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1.
Sci Rep ; 11(1): 10793, 2021 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-34031464

RESUMO

Finding novel biomarkers for human pathologies and predicting clinical outcomes for patients is challenging. This stems from the heterogeneous response of individuals to disease and is reflected in the inter-individual variability of gene expression responses that obscures differential gene expression analysis. Here, we developed an alternative approach that could be applied to dissect the disease-associated molecular changes. We define gene ensemble noise as a measure that represents a variance for a collection of genes encoding for either members of known biological pathways or subunits of annotated protein complexes and calculated within an individual. The gene ensemble noise allows for the holistic identification and interpretation of gene expression disbalance on the level of gene networks and systems. By comparing gene expression data from COVID-19, H1N1, and sepsis patients we identified common disturbances in a number of pathways and protein complexes relevant to the sepsis pathology. Among others, these include the mitochondrial respiratory chain complex I and peroxisomes. This suggests a Warburg effect and oxidative stress as common hallmarks of the immune host-pathogen response. Finally, we showed that gene ensemble noise could successfully be applied for the prediction of clinical outcome namely, the mortality of patients. Thus, we conclude that gene ensemble noise represents a promising approach for the investigation of molecular mechanisms of pathology through a prism of alterations in the coherent expression of gene circuits.


Assuntos
/patologia , Expressão Gênica , Influenza Humana/patologia , Sepse/patologia , Área Sob a Curva , /virologia , Complexo I de Transporte de Elétrons/genética , Complexo I de Transporte de Elétrons/metabolismo , Redes Reguladoras de Genes/genética , Humanos , Vírus da Influenza A Subtipo H1N1/genética , Vírus da Influenza A Subtipo H1N1/isolamento & purificação , Influenza Humana/complicações , Influenza Humana/virologia , Estresse Oxidativo/genética , Peroxissomos/genética , Peroxissomos/metabolismo , Modelos de Riscos Proporcionais , Curva ROC , /isolamento & purificação , Sepse/complicações , Sepse/genética , Sepse/mortalidade , Índice de Gravidade de Doença , Taxa de Sobrevida , Interface Usuário-Computador
2.
Int J Mol Sci ; 22(6)2021 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-33809795

RESUMO

We previously showed that ubiquitous overexpression of the chromatin remodeling factor SWItch3-related gene (SRG3) promotes M2 macrophage differentiation, resulting in anti-inflammatory responses in the experimental autoimmune encephalomyelitis model of multiple sclerosis. Since hepatic macrophages are responsible for sepsis-induced liver injury, we investigated herein the capacity of transgenic SRG3 overexpression (SRG3ß-actin mice) to modulate sepsis in mice exposed to lipopolysaccharide (LPS) plus d-galactosamine (d-GalN). Our results demonstrated that ubiquitous SRG3 overexpression significantly protects mice from LPS/d-GalN-induced lethality mediated by hepatic M1 macrophages. These protective effects of SRG3 overexpression correlated with the phenotypic conversion of hepatic macrophages from an M1 toward an M2 phenotype. Furthermore, SRG3ß-actin mice had decreased numbers and activation of natural killer (NK) cells but not natural killer T (NKT) cells in the liver during sepsis, indicating that SRG3 overexpression might contribute to cross-talk between NK cells and macrophages in the liver. Finally, we demonstrated that NKT cell-deficient CD1d KO/SRG3ß-actin mice are protected from LPS/d-GalN-induced sepsis, indicating that NKT cells are dispensable for SRG3-mediated sepsis suppression. Taken together, our findings provide strong evidence that SRG3 overexpression may serve as a therapeutic approach to control overwhelming inflammatory diseases such as sepsis.


Assuntos
Cromatina/metabolismo , Interferon gama/biossíntese , Interleucina-10/biossíntese , Fígado/patologia , Macrófagos/metabolismo , Células T Matadoras Naturais/metabolismo , Sepse/induzido quimicamente , Sepse/prevenção & controle , Fatores de Transcrição/metabolismo , Actinas/genética , Animais , Montagem e Desmontagem da Cromatina , Células Dendríticas/metabolismo , Galactosamina , Mediadores da Inflamação/metabolismo , Lipopolissacarídeos , Ativação Linfocitária/imunologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Regiões Promotoras Genéticas/genética , Substâncias Protetoras/metabolismo , Sepse/imunologia , Sepse/patologia , Índice de Gravidade de Doença
3.
J Leukoc Biol ; 109(5): 943-952, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33899953

RESUMO

Gut-associated sepsis is a major problem in patients undergoing abdominal radiation therapy; the majority of pathogens causing this type of sepsis are translocated from the gut microbiota. While treating sepsis, bacterial clearance must be achieved to ensure patient survival, and the hepatic immune response is responsible for this process. In particular, Kupffer cells play a crucial role in the hepatic immune response against infectious agents. Recently, two populations of Kupffer cells have been described: liver-resident macrophages (Mϕ) (F4/80+ CD11b- CD68+ cells) and hepatic Mϕ derived from circulating monocytes (F4/80+ CD11b+ CD68- cells). We examined the properties of both types of hepatic Mϕ obtained from irradiated and normal mice and their role in sepsis. Hepatic F4/80+ CD11b- CD68+ cells from both normal and irradiated mice did not show any antibacterial activity. However, F4/80+ CD11b+ CD68- cells from normal mice behaved as effector cells against sepsis by Enterococcus faecalis, although those from irradiated mice lost this ability. Moreover, hepatic F4/80+ CD11b+ CD68- cells from normal infected mice were shown to be IL-12+ IL-10- CD206- CCL1- (considered M1Mϕ), and hepatic F4/80+ CD11b- CD68+ cells from the same mice were shown to be IL-12- IL-10+ CD206+ CCL1- (considered M2aMϕ). When normal mice were exposed to radiation, hepatic F4/80+ CD11b+ CD68- cells altered their phenotype to IL-12- IL-10+ CD206- CCL1+ (considered M2bMϕ), independent of infection, but hepatic F4/80+ CD11b- CD68+ cells remained IL-12- IL-10+ CD206+ CCL1- (M2aMϕ). In addition, hepatic F4/80+ CD11b+ CD68- cells from irradiated mice acquired antibacterial activity upon treatment with CCL1 antisense oligodeoxynucleotides. Therefore, the characteristics of hepatic F4/80+ CD11b+ CD68- cells play a key role in the antibacterial response against gut-associated sepsis.


Assuntos
Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Antígeno CD11b/metabolismo , Enterococcus faecalis/fisiologia , Fígado/metabolismo , Sepse/imunologia , Sepse/microbiologia , Irradiação Corporal Total , Animais , Polaridade Celular/efeitos dos fármacos , Citocinas/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Fígado/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Oligonucleotídeos Antissenso/farmacologia , Sepse/patologia
4.
Life Sci ; 276: 119413, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33794256

RESUMO

Sepsis is a fatal organ dysfunction resulting from a disordered host response to infection. Endothelial cells (ECs) are usually the primary targets of inflammatory mediators in sepsis; damage to ECs plays a pivotal part in vital organ failure. In recent studies, autophagy was suggested to play a critical role in the ECs injury although the mechanisms by which ECs are injured in sepsis are not well elucidated. Autophagy is a highly conserved catabolic process that includes sequestrating plasma contents and transporting cargo to lysosomes for recycling the vital substrates required for metabolism. This pathway also counteracts microbial invasion to balance and retain homeostasis, especially during sepsis. Increasing evidence indicates that autophagy is closely associated with endothelial function. The role of autophagy in sepsis may or may not be favorable depending upon conditions. In the present review, the current knowledge of autophagy in the process of sepsis and its influence on ECs was evaluated. In addition, the potential of targeting EC autophagy for clinical treatment of sepsis was discussed.


Assuntos
Autofagia , Células Endoteliais/patologia , Sepse/patologia , Animais , Humanos
5.
BMC Infect Dis ; 21(1): 315, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33794801

RESUMO

BACKGROUND: The primary objective of our study was to examine predictors for readmission in a prospective cohort of sepsis patients admitted to an emergency department (ED) and identified by the new Sepsis-3 criteria. METHOD: A single-center observational population-based cohort study among all adult (≥18 years) patients with sepsis admitted to the emergency department of Slagelse Hospital during 1.10.2017-31.03.2018. Sepsis was defined as an increase in the sequential organ failure assessment (SOFA) score of ≥2. The primary outcome was 90-day readmission. We followed patients from the date of discharge from the index admission until the end of the follow-up period or until the time of readmission to hospital, emigration or death, whichever came first. We used competing-risks regression to estimate adjusted subhazard ratios (aSHRs) with 95% confidence intervals (CI) for covariates in the regression models. RESULTS: A total of 2110 patients were admitted with infections, whereas 714 (33.8%) suffered sepsis. A total of 52 patients had died during admission and were excluded leaving 662 patients (44.1% female) with a median age of 74.8 (interquartile range: 66.0-84.2) years for further analysis. A total of 237 (35,8%; 95% CI 32.1-39.6) patients were readmitted within 90 days, and 54(8.2%) had died after discharge without being readmitted. We found that a history of malignant disease (aSHR 1,61; 1.16-2.23), if previously admitted with sepsis within 1 year before the index admission (aSHR; 1.41; 1.08-1.84), and treatment with diuretics (aSHR 1.51; 1.17-1.94) were independent predictors for readmission. aSHR (1.49, 1.13-1.96) for diuretic treatment was almost unchanged after exclusion of patients with heart failure, while aSHR (1.47, 0.96-2.25) for malignant disease was slightly attenuated after exclusion of patients with metastatic tumors. CONCLUSIONS: More than one third of patients admitted with sepsis, and discharged alive, were readmitted within 90 days. A history of malignant disease, if previously admitted with sepsis, and diuretic treatment were independent predictors for 90-day readmission.


Assuntos
Readmissão do Paciente/estatística & dados numéricos , Sepse/patologia , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Estudos de Coortes , Diuréticos/uso terapêutico , Serviço Hospitalar de Emergência , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/patologia , Escores de Disfunção Orgânica , Estudos Prospectivos , Fatores de Risco , Fatores de Tempo
6.
Oxid Med Cell Longev ; 2021: 6667074, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33927797

RESUMO

Sepsis-induced myocardial dysfunction considerably increases mortality risk in patients with sepsis. Previous studies from our group have shown that sepsis alters the expression of structural proteins in cardiac cells, resulting in cardiomyocyte degeneration and impaired communication between cardiac cells. Caveolin-3 (CAV3) is a structural protein present in caveolae, located in the membrane of cardiac muscle cells, which regulates physiological processes such as calcium homeostasis. In sepsis, there is a disruption of calcium homeostasis, which increases the concentration of intracellular calcium, which can lead to the activation of potent cellular enzymes/proteases which cause severe cellular injury and death. The purpose of the present study was to test the hypotheses that sepsis induces CAV3 overexpression in the heart, and the regulation of L-type calcium channels directly relates to the regulation of CAV3 expression. Severe sepsis increases the expression of CAV3 in the heart, as immunostaining in our study showed CAV3 presence in the cardiomyocyte membrane and cytoplasm, in comparison with our control groups (without sepsis) that showed CAV3 presence predominantly in the plasma membrane. The administration of verapamil, an L-type calcium channel inhibitor, resulted in a decrease in mortality rates of septic mice. This effect was accompanied by a reduction in the expression of CAV3 and attenuation of cardiac lesions in septic mice treated with verapamil. Our results indicate that CAV3 has a vital role in cardiac dysfunction development in sepsis and that the regulation of L-type calcium channels may be related to its expression.


Assuntos
Caveolina 3/metabolismo , Coração/efeitos dos fármacos , Sepse/tratamento farmacológico , Verapamil/uso terapêutico , Animais , Canais de Cálcio Tipo L , Humanos , Masculino , Camundongos , Sepse/mortalidade , Sepse/patologia , Análise de Sobrevida , Verapamil/farmacologia
7.
Med Sci Monit ; 27: e929512, 2021 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-33866323

RESUMO

BACKGROUND Sepsis is a serious clinical problem that results from the systemic response of the body to infection. Left ventricular (LV) diastolic dysfunction is increasingly appreciated as a contributor to morbidity and mortality in sepsis. Animal models may offer a method of studying diastolic dysfunction while controlling for many potential clinical confounders, such as sepsis duration, premorbid condition, and therapeutic interventions. This study sought to evaluate an endotoxemia (LPS) rodent model of sepsis, with regard to echocardiographic evidence, including tissue Doppler, of LV diastolic dysfunction and histopathology findings. MATERIAL AND METHODS Fourteen male Sprague-Dawley rats were randomly allocated (1: 1) to LPS or saline (control). Mean arterial blood pressure (MAP) was measured through cannulation of the carotid artery. After a 30-min stabilization, baseline assessment with echocardiography and blood collection was performed. Rats were administered 0.9% saline or LPS (10 mg/mL). Follow-up echocardiography and blood collection were performed after 2 h. Hearts were removed post-mortem and pathology studied using histology and immunohistochemistry. RESULTS LPS was associated with hypotension (MAP 81.86±31.67 mmHg; 124.29±20.16; p=0.02) and LV impaired relaxation (myocardial early diastolic velocity [e'] 0.06±0.02 m/s; 0.09±0.02; P=0.008). Histopathology and immunohistochemistry demonstrated evidence of interstitial myocarditis (hydropic changes and inflammation). CONCLUSIONS LPS was associated with both diastolic dysfunction (impaired relaxation) and interstitial myocarditis. These features may offer a link between the structural and functional changes that have previously been described separately in clinical sepsis. This may facilitate further studies focused upon the mechanism and potential benefit treatment of sepsis-associated cardiac dysfunction.


Assuntos
Ventrículos do Coração/metabolismo , Miocardite/metabolismo , Miocárdio/metabolismo , Sepse/metabolismo , Disfunção Ventricular Esquerda/metabolismo , Animais , Diástole , Modelos Animais de Doenças , Ecocardiografia Doppler , Ventrículos do Coração/patologia , Humanos , Imuno-Histoquímica , Masculino , Miocardite/patologia , Ratos , Ratos Sprague-Dawley , Sepse/patologia , Disfunção Ventricular Esquerda/patologia
8.
Proc Natl Acad Sci U S A ; 118(10)2021 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-33658363

RESUMO

Blood pH is tightly maintained between 7.35 and 7.45, and acidosis (pH <7.3) indicates poor prognosis in sepsis, wherein lactic acid from anoxic tissues overwhelms the buffering capacity of blood. Poor sepsis prognosis is also associated with low zinc levels and the release of High mobility group box 1 (HMGB1) from activated and/or necrotic cells. HMGB1 added to whole blood at physiological pH did not bind leukocyte receptors, but lowering pH with lactic acid to mimic sepsis conditions allowed binding, implying the presence of natural inhibitor(s) preventing binding at normal pH. Testing micromolar concentrations of divalent cations showed that zinc supported the robust binding of sialylated glycoproteins with HMGB1. Further characterizing HMGB1 as a sialic acid-binding lectin, we found that optimal binding takes place at normal blood pH and is markedly reduced when pH is adjusted with lactic acid to levels found in sepsis. Glycan array studies confirmed the binding of HMGB1 to sialylated glycan sequences typically found on plasma glycoproteins, with binding again being dependent on zinc and normal blood pH. Thus, HMGB1-mediated hyperactivation of innate immunity in sepsis requires acidosis, and micromolar zinc concentrations are protective. We suggest that the potent inflammatory effects of HMGB1 are kept in check via sequestration by plasma sialoglycoproteins at physiological pH and triggered when pH and zinc levels fall in late stages of sepsis. Current clinical trials independently studying zinc supplementation, HMGB1 inhibition, or pH normalization may be more successful if these approaches are combined and perhaps supplemented by infusions of heavily sialylated molecules.


Assuntos
Acidose/sangue , Proteína HMGB1/sangue , Sepse/sangue , Sialoglicoproteínas/sangue , Zinco/sangue , Acidose/imunologia , Acidose/metabolismo , Acidose/patologia , Proteínas de Transporte , Proteína HMGB1/farmacologia , Humanos , Concentração de Íons de Hidrogênio , Imunidade Inata , Lipopolissacarídeos/farmacologia , Polissacarídeos/química , Sepse/imunologia , Sepse/patologia , Ácidos Siálicos/química , Sialoglicoproteínas/química , Zinco/metabolismo
9.
Int Immunopharmacol ; 95: 107529, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33744777

RESUMO

Sepsis is a systemic inflammatory response syndrome resulted from severe infection. Excessive inflammation response plays an important role in sepsis-induced acute lung injury (ALI). Loganin is an iridoid glycoside isolated from Corni fructus and exerts an anti-inflammatory effect in multiple inflammatory diseases; however, the role of loganin in sepsis-induced ALI remains unknown. In the current study, the cecal ligation and puncture (CLP)-induced murine sepsis model was constructed to investigate the anti-inflammatory property of loganin in sepsis-induced ALI. Lipopolysaccharide (LPS)-treated Raw 264.7 cells and primary murine peritoneal macrophages were established to further explore underlying mechanism of loganin. Results showed that intragastrical administration of loganin significantly increased murine survival, reduced the alveolar structure damage and inflammatory cell infiltration. Loganin suppressed the release of the M1 macrophage-associated pro-inflammatory cytokines and induced the activation of M2-type anti-inflammatory cytokines. Besides, loganin dramatically inhibited NLRP3 inflammasome-mediated caspase-1 activation and subsequent IL-1ß secretion. Further in vitro studies confirmed that loganin efficiently inhibited M1 macrophage polarization and NLRP3 inflammasome activation by blocking the extra-cellular signal-regulated kinase (ERK) and nuclear factor-kappa B (NF-κB) pathways. Taken together, the anti-inflammatory effect of loganin in sepsis-induced ALI was associated with the ERK and NF-κB pathway-mediated macrophage polarization and NLRP3 inflammasome activation. Our study offers a favorable mechanistic basis to support the therapeutic potential of loganin in anti-inflammatory diseases, such as sepsis-induced ALI.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Anti-Inflamatórios/uso terapêutico , Inflamassomos/antagonistas & inibidores , Iridoides/uso terapêutico , Macrófagos/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Sepse/tratamento farmacológico , Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/imunologia , Lesão Pulmonar Aguda/patologia , Animais , Anti-Inflamatórios/farmacologia , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Caspase 1/imunologia , Inflamassomos/imunologia , Interleucina-1beta/imunologia , Iridoides/farmacologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Células RAW 264.7 , Sepse/complicações , Sepse/imunologia , Sepse/patologia
10.
Life Sci ; 276: 119434, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33785343

RESUMO

AIMS: Immunosuppressive myeloid-derived suppressor cells (MDSCs) continuously expand and lead to poor outcome during sepsis. The activation of liver X receptor (LXR) can mitigate sepsis-induced liver and myocardial damage. This study aims to determine whether LXR plays a protective role in sepsis by regulating MDSCs. MAIN METHODS: Cecal ligation and puncture(CLP)was used to induce sepsis in mice. The mice were then treated with LXR agonist GW3965 (3 mg/kg) or vehicle 1 h, 6 h, 12 h, 24 h, 48 h, 72 h postoperatively. The effect of LXR on the survival rate and multi-organ injury induced by sepsis was evaluated by survival analysis, histological staining, biochemical analysis and ELISAs. The percentages of MDSCs and T cells were detected using flow cytometry. The mRNA expressions of LXR and ATP-binding cassette transporter A1 (ABCA1) were measured using real-time quantitative PCR (RT-qPCR). ABCA1 protein level was determined using immunofluorescence staining. KEY FINDINGS: LXR agonist GW3965 treatment improved the survival of septic mice, accompanied by reduced multi-organ injury and a decreased level of inflammatory cytokines. Furthermore, GW3965 treatment decreased MDSCs abundance in spleen by boosting the apoptosis of spleen MDSCs, therefore ameliorating their immunosuppressive activity. Meanwhile, bacteria clearance in tissues was enhanced after the GW3965 administration in septic mice. Mechanistically, GW3965 activated LXRß and its downstream target ABCA1 to initiate the apoptosis of spleen MDSCs. SIGNIFICANCE: These findings provide new insights into the relationship between LXR and MDSCs in sepsis, thus revealing a potentially effective approach to target the immunosuppression of sepsis.


Assuntos
Apoptose , Benzoatos/farmacologia , Benzilaminas/farmacologia , Receptores X do Fígado/agonistas , Células Supressoras Mieloides/patologia , Substâncias Protetoras/farmacologia , Sepse/tratamento farmacológico , Transportador 1 de Cassete de Ligação de ATP/genética , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Animais , Citocinas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Sepse/metabolismo , Sepse/patologia
11.
J Vis Exp ; (168)2021 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-33682855

RESUMO

Sepsis and septic shock remain the leading cause of death in intensive care units. Despite significant improvements in sepsis management, mortality still ranges between 20 and 30%. Novel treatment approaches in order to reduce sepsis-related multiorgan failure and death are urgently needed. Robust animal models allow for one or multiple treatment approaches as well as for testing their effect on physiological and molecular parameters. In this article, a simple animal model is presented. First, general anesthesia is induced in animals either with the use of volatile or by intraperitoneal anesthesia. After placement of an intravenous catheter (tail vein), tracheostomy, and insertion of an intraarterial catheter (tail artery), mechanical ventilation is started. Baseline values of mean arterial blood pressure, arterial blood oxygen saturation, and heart rate are recorded. The injection of lipopolysaccharides (1 milligram/kilogram body weight) dissolved in phosphate-buffered saline induces a strong and reproducible inflammatory response via the toll-like receptor 4. Fluid corrections as well as the application of norepinephrine are performed based on well-established protocols. The animal model presented in this article is easy to learn and strongly oriented towards clinical sepsis treatment in an intensive care unit with sedation, mechanical ventilation, continuous blood pressure monitoring, and repetitive blood sampling. Also, the model is reliable, allowing for reproducible data with a limited number of animals in accordance with the 3R (reduce, replace, refine) principles of animal research. While animal experiments in sepsis research cannot easily replaced, repetitive measurements allow for a reduction of animals and keeping septic animals anesthetized diminishes suffering.


Assuntos
Endotoxinas/toxicidade , Unidades de Terapia Intensiva , Anestesia , Animais , Artérias/fisiologia , Modelos Animais de Doenças , Masculino , Monitorização Fisiológica , Ratos Wistar , Reprodutibilidade dos Testes , Sepse/patologia , Traqueostomia , Veias/fisiologia
12.
Mol Med Rep ; 23(5)2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33760211

RESUMO

Sepsis­induced cardiorenal syndrome is one of the multiple organ dysfunctions observed in sepsis. It is determined by a primary dysfunction in one organ that leads to secondary injury to another organ. Studies have shown the involvement of microRNAs (miRs) in the diagnosis and prognosis of several pathologies. However, the implication of miR­126 in the podocyte damage associated with sepsis has not been evaluated until now. In the current study, the miR­126 expression was downregulated in a podocyte injury model together with downregulation of nephrin expression. The transfection of podocytes from podocyte injury group with miR­126 mimics demonstrated an increase in cell proliferation and a decrease in cell apoptosis. Bioinformatics analysis predicted that the target of miR­126 was epidermal growth factor­like domain multiple 6 (EGFL6) and dyskeratosis congenita 1 (DKC1) and these were confirmed by dual­luciferase reporter assay. miR­126 upregulation determined EGFL6 and DKC1 upregulation and prevented podocyte injury. The current study demonstrated that overexpression of miR­126 could protect podocytes from sepsis­induced injury through an EGFL6/DKC1 signaling pathway.


Assuntos
Proteínas de Ligação ao Cálcio/genética , Moléculas de Adesão Celular/genética , Proteínas de Ciclo Celular/genética , MicroRNAs/genética , Proteínas Nucleares/genética , Sepse/genética , Apoptose/genética , Linhagem Celular , Proliferação de Células/genética , Regulação da Expressão Gênica/genética , Humanos , Podócitos/metabolismo , Podócitos/patologia , Sepse/patologia , Transdução de Sinais/genética
13.
Int J Mol Sci ; 22(5)2021 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-33673691

RESUMO

(1) Background. Repetitive animal studies that have disappointed upon translation into clinical therapies have led to an increased appreciation of humanized mice as a remedy to the shortcomings of rodent-based models. However, their limitations have to be understood in depth. (2) Methods. This is a narrative, comprehensive review of humanized mice and sepsis literature to understand the model's benefits and shortcomings. (3) Results: Studies involving humanized models of sepsis include bacterial, viral, and protozoan etiology. Humanized mice provided several unique insights into the etiology and natural history of sepsis and are particularly useful in studying Ebola, and certain viral and protozoan infections. However, studies are relatively sparse and based on several different models of sepsis and humanized animals. (4) Conclusions. The utilization of humanized mice as a model for sepsis presents complex limitations that, once surpassed, hold some potential for the advancement of sepsis etiology and treatment.


Assuntos
Modelos Animais de Doenças , Sepse/etiologia , Sepse/terapia , Animais , Humanos , Camundongos , Sepse/patologia
14.
Mol Med Rep ; 23(5)2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33760172

RESUMO

Sepsis is a life­threatening organ dysfunction caused by a dysregulated host response to infection, and is a leading cause of mortality worldwide. Myocardial dysfunction is associated with poor prognosis in patients with sepsis and contributes to a high risk of mortality. However, the pathophysiological mechanisms underlying sepsis­induced myocardial dysfunction are not completely understood. The aim of the present study was to investigate the role of toll­like receptor 4 (TLR4)/c­Jun N­terminal kinase (JNK) signaling in pro­inflammatory cytokine expression and cardiac dysfunction during lipopolysaccharide (LPS)­induced sepsis in mice. C57BL/6 mice were pretreated with TAK­242 or saline for 1 h and then subjected to LPS (12 mg/kg, intraperitoneal) treatment. Cardiac function was assessed using an echocardiogram. The morphological changes of the myocardium were examined by hematoxylin and eosin staining and transmission electron microscopy. The serum protein levels of cardiac troponin I (cTnI) and tumor necrosis factor­α (TNF­α) were determined by an enzyme­linked immunosorbent assay (ELISA). The TLR4 and JNK mRNA levels were analyzed via reverse transcription­quantitative PCR. TLR4, JNK and phosphorylated­JNK protein levels were measured by western blotting. In response to LPS, the activation of TLR4 and JNK in the myocardium was upregulated. There were significant increases in the serum levels of TNF­α and cTnI, as well as histopathological changes in the myocardium and suppressed cardiac function, following LPS stimulation. Inhibition of TLR4 activation using TAK­242 led to a decrease in the activation of JNK and reduced the protein expression of TNF­α in plasma, and alleviated histological myocardial injury and improved cardiac function during sepsis in mice. The present data suggested that the TLR4/JNK signaling pathway played a critical role in regulating the production of pro­inflammatory cytokines and myocardial dysfunction induced by LPS.


Assuntos
Insuficiência Cardíaca/genética , Sistema de Sinalização das MAP Quinases/genética , Sepse/genética , Receptor 4 Toll-Like/genética , Animais , Apoptose/genética , Citocinas/genética , Modelos Animais de Doenças , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/patologia , Humanos , Interleucina-6/genética , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Lipopolissacarídeos/toxicidade , Camundongos , Miocárdio/patologia , NF-kappa B/genética , Fosforilação/genética , Sepse/induzido quimicamente , Sepse/complicações , Sepse/patologia , Troponina I/genética , Fator de Necrose Tumoral alfa/genética
15.
Int J Mol Sci ; 22(4)2021 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-33567720

RESUMO

Neutrophil granulocytes are the vanguard of innate immunity in response to numerous pathogens. Their activity drives the clearance of microbe- and damage-associated molecular patterns, thereby contributing substantially to the resolution of inflammation. However, excessive stimulation during sepsis leads to cellular unresponsiveness, immunological dysfunction, bacterial expansion, and subsequent multiple organ dysfunction. During the short lifespan of neutrophils, they can become significantly activated by complement factors, cytokines, and other inflammatory mediators. Following stimulation, the cells respond with a defined (electro-)physiological pattern, including depolarization, calcium influx, and alkalization as well as with increased metabolic activity and polarization of the actin cytoskeleton. Activity of ion transport proteins and aquaporins is critical for multiple cellular functions of innate immune cells, including chemotaxis, generation of reactive oxygen species, and phagocytosis of both pathogens and tissue debris. In this review, we first describe the ion transport proteins and aquaporins involved in the neutrophil ion-water fluxes in response to chemoattractants. We then relate ion and water flux to cellular functions with a focus on danger sensing, chemotaxis, phagocytosis, and oxidative burst and approach the role of altered ion transport protein expression and activity in impaired cellular functions and cell death during systemic inflammation as in sepsis.


Assuntos
Granulócitos/patologia , Imunidade Inata/imunologia , Inflamação/complicações , Neutrófilos/patologia , Explosão Respiratória , Sepse/patologia , Animais , Humanos , Espécies Reativas de Oxigênio , Sepse/etiologia
16.
Biomed Res Int ; 2021: 6678165, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33604382

RESUMO

Objective: We aimed to investigate the protective effect of s-nitrosoglutathione (SNG) pretreatment on acute kidney injury (AKI) in septic rats. Methods: We constructed a rat model of sepsis by cecal ligation and puncture and observed the survival of the rats. We obtained kidney and blood samples from rats, observed the pathological damage to the kidney tissues, and evaluated kidney function and the expression levels of inflammatory factors. We also detected the expression of induced nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in the kidneys by immunohistochemistry and evaluated the apoptosis of kidney tubular epithelial cells (KTEC) by TUNEL. Results: Pretreatment with SNG significantly reduced the mortality of septic rats, attenuated kidney pathological damage, and decreased the levels of serum creatinine, plasma neutrophil gelatinase-associated lipocalin, and plasma kidney injury molecule-1. Moreover, SNG pretreatment decreased the levels of TNF-α and IL-1ß in serum and kidney and reduced the expressions of NO, iNOS, PGE2, and COX-2 in the kidneys. Furthermore, pretreatment with SNG significantly reduced the apoptotic rate of KTEC and decreased the levels of caspase-3 and Bax mRNA, but increased the level of Bcl-2 mRNA. Conclusion: Pretreatment with SNG has a protective effect on AKI in septic rats, and the specific mechanisms are related to inhibition of inflammation, oxidation, and apoptosis.


Assuntos
Injúria Renal Aguda , Apoptose/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/farmacologia , S-Nitrosoglutationa/farmacologia , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/patologia , Animais , Inflamação/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Masculino , Ratos , Ratos Sprague-Dawley , Sepse/metabolismo , Sepse/patologia
17.
Nat Commun ; 12(1): 308, 2021 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-33436632

RESUMO

Accumulating evidence shows that RAGE has an important function in the pathogenesis of sepsis. However, the mechanisms by which RAGE transduces signals to downstream kinase cascades during septic shock are not clear. Here, we identify SLP76 as a binding partner for the cytosolic tail of RAGE both in vitro and in vivo and demonstrate that SLP76 binds RAGE through its sterile α motif (SAM) to mediate downstream signaling. Genetic deficiency of RAGE or SLP76 reduces AGE-induced phosphorylation of p38 MAPK, ERK1/2 and IKKα/ß, as well as cytokine release. Delivery of the SAM domain into macrophages via the TAT cell-penetrating peptide blocks proinflammatory cytokine production. Furthermore, administration of TAT-SAM attenuates inflammatory cytokine release and tissue damage in mice subjected to cecal ligation and puncture (CLP) and protects these mice from the lethality of sepsis. These findings reveal an important function for SLP76 in RAGE-mediated pro-inflammatory signaling and shed light on the development of SLP76-targeted therapeutics for sepsis.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Terapia de Alvo Molecular , Fosfoproteínas/metabolismo , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Sepse/tratamento farmacológico , Animais , Bacteriófago T7/metabolismo , Quimiocinas/genética , Quimiocinas/metabolismo , Produtos Finais de Glicação Avançada/metabolismo , Células HEK293 , Humanos , Inflamação/metabolismo , Inflamação/patologia , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Modelos Biológicos , Peptídeos/metabolismo , Ligação Proteica , Domínios Proteicos , Células RAW 264.7 , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptor para Produtos Finais de Glicação Avançada/química , Sepse/patologia , Transdução de Sinais
19.
Exp Cell Res ; 399(2): 112473, 2021 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-33428902

RESUMO

Sepsis is a complicated multi-system disorder characterized by a dysregulated host response to infection. Despite substantial progress in the understanding of mechanisms of sepsis, translation of these advances into clinically effective therapies remains challenging. Mesenchymal Stromal Cells (MSCs) possess immunomodulatory properties that have shown therapeutic promise in preclinical models of sepsis. The therapeutic effects of MSCs may vary depending on the source and type of these cells. In this comparative study, the gene expression pattern and surface markers of bone marrow-derived MSCs (BM-MSCs) and umbilical cord-derived MSCs (UC-MSCs) as well as their therapeutic effects in a clinically relevant mouse model of polymicrobial sepsis, cecal ligation and puncture (CLP), were investigated. The results showed remarkable differences in gene expression profile, surface markers and therapeutic potency in terms of enhancing survival and pro/anti-inflammatory responses between the two MSC types. BM-MSCs improved survival concomitant with an enhanced systemic bacterial clearance and improved inflammatory profile post CLP surgery. Despite some improvement in the inflammatory profile of the septic animals, treatment with UC-MSCs did not enhance survival or bacterial clearance. Overall, the beneficial therapeutic effects of BM-MSCs over UC-MSCs may likely be attributed to their pro-inflammatory function, and to some extent anti-inflammatory features, reflected in their gene expression pattern enhancing macrophage polarization to M1/M2 phenotypes resulting in a balanced pro- and anti-inflammatory response against polymicrobial sepsis.


Assuntos
Células da Medula Óssea/citologia , Transplante de Medula Óssea , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/citologia , Sepse/terapia , Animais , Células da Medula Óssea/imunologia , Células da Medula Óssea/metabolismo , Transplante de Medula Óssea/métodos , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Imunofenotipagem , Masculino , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/imunologia , Células-Tronco Mesenquimais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Sepse/genética , Sepse/imunologia , Sepse/patologia
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