get robust proof of MSC beneficial effects.展开更多
Severe acute respiratory syndrome coronavirus-2 and the related coronavirus disease-19(COVID-19)is a worldwide emerging situation,which was initially reported in December 2019 in Wuhan,China.Currently,more than 725884...Severe acute respiratory syndrome coronavirus-2 and the related coronavirus disease-19(COVID-19)is a worldwide emerging situation,which was initially reported in December 2019 in Wuhan,China.Currently,more than 7258842 new cases,and more than 411879 deaths have been reported globally.This new highly transmitted coronavirus is responsible for the development of severe acute respiratory distress syndrome.Due to this disorder,a great number of patients are hospitalized in the intensive care unit followed by connection to extracorporeal membrane oxygenation for breath supporting and survival.Severe acute respiratory distress syndrome is mostly accompanied by the secretion of proinflammatory cytokines,including interleukin(IL)-2,IL-6,IL-7,granulocyte colony-stimulating factor(GSCF),interferon-inducible protein 10(IP10),monocyte chemotactic protein-1(MCP1),macrophage inflammatory protein 1A(MIP1A),and tumor necrosis factor alpha(TNF-α),an event which is known as“cytokine storm”.Further disease pathology involves a generalized modulation of immune responses,leading to fatal multiorgan failure.Currently,no specific treatment or vaccination against severe acute respiratory syndrome coronavirus-2(SARS-CoV-2)has been developed.Mesenchymal stromal cells(MSCs),which are known for their immunosuppressive actions,could be applied as an alternative co-therapy in critically-ill COVID-19 patients.Specifically,MSCs can regulate the immune responses through the conversion of Th1 to Th2,activation of M2 macrophages,and modulation of dendritic cells maturation.These key immunoregulatory properties of MSCs may be exerted either by produced soluble factors or by cell-cell contact interactions.To date,several clinical trials have been registered to assess the safety,efficacy,and therapeutic potential of MSCs in COVID-19.Moreover,MSC treatment may be effective for the reversion of ground-glass opacity of damaged lungs and reduce the tissue fibrosis.Taking into account the multifunctional properties of MSCs,the proposed stem-cell-based therapy may be proven significantly effective in critically-ill COVID-19 patients.The current therapeutic strategy may improve the patient’s overall condition and in parallel may decrease the mortality rate of the current disease.展开更多
Coronavirus disease 2019(COVID-19),a pandemic disease caused by the severe acute respiratory syndrome coronavirus 2(SARS-CoV2),is growing at an exponential rate worldwide.Manifestations of this disease are heterogeneo...Coronavirus disease 2019(COVID-19),a pandemic disease caused by the severe acute respiratory syndrome coronavirus 2(SARS-CoV2),is growing at an exponential rate worldwide.Manifestations of this disease are heterogeneous;however,advanced cases often exhibit various acute respiratory distress syndrome-like symptoms,systemic inflammatory reactions,coagulopathy,and organ involvements.A common theme in advanced COVID-19 is unrestrained immune activation,classically referred to as a“cytokine storm”,as well as deficiencies in immune regulatory mechanisms such as T regulatory cells.While mesenchymal stem cells(MSCs)themselves are objects of cytokine regulation,they can secrete cytokines to modulate immune cells by inducing antiinflammatory regulatory Treg cells,macrophages and neutrophils;and by reducing the activation of T and B cells,dendritic and nature killer cells.Consequently,they have therapeutic potential for treating severe cases of COVID-19.Here we discuss the unique ability of MSCs,to act as a“living antiinflammatory”,which can“rebalance”the cytokine/immune responses to restore equilibrium.We also discuss current MSC trials and present different concepts for optimization of MSC therapy in patients with COVID-19 acute respiratory distress syndrome.展开更多
Background: Vitamin D has garnered much attention for its role in immune function, more specifically, it’s conceivable link to the clinical severity of Covid-19 infections and therefore its potential application in p...Background: Vitamin D has garnered much attention for its role in immune function, more specifically, it’s conceivable link to the clinical severity of Covid-19 infections and therefore its potential application in prophylactic or therapeutic treatment. Vitamin D appears capable of inhibiting pulmonary inflammatory responses while enhancing innate defence mechanisms against respiratory pathogens with population-based studies showing an association between circulating vitamin D levels and lung function. We understand that infection with Sars-Cov-2 induces production of pro and anti-inflammatory cytokines, whilst Vitamin D downregulates production of pro-inflammatory Th1 cytokines including tumour necrosis factor and interferon Y, whilst increasing expression of anti-inflammatory cytokines by macrophages. Vitamin D is also involved in the renin-angiotensin system which is regulated by entry of the SARS-Cov-2 virus into cells via the ACE2 receptor, leading to cytokine storms, with subsequent fatal respiratory distress syndrome. The theoretical implications for Vitamin D status in the presentation of Covid-19 (the disease state of Sars-Cov-2) exist, yet data on its application is currently limited. Geographical variables depicting patterns between sun exposure, diet or Vit D status, and risk of death from Covid-19 have shown strong negative correlation. Aim: We aim to assess levels of Vitamin D deficiency in ICU patients who have tested positive for Sars-Cov-2 and who have exhibited respiratory symptoms. In this way, we hope to identify the possibility of Vitamin D as a significant contributing factor to disease progression in Covid patients. Sample: Male or Female patients of any age, who were admitted to the Intensive Care Unit exhibiting respiratory symptoms, with a positive Sars-Cov-2 PCR test, between 12/3/21 and 25/2/21. sample total: 79. Results: Testing was very inconsistent with only 67.1% having their Vitamin D levels checked. There was average delay in testing levels by 2 days. 64% of patients were found to be very deficient. Conclusion: This study highlights the strong correlation between Vitamin D status and severity of Covid-19 disease and thus demonstrates a potential huge shortfall in the testing and treatment of this immunodeficiency as it relates to Covid-19. Based on recommendations of Vitamin D levels required for protection of this viral syndrome, as much as 100% of patients sampled with severe disease could be deficient in Vitamin D.展开更多
Coronavirus Disease 2019(COVID-19)was first identified in China at the end of 2019.Acute respiratory distress syndrome(ARDS)represents the most common and serious complication of COVID-19.Cytokine storms are a pathoph...Coronavirus Disease 2019(COVID-19)was first identified in China at the end of 2019.Acute respiratory distress syndrome(ARDS)represents the most common and serious complication of COVID-19.Cytokine storms are a pathophysiological feature of COVID-19 and play an important role in distinguishing hyper-inflammatory subphenotypes of ARDS.Accordingly,in this review,we focus on hyper-inflammatory host responses in ARDS that play a critical role in the differentiated development of COVID-19.Furthermore,we discuss inflammationrelated indicators that have the potential to identify hyper-inflammatory subphenotypes of COVID-19,especially for those with a high risk of ARDS.Finally,we explore the possibility of improving the quality of monitoring and treatment of COVID-19 patients and in reducing the incidence of critical illness and mortality via better distinguishing hyper-and hypoinflammatory subphenotypes of COVID-19.展开更多
基金supported by grants from The Ministry of Science and Technology of China(2020YFC2002800 to Jing Wang)the National Natural Science Foundation of China(82371760 to Jing Wang and 82272181 to Yan Luo).
文摘Cytokine storm syndrome(CSS)is a life-threatening systemic inflammatory syndrome involving innate immune hyperactivity triggered by various therapies,infections,and autoimmune conditions.However,the potential interplay between innate immune cells is not fully understood.Here,using poly I:C and lipopolysaccharide(LPS)-induced cytokine storm models,a protective role of neutrophils through the modulation of macrophage activation was identified in a CSS model.Intravital imaging revealed neutrophil-derived extracellular vesicles(NDEVs)in the liver and spleen,which were captured by macrophages.NDEVs suppressed proinflammatory cytokine production by macrophages when cocultured in vitro or infused into CSS models.Metabolic profiling of macrophages treated with NDEV revealed elevated levels of the anti-inflammatory metabolite,itaconate,which is produced from cis-aconitate in the Krebs cycle by cis-aconitate decarboxylase(Acod1,encoded by Irg1).Irg1 in macrophages,but not in neutrophils,was critical for the NDEV-mediated anti-inflammatory effects.Mechanistically,NDEVs delivered miR-27a-3p,which suppressed the expression of Suclg1,the gene encoding the enzyme that metabolizes itaconate,thereby resulting in the accumulation of itaconate in macrophages.These findings demonstrated that neutrophil-to-macrophage communication mediated by extracellular vesicles is critical for promoting the anti-inflammatory reprogramming of macrophages in CSS and may have potential implications for the treatment of this fatal condition.
文摘Theoretically, mesenchymal stem cells (MSCs) are very promising as adjuvanttherapy to alleviate coronavirus disease 2019 (COVID-19)-associated acute lunginjury and cytokine storm. Several published studies, which used MSCs toalleviate COVID-19-associated acute lung injury and cytokine storm, reportedpromising results. However, the evidence came from a case report, case series,and clinical trials with a limited number of participants. Therefore, more studiesare needed to get robust proof of MSC beneficial effects.
文摘Severe acute respiratory syndrome coronavirus-2 and the related coronavirus disease-19(COVID-19)is a worldwide emerging situation,which was initially reported in December 2019 in Wuhan,China.Currently,more than 7258842 new cases,and more than 411879 deaths have been reported globally.This new highly transmitted coronavirus is responsible for the development of severe acute respiratory distress syndrome.Due to this disorder,a great number of patients are hospitalized in the intensive care unit followed by connection to extracorporeal membrane oxygenation for breath supporting and survival.Severe acute respiratory distress syndrome is mostly accompanied by the secretion of proinflammatory cytokines,including interleukin(IL)-2,IL-6,IL-7,granulocyte colony-stimulating factor(GSCF),interferon-inducible protein 10(IP10),monocyte chemotactic protein-1(MCP1),macrophage inflammatory protein 1A(MIP1A),and tumor necrosis factor alpha(TNF-α),an event which is known as“cytokine storm”.Further disease pathology involves a generalized modulation of immune responses,leading to fatal multiorgan failure.Currently,no specific treatment or vaccination against severe acute respiratory syndrome coronavirus-2(SARS-CoV-2)has been developed.Mesenchymal stromal cells(MSCs),which are known for their immunosuppressive actions,could be applied as an alternative co-therapy in critically-ill COVID-19 patients.Specifically,MSCs can regulate the immune responses through the conversion of Th1 to Th2,activation of M2 macrophages,and modulation of dendritic cells maturation.These key immunoregulatory properties of MSCs may be exerted either by produced soluble factors or by cell-cell contact interactions.To date,several clinical trials have been registered to assess the safety,efficacy,and therapeutic potential of MSCs in COVID-19.Moreover,MSC treatment may be effective for the reversion of ground-glass opacity of damaged lungs and reduce the tissue fibrosis.Taking into account the multifunctional properties of MSCs,the proposed stem-cell-based therapy may be proven significantly effective in critically-ill COVID-19 patients.The current therapeutic strategy may improve the patient’s overall condition and in parallel may decrease the mortality rate of the current disease.
文摘Coronavirus disease 2019(COVID-19),a pandemic disease caused by the severe acute respiratory syndrome coronavirus 2(SARS-CoV2),is growing at an exponential rate worldwide.Manifestations of this disease are heterogeneous;however,advanced cases often exhibit various acute respiratory distress syndrome-like symptoms,systemic inflammatory reactions,coagulopathy,and organ involvements.A common theme in advanced COVID-19 is unrestrained immune activation,classically referred to as a“cytokine storm”,as well as deficiencies in immune regulatory mechanisms such as T regulatory cells.While mesenchymal stem cells(MSCs)themselves are objects of cytokine regulation,they can secrete cytokines to modulate immune cells by inducing antiinflammatory regulatory Treg cells,macrophages and neutrophils;and by reducing the activation of T and B cells,dendritic and nature killer cells.Consequently,they have therapeutic potential for treating severe cases of COVID-19.Here we discuss the unique ability of MSCs,to act as a“living antiinflammatory”,which can“rebalance”the cytokine/immune responses to restore equilibrium.We also discuss current MSC trials and present different concepts for optimization of MSC therapy in patients with COVID-19 acute respiratory distress syndrome.
文摘Background: Vitamin D has garnered much attention for its role in immune function, more specifically, it’s conceivable link to the clinical severity of Covid-19 infections and therefore its potential application in prophylactic or therapeutic treatment. Vitamin D appears capable of inhibiting pulmonary inflammatory responses while enhancing innate defence mechanisms against respiratory pathogens with population-based studies showing an association between circulating vitamin D levels and lung function. We understand that infection with Sars-Cov-2 induces production of pro and anti-inflammatory cytokines, whilst Vitamin D downregulates production of pro-inflammatory Th1 cytokines including tumour necrosis factor and interferon Y, whilst increasing expression of anti-inflammatory cytokines by macrophages. Vitamin D is also involved in the renin-angiotensin system which is regulated by entry of the SARS-Cov-2 virus into cells via the ACE2 receptor, leading to cytokine storms, with subsequent fatal respiratory distress syndrome. The theoretical implications for Vitamin D status in the presentation of Covid-19 (the disease state of Sars-Cov-2) exist, yet data on its application is currently limited. Geographical variables depicting patterns between sun exposure, diet or Vit D status, and risk of death from Covid-19 have shown strong negative correlation. Aim: We aim to assess levels of Vitamin D deficiency in ICU patients who have tested positive for Sars-Cov-2 and who have exhibited respiratory symptoms. In this way, we hope to identify the possibility of Vitamin D as a significant contributing factor to disease progression in Covid patients. Sample: Male or Female patients of any age, who were admitted to the Intensive Care Unit exhibiting respiratory symptoms, with a positive Sars-Cov-2 PCR test, between 12/3/21 and 25/2/21. sample total: 79. Results: Testing was very inconsistent with only 67.1% having their Vitamin D levels checked. There was average delay in testing levels by 2 days. 64% of patients were found to be very deficient. Conclusion: This study highlights the strong correlation between Vitamin D status and severity of Covid-19 disease and thus demonstrates a potential huge shortfall in the testing and treatment of this immunodeficiency as it relates to Covid-19. Based on recommendations of Vitamin D levels required for protection of this viral syndrome, as much as 100% of patients sampled with severe disease could be deficient in Vitamin D.
基金This work was supported by the National Medical Team in Wuhan(from The First Affiliated Hospital of Chongqing Medical University)and Wuhan No.1 Hospital.This article also commemorates the Chinese medical staff who gave their lives in the first-line defense against COVID-19.Finally,we thank Accdon(www.accdon.com)for its linguistic assistance during the preparation of this manuscript.
文摘Coronavirus Disease 2019(COVID-19)was first identified in China at the end of 2019.Acute respiratory distress syndrome(ARDS)represents the most common and serious complication of COVID-19.Cytokine storms are a pathophysiological feature of COVID-19 and play an important role in distinguishing hyper-inflammatory subphenotypes of ARDS.Accordingly,in this review,we focus on hyper-inflammatory host responses in ARDS that play a critical role in the differentiated development of COVID-19.Furthermore,we discuss inflammationrelated indicators that have the potential to identify hyper-inflammatory subphenotypes of COVID-19,especially for those with a high risk of ARDS.Finally,we explore the possibility of improving the quality of monitoring and treatment of COVID-19 patients and in reducing the incidence of critical illness and mortality via better distinguishing hyper-and hypoinflammatory subphenotypes of COVID-19.
