Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 4.726
Filtrar
1.
DNA Cell Biol ; 40(11): 1396-1406, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34767734

RESUMO

Sepsis has become a major public health problem worldwide. Methylprednisolone sodium succinate (MP) is a commonly used drug to prevent inflammation. However, the role and underlying mechanism of MP in sepsis remain vague. MP inhibited the lipopolysaccharide (LPS)-induced production of tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-17 and suppressed cell growth in alveolar type II epithelial cells (ATII cells). Small nucleolar RNA host gene 5 (SNHG5) expression was inhibited by LPS and restored by MP. Upregulation of SNHG5 inhibited the cellular role of LPS in ATII cells, and further, downregulation of SNHG5 inhibited the cellular role of MP in ATII cells under LPS conditions. SNHG5 elevated the expression of Copine 1 (CPNE1) by enhancing the mRNA stability of CPNE1. Increasing CPNE1 expression restored the silenced SNHG5-induced inhibitor role of MP in ATII cells under LPS conditions. Finally, MP attenuated lung injury and TNF-α and IL-17 secretion in an LPS-induced sepsis mouse model. Overall, this study investigated the mechanism underlying the effect of MP treatment in sepsis and, for the first time, revealed the important role of the SNHG5/CPNE1 pathway in the development and treatment of sepsis and the potential to serve as a diagnostic and therapeutic target for sepsis.


Assuntos
Proteínas de Ligação ao Cálcio/metabolismo , Metilprednisolona/farmacologia , Sepse/tratamento farmacológico , Células Epiteliais Alveolares/efeitos dos fármacos , Células Epiteliais Alveolares/metabolismo , Animais , Apoptose/efeitos dos fármacos , Proteínas de Ligação ao Cálcio/efeitos dos fármacos , Proteínas de Ligação ao Cálcio/genética , Proteínas de Transporte , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/genética , Feminino , Inflamação , Lipopolissacarídeos/farmacologia , Metilprednisolona/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , RNA Longo não Codificante/genética , RNA Nucleolar Pequeno/genética , Sepse/metabolismo , Transdução de Sinais/efeitos dos fármacos
2.
Front Immunol ; 12: 744799, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34594344

RESUMO

Sepsis is a global health emergency, which is caused by various sources of infection that lead to changes in gene expression, protein-coding, and metabolism. Advancements in "omics" technologies have provided valuable tools to unravel the mechanisms involved in the pathogenesis of this disease. In this study, we performed shotgun mass spectrometry in peripheral blood mononuclear cells (PBMC) from septic patients (N=24) and healthy controls (N=9) and combined these results with two public microarray leukocytes datasets. Through combination of transcriptome and proteome profiling, we identified 170 co-differentially expressed genes/proteins. Among these, 122 genes/proteins displayed the same expression trend. Ingenuity Pathway Analysis revealed pathways related to lymphocyte functions with decreased status, and defense processes that were predicted to be strongly increased. Protein-protein interaction network analyses revealed two densely connected regions, which mainly included down-regulated genes/proteins that were related to the transcription of RNA, translation of proteins, and mitochondrial translation. Additionally, we identified one module comprising of up-regulated genes/proteins, which were mainly related to low-density neutrophils (LDNs). LDNs were reported in sepsis and in COVID-19. Changes in gene expression level were validated using quantitative real-time PCR in PBMCs from patients with sepsis. To further support that the source of the upregulated module of genes/proteins found in our results were derived from LDNs, we identified an increase of this population by flow cytometry in PBMC samples obtained from the same cohort of septic patients included in the proteomic analysis. This study provides new insights into a reprioritization of biological functions in response to sepsis that involved a transcriptional and translational shutdown of genes/proteins, with exception of a set of genes/proteins related to LDNs and host-defense system.


Assuntos
Leucócitos Mononucleares/metabolismo , Neutrófilos/metabolismo , Sepse/metabolismo , Bases de Dados Factuais , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Humanos , Leucócitos Mononucleares/citologia , Células Supressoras Mieloides/citologia , Células Supressoras Mieloides/metabolismo , Neutrófilos/citologia , Mapas de Interação de Proteínas , Proteômica , Sepse/genética , Sepse/imunologia
3.
Int J Mol Sci ; 22(19)2021 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-34638670

RESUMO

Platelets, cellular mediators of thrombosis, are activated during sepsis and are increasingly recognized as mediators of the immune response. Platelet activation is significantly increased in sepsis patients compared to ICU control patients. Despite this correlation, the role of activated platelets in contributing to sepsis pathophysiology remains unclear. We previously demonstrated NOD-like receptor protein 3 inflammasome (NLRP3) inflammasome activation in sepsis-induced platelets from cecal-ligation puncture (CLP) rats. Activated platelets were associated with increased pulmonary edema and glomerular injury in CLP vs. SHAM controls. In this study, we investigated whether inhibition of platelet activation would attenuate NLRP3 activation and renal and pulmonary injury in response to CLP. CLP was performed in male and female Sprague Dawley (SD) rats (n = 10/group) to induce abdominal sepsis and SHAM rats served as controls. A subset of CLP animals was treated with Clopidogrel (10 mg/kg/day, CLP + CLOP) to inhibit platelet activation. At 72 h post-CLP, platelet activation and NLRP3 inflammasome assembly were evaluated, IL-1ß and IL-18 were measured in plasma, and tissues, renal and pulmonary pathology, and renal function were assessed. Activated platelets were 7.8 ± 3.6% in Sham, 22 ± 6% in CLP and significantly decreased to 14.5 ± 0.6% in CLP + CLOP (n = 8-10/group, p < 0.05). NLRP3 inflammasome assembly was inhibited in platelets of CLP + CLOP animals vs. CLP. Significant increases in plasma and kidney IL-1ß and IL-18 in response to CLP were decreased with Clopidogrel treatment. Renal injury, but not lung histology or renal function was improved in CLP + CLOP vs. CLP. These data provide evidence that activated platelets may contribute to sepsis-induced renal injury, possibly via NLRP3 activation in platelets. Platelets may be a therapeutic target to decrease renal injury in septic patients.


Assuntos
Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Inflamassomos/efeitos dos fármacos , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Inibidores da Agregação Plaquetária/farmacologia , Sepse/metabolismo , Animais , Feminino , Interleucina-18/metabolismo , Interleucina-1beta/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Ligadura , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Masculino , Proteínas NLR/metabolismo , Ativação Plaquetária/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
4.
Int J Mol Sci ; 22(19)2021 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-34638860

RESUMO

(1) Background: Sepsis is one of the most common critical care illnesses with increasing survivorship. The quality of life in sepsis survivors is adversely affected by several co-morbidities, including increased incidence of dementia, stroke, cardiac disease and at least temporary deterioration in cognitive dysfunction. One of the potential explanations for their progression is the persistence of lipid profile abnormalities induced during acute sepsis into recovery, resulting in acceleration of atherosclerosis. (2) Methods: This is a targeted review of the abnormalities in the long-term lipid profile abnormalities after sepsis; (3) Results: There is a well-established body of evidence demonstrating acute alteration in lipid profile (HDL-c ↓↓, LDL-C -c ↓↓). In contrast, a limited number of studies demonstrated depression of HDL-c levels with a concomitant increase in LDL-C -c in the wake of sepsis. VLDL-C -c and Lp(a) remained unaltered in few studies as well. Apolipoprotein A1 was altered in survivors suggesting abnormalities in lipoprotein metabolism concomitant to overall lipoprotein abnormalities. However, most of the studies were limited to a four-month follow-up and patient groups were relatively small. Only one study looked at the atherosclerosis progression in sepsis survivors using clinical correlates, demonstrating an acceleration of plaque formation in the aorta, and a large metanalysis suggested an increase in the risk of stroke or acute coronary event between 3% to 9% in sepsis survivors. (4) Conclusions: The limited evidence suggests an emergence and persistence of the proatherogenic lipid profile in sepsis survivors that potentially contributes, along with other factors, to the clinical sequel of atherosclerosis.


Assuntos
Aterosclerose/metabolismo , Colesterol/metabolismo , Lipoproteínas/metabolismo , Sepse/metabolismo , Apolipoproteínas/metabolismo , Aterosclerose/complicações , HDL-Colesterol/metabolismo , LDL-Colesterol/metabolismo , Progressão da Doença , Humanos , Sepse/complicações , Triglicerídeos/metabolismo
5.
Int J Mol Sci ; 22(19)2021 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-34638575

RESUMO

Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to an infection; it carries a risk for mortality, considerably exceeding that of a mere infection. Sepsis is the leading cause for acute kidney injury (AKI) and the requirement for renal replacement therapy (RRT) in intensive care unit (ICU) patients. Almost every second critically ill patient with sepsis will develop AKI. In septic shock, the dysregulated host response to infectious pathogens leads to a cytokine storm with uncontrolled production and release of humoral proinflammatory mediators that evoke cellular toxicity and promote the development of organ dysfunction and increased mortality. In addition to treating AKI, RRT techniques can be employed for extracorporeal adsorption of inflammatory mediators using specifically developed adsorption membranes, hemoperfusion sorbent cartridges or columns; these techniques are intended to decrease the level and early deleterious effects of circulating proinflammatory cytokines and endotoxins during the first hours and days of septic shock treatment, in order to improve patient outcomes. Several methods and devices, such as high cut-off membranes, the Oxiris®-AN69 membrane, CytoSorb® and HA380 cytokine hemoadsorption, polymyxin B endotoxin adsorption, and plasmapheresis have been examined in small study series or are under evaluation as ways of improving patient outcomes in septic shock. However, to date, the data on actual outcome benefits have remained controversial, as discussed in this review.


Assuntos
Choque Séptico/terapia , Injúria Renal Aguda/terapia , Animais , Citocinas/metabolismo , Humanos , Mediadores da Inflamação/metabolismo , Rim/metabolismo , Terapia de Substituição Renal/métodos , Sepse/metabolismo , Sepse/terapia , Choque Séptico/metabolismo
6.
Exp Cell Res ; 407(2): 112784, 2021 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-34508746

RESUMO

Inflammation is an essential factor contributing to sepsis-induced endothelial cell (EC) activation. Interleukin-35 (IL-35) is an anti-inflammatory/immunosuppressive cytokine that exerts protective effects on many inflammatory diseases. In this study, we investigated the effects of IL-35 on lipopolysaccharide (LPS)-induced EC activation and the potential underlying mechanism. Human umbilical vein endothelial cells (HUVECs) were incubated with LPS (1 µg/ml) for 24 h and then cocultured with different concentrations (0, 1, 10, or 100 ng/ml) of recombinant human IL-35 (rhIL-35) for 12 h. Flow cytometry analysis revealed that IL-35 inhibited LPS-induced HUVEC apoptosis in a dose-dependent manner. RT-qPCR and Western blot analyses showed significantly higher mRNA and protein levels of the adhesion molecules intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) and the inflammatory factors IL-6 and IL-8 in the LPS group than in the control group. These changes were alleviated by IL-35 treatment, suggesting that IL-35 protects ECs by downregulating inflammation. Furthermore, IL-35 induced signal transducer and activator of transcription 1 (STAT1) and STAT4 activation and promoted their interaction. Blocking STAT1 or STAT4 expression by fludarabine (STAT1 inhibitor) treatment or siRNA-STAT4-interfering fragment transfection inhibited the protective effect of IL-35 on ECs. Moreover, we observed a similar protective effect of IL-35 treatment on ECs in a mouse sepsis model induced by intraperitoneal LPS injection. This study indicated that IL-35 exerts anti-inflammatory and antiapoptotic effects on LPS-induced EC activation by activating the STAT1 and STAT4 signaling pathways.


Assuntos
Anti-Inflamatórios/farmacologia , Apoptose , Endotélio Vascular/metabolismo , Inflamação/prevenção & controle , Interleucinas/metabolismo , Lipopolissacarídeos/toxicidade , Sepse/prevenção & controle , Animais , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/patologia , Regulação da Expressão Gênica , Humanos , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/patologia , Interleucinas/administração & dosagem , Interleucinas/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/genética , NF-kappa B/metabolismo , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT4/genética , Fator de Transcrição STAT4/metabolismo , Sepse/induzido quimicamente , Sepse/metabolismo , Sepse/patologia , Transdução de Sinais
7.
Int J Mol Sci ; 22(18)2021 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-34575939

RESUMO

The peroxisome proliferator-activated receptor (PPAR) family of transcription factors has been demonstrated to play critical roles in regulating fuel selection, energy expenditure and inflammation in skeletal muscle and other tissues. Activation of PPARs, through endogenous fatty acids and fatty acid metabolites or synthetic compounds, has been demonstrated to have lipid-lowering and anti-diabetic actions. This review will aim to provide a comprehensive overview of the functions of PPARs in energy homeostasis, with a focus on the impacts of PPAR agonism on muscle metabolism and function. The dysregulation of energy homeostasis in skeletal muscle is a frequent underlying characteristic of inflammation-related conditions such as sepsis. However, the potential benefits of PPAR agonism on skeletal muscle protein and fuel metabolism under these conditions remains under-investigated and is an area of research opportunity. Thus, the effects of PPARγ agonism on muscle inflammation and protein and carbohydrate metabolism will be highlighted, particularly with its potential relevance in sepsis-related metabolic dysfunction. The impact of PPARδ agonism on muscle mitochondrial function, substrate metabolism and contractile function will also be described.


Assuntos
Inflamação/genética , Músculo Esquelético/metabolismo , PPAR gama/genética , Sepse/genética , Metabolismo Energético/genética , Humanos , Inflamação/metabolismo , Inflamação/patologia , Contração Muscular/genética , Receptores Ativados por Proliferador de Peroxissomo/genética , Sepse/metabolismo , Sepse/patologia
8.
Immunity ; 54(9): 2024-2041.e8, 2021 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-34473957

RESUMO

Sepsis results in elevated adenosine in circulation. Extracellular adenosine triggers immunosuppressive signaling via the A2a receptor (A2aR). Sepsis survivors develop persistent immunosuppression with increased risk of recurrent infections. We utilized the cecal ligation and puncture (CLP) model of sepsis and subsequent infection to assess the role of adenosine in post-sepsis immune suppression. A2aR-deficient mice showed improved resistance to post-sepsis infections. Sepsis expanded a subset of CD39hi B cells and elevated extracellular adenosine, which was absent in mice lacking CD39-expressing B cells. Sepsis-surviving B cell-deficient mice were more resistant to secondary infections. Mechanistically, metabolic reprogramming of septic B cells increased production of ATP, which was converted into adenosine by CD39 on plasmablasts. Adenosine signaling via A2aR impaired macrophage bactericidal activity and enhanced interleukin-10 production. Septic individuals exhibited expanded CD39hi plasmablasts and adenosine accumulation. Our study reveals CD39hi plasmablasts and adenosine as important drivers of sepsis-induced immunosuppression with relevance in human disease.


Assuntos
Adenosina/imunologia , Antígenos CD/imunologia , Apirase/imunologia , Tolerância Imunológica/imunologia , Macrófagos/imunologia , Plasmócitos/imunologia , Sepse/imunologia , Adenosina/metabolismo , Animais , Antígenos CD/metabolismo , Apirase/metabolismo , Reprogramação Celular/imunologia , Macrófagos/metabolismo , Camundongos , Plasmócitos/metabolismo , Receptor A2A de Adenosina/imunologia , Receptor A2A de Adenosina/metabolismo , Sepse/metabolismo
9.
Ann Surg ; 274(4): 664-673, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34506322

RESUMO

OBJECTIVE: To analyze serial biomarkers of the persistent inflammation, immunosuppression, and catabolism syndrome (PICS) to gain insight into the pathobiology of chronic critical illness (CCI) after surgical sepsis. BACKGROUND: Although early deaths after surgical intensive care unit sepsis have decreased and most survivors rapidly recover (RAP), one third develop the adverse clinical trajectory of CCI. However, the underlying pathobiology of its dismal long-term outcomes remains unclear. METHODS: PICS biomarkers over 14 days from 124 CCI and 225 RAP sepsis survivors were analyzed to determine associations and prediction models for (1) CCI (≥14 intensive care unit days with organ dysfunction) and (2) dismal 1-year outcomes (Zubrod 4/5 performance scores). Clinical prediction models were created using PIRO variables (predisposition, insult, response, and organ dysfunction). Biomarkers were then added to determine if they strengthened predictions. RESULTS: CCI (vs RAP) and Zubrod 4/5 (vs Zubrod 0-3) cohorts had greater elevations in biomarkers of inflammation (interleukin [IL]-6, IL-8, interferon gamma-induced protein [IP-10], monocyte chemoattractant protein 1), immunosuppression (IL-10, soluble programmed death ligand-1), stress metabolism (C-reactive protein, glucagon-like peptide 1), and angiogenesis (angiopoietin-2, vascular endothelial growth factor, vascular endothelial growth factor receptor-1, stromal cell-derived factor) at most time-points. Clinical models predicted CCI on day 4 (area under the receiver operating characteristics curve [AUC] = 0.89) and 1 year Zubrod 4/5 on day 7 (AUC = 0.80). IL-10 and IP-10 on day 4 minimally improved prediction of CCI (AUC = 0.90). However, IL-10, IL-6, IL-8, monocyte chemoattractant protein 1, IP-10, angiopoietin-2, glucagon-like peptide 1, soluble programmed death ligand-1, and stromal cell-derived factor on day 7 considerably improved the prediction of Zubrod 4/5 status (AUC = 0.88). CONCLUSIONS: Persistent elevations of PICS biomarkers in the CCI and Zubrod 4/5 cohorts and their improved prediction of Zubrod 4/5 validate that PICS plays a role in CCI pathobiology.


Assuntos
Biomarcadores/metabolismo , Estado Terminal , Tolerância Imunológica , Inflamação , Complicações Pós-Operatórias/metabolismo , Sepse/metabolismo , Adulto , Idoso , Suscetibilidade a Doenças , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/terapia , Valor Preditivo dos Testes , Estudos Prospectivos , Sepse/etiologia , Sepse/terapia , Síndrome
10.
Biochem Biophys Res Commun ; 577: 38-44, 2021 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-34507063

RESUMO

Sepsis is a life-threatening inflammatory syndrome secondary to infection. Thanks to the advances of antibiotics and life-supporting techniques, the mortality of sepsis has been decreasing in recent decades. Nevertheless, sepsis-associated encephalopathy (SAE) is still common in septic patients, which promotes the mortality of septic patients and results in cognitive dysfunction in survivors. Full understanding and effective medicine in the treatment of SAE is currently scant. Here, we revealed a novel role of cGAS signaling in the pathogenesis of SAE. Deficiency of cGas significantly restored cognitive impairment in sepsis mice model. The restoration may attribute to the recovery of neo-neuron decline that associated with the decrease of activated microglia and astrocytes in the hippocampus of cGas-deficient mice. In addition, type I interferon (IFN) signaling, a downstream of cGAS pathway, was boosted in the hippocampus of septic mice, which was dramatically attenuated by deleting cGas. Moreover, administration of recombinant IFNß markedly reversed the protection of ablation of cGas in the cognitive impairment in sepsis. Collectively, cGAS promotes the pathogenesis of SAE by up-regulating type I IFN signaling. Blocking cGAS may be a promising strategy for preventing encephalopathy in sepsis.


Assuntos
Modelos Animais de Doenças , Nucleotidiltransferases/genética , Encefalopatia Associada a Sepse/genética , Transdução de Sinais/genética , Animais , Animais Recém-Nascidos , Astrócitos/metabolismo , Disfunção Cognitiva/genética , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/fisiopatologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Humanos , Interferon Tipo I/metabolismo , Masculino , Aprendizagem em Labirinto/fisiologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microglia/metabolismo , Neurônios/metabolismo , Nucleotidiltransferases/deficiência , Substâncias Protetoras/metabolismo , Sepse/genética , Sepse/metabolismo , Sepse/fisiopatologia , Encefalopatia Associada a Sepse/metabolismo
11.
Nutrients ; 13(7)2021 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-34371879

RESUMO

Sepsis is an extremely complex clinical syndrome, usually involving an excessive inflammatory response including an overshooting cytokine release that damages tissue and organs of the patient. Due to the severity of this condition, it is estimated that over 11 million people die from sepsis each year. Despite intensive research in the field, there is still no specific therapy for sepsis. Many sepsis patients show a marked deficiency of vitamin C. 9 out of 10 sepsis patients have a hypovitaminosis C, and every third patient even shows a clinical deficiency in the scurvy range. In addition, low vitamin C levels of intensive care sepsis patients correlate with a higher need for vasopressors, higher Sequential Organ Failure Assessment (SOFA) scores, and increased mortality. Based on this observation and the conducted clinical trials using vitamin C as sepsis therapy in intensive care patients, the aim of the present ex vivo study was to evaluate the effects of high-dose vitamin C alone and in a triple combination supplemented with vitamin B1 (thiamine) and hydrocortisone on the lipopolysaccharide (LPS)-induced cytokine response in peripheral blood mononuclear cells (PBMCs) from healthy human donors. We found that all corticosteroid combinations strongly reduced the cytokine response on RNA- and protein levels, while high-dose vitamin C alone significantly diminished the PBMC mediated secretion of the cytokines interleukin (IL)-10, IL-23, and monocyte chemo-attractant protein (MCP-1), which mediate the inflammatory response. However, vitamin C showed no enhancing effect on the secretion of further cytokines studied. This data provides important insights into the possible immunomodulatory function of vitamin C in an ex vivo setting of human PBMCs and the modulation of their cytokine profile in the context of sepsis. Since vitamin C is a vital micronutrient, the restoration of physiologically adequate concentrations should be integrated into routine sepsis therapy, and the therapeutic effects of supraphysiological concentrations of vitamin C in sepsis patients should be further investigated in clinical trials.


Assuntos
Anti-Inflamatórios/farmacologia , Ácido Ascórbico/farmacologia , Hidrocortisona/farmacologia , Leucócitos Mononucleares/efeitos dos fármacos , Sepse/tratamento farmacológico , Tiamina/farmacologia , Adulto , Células Cultivadas , Citocinas/genética , Citocinas/metabolismo , Quimioterapia Combinada , Feminino , Regulação da Expressão Gênica , Humanos , Mediadores da Inflamação/metabolismo , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Sepse/metabolismo , Adulto Jovem
12.
Int J Mol Sci ; 22(16)2021 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-34445610

RESUMO

Sepsis is characterized by a dysregulated immune response to infections that causes life-threatening organ dysfunction and even death. When infections occur, bacterial cell wall components (endotoxin or lipopolysaccharide), known as pathogen-associated molecular patterns, bind to pattern recognition receptors, such as toll-like receptors, to initiate an inflammatory response for pathogen elimination. However, strong activation of the immune system leads to cellular dysfunction and ultimately organ failure. Damage-associated molecular patterns (DAMPs), which are released by injured host cells, are well-recognized triggers that result in the elevation of inflammatory cytokine levels. A cytokine storm is thus amplified and sustained in this vicious cycle. Interestingly, during sepsis, neutrophils transition from powerful antimicrobial protectors into dangerous mediators of tissue injury and organ dysfunction. Thus, the concept of blood purification has evolved to include inflammatory cells and mediators. In this review, we summarize recent advances in knowledge regarding the role of lipopolysaccharides, cytokines, DAMPs, and neutrophils in the pathogenesis of sepsis. Additionally, we discuss the potential of blood purification, especially the adsorption technology, for removing immune cells and molecular mediators, thereby serving as a therapeutic strategy against sepsis. Finally, we describe the concept of our immune-modulating blood purification system.


Assuntos
Alarminas/metabolismo , Síndrome da Liberação de Citocina/complicações , Padrões Moleculares Associados a Patógenos/metabolismo , Troca Plasmática/métodos , Sepse/patologia , Animais , Humanos , Imunidade Inata , Sepse/etiologia , Sepse/metabolismo , Sepse/terapia
13.
Am J Physiol Endocrinol Metab ; 321(3): E433-E442, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34370596

RESUMO

Sepsis is a dysregulated systemic response to infection and can lead to organ damage and death. Obesity is a significant problem worldwide and affects outcomes from sepsis. Our laboratory demonstrated that white adipose tissue (WAT) undergoes browning during sepsis, a process whereby WAT adopts a brown adipose tissue phenotype. However, this browning process was not observed in obese mice during sepsis. White adipose tissue browning is detrimental in patients with burn injury and cancer. We hypothesize that norepinephrine (NE) induces WAT browning in nonobese mice but not in obese mice similarly to sepsis-induced WAT browning. Six-week-old C57BL/6 male mice were randomized to a high-fat diet or normal diet. After 6-7 wk of feeding, polymicrobial sepsis was induced by cecal ligation and puncture (CLP). Norepinephrine was administered intraperitoneally via osmotic minipumps for 18 h or 72 h (no CLP) at which time tissue and plasma were harvested. Controls were mice that underwent CLP (no NE) with 18-h harvest. A separate group of mice underwent pretreatment with NE or vehicle infusion for 72 h, CLP was performed, and at 18 h had tissue and plasma harvested. Sepsis resulted in significant weight loss in both nonobese and obese mice. NE treatment alone caused weight loss in obese mice. Septic nonobese mice had higher uncoupling protein-1 (UCP1) expression compared with control and obese septic mice. NE treatment increased UCP1 expression in nonobese, but not obese mice. NE-treated obese septic mice had lower lung myeloperoxidase (MPO) activity, alanine aminotransferase (ALT), aspartate aminotransferase (AST), TNFα, and IL-6 levels compared with NE-treated nonobese septic mice. Obesity protects mice from septic-induced and NE-induced WAT browning.NEW & NOTEWORTHY White adipose tissue browning is detrimental in patients with burn injury and cancer. WAT browning occurs in nonobese mice and can be induced by ß receptor norepinephrine infusion, but obese mice are resistant to sepsis-induced and norepinephrine-induced WAT browning. We propose that the lack of WAT browning and unchanged inflammatory cytokine response may contribute to the protection of obese mice from sepsis.


Assuntos
Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Norepinefrina/administração & dosagem , Obesidade/metabolismo , Sepse/metabolismo , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Branco/diagnóstico por imagem , Animais , Dieta Hiperlipídica , Masculino , Camundongos Endogâmicos C57BL , Obesidade/complicações , Sepse/complicações
14.
Front Immunol ; 12: 685523, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34335587

RESUMO

Recent studies have shown that autophagy upregulation can attenuate sepsis-induced acute kidney injury (SAKI). The tumor suppressor p53 has emerged as an autophagy regulator in various forms of acute kidney injury (AKI). Our previous studies showed that p53 acetylation exacerbated hemorrhagic shock-induced AKI and lipopolysaccharide (LPS)-induced endothelial barrier dysfunction. However, the role of p53-regulated autophagy in SAKI has not been examined and requires clarification. In this study, we observed the dynamic changes of autophagy in renal tubular epithelial cells (RTECs) and verified the protective effects of autophagy activation on SAKI. We also examined the changes in the protein expression, intracellular distribution (nuclear and cytoplasmic), and acetylation/deacetylation levels of p53 during SAKI following cecal ligation and puncture (CLP) or LPS treatment in mice and in a LPS-challenged human RTEC cell line (HK-2 cells). After sepsis stimulation, the autophagy levels of RTECs increased temporarily, followed by a sharp decrease. Autophagy inhibition was accompanied by an increased renal tubular injury score. By contrast, autophagy agonists could reduce renal tubular damage following sepsis. Surprisingly, the expression of p53 protein in both the renal cortex and HK-2 cells did not significantly change following sepsis stimulation. However, the translocation of p53 from the nucleus to the cytoplasm increased, and the acetylation of p53 was enhanced. In the mechanistic study, we found that the induction of p53 deacetylation, due to either the resveratrol/quercetin -induced activation of the deacetylase Sirtuin 1 (Sirt1) or the mutation of the acetylated lysine site in p53, promoted RTEC autophagy and alleviated SAKI. In addition, we found that acetylated p53 was easier to bind with Beclin1 and accelerated its ubiquitination-mediated degradation. Our study underscores the importance of deacetylated p53-mediated RTEC autophagy in future SAKI treatments.


Assuntos
Injúria Renal Aguda/enzimologia , Autofagia/efeitos dos fármacos , Túbulos Renais/enzimologia , Sepse/complicações , Proteína Supressora de Tumor p53/metabolismo , Acetilação , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/patologia , Injúria Renal Aguda/prevenção & controle , Animais , Proteína Beclina-1/metabolismo , Linhagem Celular , Modelos Animais de Doenças , Humanos , Túbulos Renais/efeitos dos fármacos , Túbulos Renais/ultraestrutura , Lipopolissacarídeos/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Sepse/metabolismo , Sirtuína 1/genética , Sirtuína 1/metabolismo , Análise de Sobrevida , Proteína Supressora de Tumor p53/genética
15.
Oxid Med Cell Longev ; 2021: 2989974, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34457111

RESUMO

In the present study, we used lipopolysaccharide- (LPS-) stimulated H9C2 cardiomyocytes to investigate whether irisin treatment attenuates septic cardiomyopathy via Fundc1-related mitophagy. Fundc1 levels and mitophagy were significantly reduced in LPS-stimulated H9C2 cardiomyocytes but were significantly increased by irisin treatment. Irisin significantly increased ATP production and the activities of mitochondrial complexes I and III in the LPS-stimulated cardiomyocytes. Irisin also improved glucose metabolism and significantly reduced LPS-induced levels of reactive oxygen species by increasing the activities of antioxidant enzymes, glutathione peroxidase (GPX), and superoxide dismutase (SOD), as well as levels of reduced glutathione (GSH). TUNEL assays showed that irisin significantly reduced LPS-stimulated cardiomyocyte apoptosis by suppressing the activation of caspase-3 and caspase-9. However, the beneficial effects of irisin on oxidative stress, mitochondrial metabolism, and viability of LPS-stimulated H9C2 cardiomyocytes were abolished by silencing Fundc1. These results demonstrate that irisin abrogates mitochondrial dysfunction, oxidative stress, and apoptosis through Fundc1-related mitophagy in LPS-stimulated H9C2 cardiomyocytes. This suggests irisin is a potentially useful treatment for septic cardiomyopathy, though further investigations are necessary to confirm our findings.


Assuntos
Apoptose , Cardiomiopatias/patologia , Fibronectinas/metabolismo , Proteínas de Membrana/metabolismo , Mitocôndrias/patologia , Proteínas Mitocondriais/metabolismo , Miócitos Cardíacos/patologia , Estresse Oxidativo , Sepse/patologia , Animais , Cardiomiopatias/etiologia , Cardiomiopatias/metabolismo , Células Cultivadas , Fibronectinas/genética , Proteínas de Membrana/genética , Mitocôndrias/metabolismo , Proteínas Mitocondriais/genética , Mitofagia , Miócitos Cardíacos/metabolismo , Ratos , Sepse/etiologia , Sepse/metabolismo
16.
Mol Immunol ; 138: 99-109, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34365196

RESUMO

BACKGROUND: It has been reported that ROCK1 participates in the progression of multiple diseases, including septic intestinal barrier, cardiac dysfunction and acute lung injury. However, its regulatory role and specific mechanism in sepsis-induced acute kidney injury (AKI) remain unclear. METHODS: Cecal ligation puncture (CLP) was conducted to establish sepsis mouse model, and in vitro model was achieved by lipopolysaccharide (LPS) stimulation. Genes expression was evaluated by qRT-PCR, western blot or ELISA was conducted to assess the levels of proteins. Hoechst staining was performed to evaluate cell pyroptosis. LDH activity assay was detected to assess cytotoxicity. Immunohistochemistry was conducted to detect Ly-6G expression and neutrophils distribution in kidney tissues of mice. H&E and TUNEL staining were carried to evaluate kidney injury of mice. RESULTS: Our findings illuminated that ROCK1 was highly expressed in sepsis-induced AKI, and ROCK1 knockdown inhibited NLRP3-mediated cell pyroptosis in LPS-induced HK-2 cells. Moreover, ROCK1 modulated HK-2 cell pyroptosis by regulating endoplasmic reticulum stress (ERS). TLR2 inhibitor could suppress ERS mediated cell pyroptosis under LPS treatment. Further, TLR2 activator partially reversed the effects of ROCK1 inhibition on ERS mediated pyroptosis in LPS-treated HK-2 cells and CLP mice. CONCLUSION: In conclusion, ROCK1 may regulate sepsis-induced AKI via TLR2-mediated ERS/pyroptosis axis. Our data demonstrated the role and underlying mechanism of ROCK1 in septic AKI, providing theoretical basis for sepsis-induced AKI treatment.


Assuntos
Injúria Renal Aguda/metabolismo , Estresse do Retículo Endoplasmático/imunologia , Piroptose/imunologia , Receptor 2 Toll-Like/metabolismo , Quinases Associadas a rho/metabolismo , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/imunologia , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Sepse/complicações , Sepse/imunologia , Sepse/metabolismo
17.
Biomed Pharmacother ; 138: 111524, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34311527

RESUMO

BACKGROUND: Sepsis-associated cardiac dysfunction results in increased mortality. Hyperoside (Hyp) is a flavonoid, showing significant anti-inflammatory effects. However, its pharmacological effects on sepsis-induced cardiac dysfunction remain unknown. In this study, we attempted to explore whether Hyp could prevent cardiac dysfunction and its underlying mechanisms. METHODS: We established a mice mode of sepsis by cecal ligation and puncture (CLP) treatment, and constructed a cell model of myocardial injury by lipopolysaccharide (LPS) stimulation. The cardiac function indicators and the inflammatory cytokine levels were measured. Effect of Hyp on cardiomyocyte viability was evaluated using MTT assay. The expression and functional role of microRNA-21 (miR-21), a documented molecule that regulated by Hyp, was evaluated in the constructed models, and the potential targets of miR-21 were predicted. RESULTS: Hyp alleviated the impaired cardiac function and stimulated inflammation caused by CLP in the in vivo sepsis model, and alleviated the LPS-induced decrease in cell viability and increase in inflammation of cardiomyocytes. Additionally, Hyp significantly inhibited the expression of miR-21 in LPS-induced cardiomyocytes, and the increased cell viability and decreased inflammation caused by Hyp in the in vitro model could be reversed by miR-21 overexpression. In animal model of sepsis, the protective influence of Hyp against sepsis-induced cardiac dysfunction was attenuated by miR-21 upregulation. CONCLUSION: Our findings demonstrated that Hyp may serve as a promising natural drug for the treatment of sepsis-associated cardiac dysfunction, and its protective role may exerted through regulating cardiomyocyte viability and inflammation by suppressing miR-21.


Assuntos
Anti-Inflamatórios/farmacologia , Cardiopatias/prevenção & controle , MicroRNAs/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Quercetina/análogos & derivados , Sepse/tratamento farmacológico , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Modelos Animais de Doenças , Regulação para Baixo , Cardiopatias/metabolismo , Cardiopatias/patologia , Cardiopatias/fisiopatologia , Humanos , Mediadores da Inflamação/metabolismo , Masculino , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Quercetina/farmacologia , Sepse/metabolismo , Sepse/patologia , Sepse/fisiopatologia , Transdução de Sinais
18.
Life Sci ; 282: 119807, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34245771

RESUMO

AIM: This study was designed to investigate the changes of liver injury and Nrf2 signaling pathway in the process of sepsis. We also aimed to examine the role of Nrf2 in resisting oxidative stress and relieving inflammation in sepsis-induced hepatic injury. MAIN METHODS: By operating cecal ligation and puncture (CLP) on Nrf2-/- mice and wild type mice, a sepsis-induced hepatic injury model was established. We compared and contrasted the wild type mice with the Nrf2-/- mice during sepsis-induced hepatic injury, and evaluated the liver damage by biochemical analyses and staining hematoxylin-eosin (HE). Western blot or real-time PCR was performed to detect Nrf2 and its regulated genes NQO-1, GCLM and HO-1. Additionally, we detected the expressions and secretion of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), Interleukin-6 (IL-6), IL-1ß and anti-inflammatory cytokines IL-10. We assessed the oxidative stress through the levels of MDA and NO. KEY FINDINGS: The results showed that Nrf2 expressions at mRNA and protein levels were increased 1 day after CLP, namely the early stage of sepsis. Compared with wild type mice after CLP, Nrf2-/- mice showed more severe liver injury, accompanied by higher expression of inflammatory cytokines and oxidative stress. Notably, Nrf2-regulated genes GCLM and NQO-1, were strongly downregulated in Nrf2-/- mice. SIGNIFICANCE: Nrf2 was probably implicated in decreasing inflammatory cytokine levels and counteracting oxidative stress to alleviate sepsis-induced hepatic injury, mainly through regulating GCLM and NQO-1 in the early stage after CLP.


Assuntos
Regulação da Expressão Gênica , Hepatopatias/prevenção & controle , Fígado , Fator 2 Relacionado a NF-E2/biossíntese , Estresse Oxidativo , Sepse/metabolismo , Animais , Fígado/lesões , Fígado/metabolismo , Hepatopatias/etiologia , Hepatopatias/genética , Hepatopatias/metabolismo , Camundongos , Camundongos Knockout , Fator 2 Relacionado a NF-E2/genética , Sepse/complicações , Sepse/genética
19.
Int J Mol Sci ; 22(14)2021 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-34299338

RESUMO

Obesity manifests itself with low-grade chronic inflammation that shapes immune responses during infection. Albeit obese individuals are at risk of higher mortality due to comorbidities, they are better protected from systemic inflammation. Recently, we showed that in the vasculature of obese mice kept on high-fat diet (HFD), neutrophils produce less neutrophil extracellular traps (NETs) than in lean controls (normal diet, ND). NETs are used by neutrophils to counteract severe infection, but they also cause collateral damage. Hardly anything is known about metabolic requirements for their formation, especially in the context of obesity and/or sepsis. Thus, we aimed to study the immunometabolism of NET formation by application of ex vivo neutrophil analyses (Seahorse analyzer, selective inhibitors, confocal imaging) and intravital microscopy. The obtained data show that glycolysis and/or pentose phosphate pathway are involved in NETs release by ND neutrophils in both physiological and inflammatory conditions. In contrast, such cells of septic HFD mice utilize these routes only to spontaneously cast NETs, while after secondary ex vivo activation they exhibit so called "exhausted phenotype", which manifests itself in diminished NET release despite high glycolytic potential and flexibility to oxidize fatty acids. Moreover, impact of ATP synthase inhibition on NET formation is revealed. Overall, the study shows that the neutrophil potential to cast NETs depends on both the metabolic and inflammatory state of the individual.


Assuntos
Armadilhas Extracelulares/metabolismo , Obesidade/metabolismo , Animais , Dieta Hiperlipídica , Armadilhas Extracelulares/imunologia , Glicólise , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/patologia , Lipopolissacarídeos/farmacologia , Masculino , Redes e Vias Metabólicas , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/imunologia , Neutrófilos/metabolismo , Obesidade/imunologia , Obesidade/patologia , Via de Pentose Fosfato , Sepse/metabolismo
20.
Front Immunol ; 12: 659193, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34326834

RESUMO

Sepsis is a heterogeneous syndrome induced by infection and results in high mortality. Even though more than 100 biomarkers for sepsis prognosis were evaluated, prediction of patient outcomes in sepsis continues to be driven by clinical signs because of unsatisfactory specificity and sensitivity of these biomarkers. This study aimed to elucidate the key candidate genes involved in sepsis response and explore their downstream effects based on weighted gene co-expression network analysis (WGCNA). The dataset GSE63042 with sepsis outcome information was obtained from the Gene Expression Omnibus (GEO) database and then consensus WGCNA was conducted. We identified the hub gene SDF4 (stromal cell derived factor 4) from the M6 module, which was significantly associated with mortality. Subsequently, two datasets (GSE54514 and E-MTAB-4421) and cohort validation (n=89) were performed. Logistic regression analysis was used to build a prediction model and the combined score resulting in a satisfactory prognosis value (area under the ROC curve=0.908). The model was subsequently tested by another sepsis cohort (n=70, ROC= 0.925). We next demonstrated that endoplasmic reticulum (ER) stress tended to be more severe in patients PBMCs with negative outcomes compared to those with positive outcomes and SDF4 was related to this phenomenon. In addition, our results indicated that adenovirus-mediated Sdf4 overexpression attenuated ER stress in cecal ligation and puncture (CLP) mice lung. In summary, our study indicates that incorporation of SDF4 can improve clinical parameters predictive value for the prognosis of sepsis, and decreased expression levels of SDF4 contributes to excessive ER stress, which is associated with worsened outcomes, whereas overexpression of SDF4 attenuated such activation.


Assuntos
Biomarcadores , Proteínas de Ligação ao Cálcio/metabolismo , Estresse do Retículo Endoplasmático , Glicoproteínas/metabolismo , Sepse/metabolismo , Sepse/mortalidade , Proteínas de Ligação ao Cálcio/sangue , Proteínas de Ligação ao Cálcio/genética , Biologia Computacional , Bases de Dados Genéticas , Suscetibilidade a Doenças , Imunofluorescência , Perfilação da Expressão Gênica , Glicoproteínas/sangue , Glicoproteínas/genética , Humanos , Imuno-Histoquímica , Prognóstico , Curva ROC , Sepse/diagnóstico , Sepse/etiologia , Transcriptoma
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...