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1.
Rev Soc Bras Med Trop ; 53: e20200016, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32348434

RESUMO

INTRODUCTION: Sepsis is an important cause of mortality and morbidity, and inflammatory response and oxidative stress play major roles underlying its pathophysiology. Here, we evaluated the effect of intraperitoneal etanercept administration on oxidative stress and inflammation indicators in the kidney and blood of experimental sepsis-induced rats. METHODS: Twenty-eight adult Sprague Dawley rats were classified into Control (Group 1), Sepsis (Group 2), Sepsis+Cefazolin (Group 3), and Sepsis+Cefazolin+Etanercept (Group 4) groups. Kidney tissue and serum samples were obtained for biochemical and histopathological investigations and examined for the C reactive protein (CRP), tumor necrosis factor-alpha (TNF-α), triggering receptor expressed on myeloid cells (TREM), and malondialdehyde (MDA) levels. RESULTS: The levels of TNF-α, TREM, and MDA in serum and kidney samples were significantly higher in rats from sepsis group than in rats from control group (p < 0.05). Group 3 showed a significant reduction in serum levels of TNF-α, CRP, and TREM as compared with Group 2 (p < 0.05). Serum TNF-α, CRP, TREM, and MDA levels and kidney TNF-α and TREM levels were significantly lower in Group 4 than in Group 2 (p < 0.05). Serum TNF-α and TREM levels in Group 4 were significantly lower than those in Group 3, and histopathological scores were significantly lower in Group 3 and Group 4 than in Group 2 (p < 0.05). Histopathological scores of Group 4 were significantly lower than those of Group 3 (p < 0.05). CONCLUSIONS: Etanercept, a TNF-α inhibitor, may ameliorate sepsis-induced oxidative stress, inflammation, and histopathological damage.


Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Etanercepte/administração & dosagem , Inflamação/prevenção & controle , Rim/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Sepse/patologia , Fator de Necrose Tumoral alfa/sangue , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Modelos Animais de Doenças , Etanercepte/farmacologia , Inflamação/patologia , Injeções Intraperitoneais , Ratos , Ratos Sprague-Dawley , Sepse/sangue
2.
Am J Pathol ; 190(4): 791-798, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32035882

RESUMO

Along with the recognition of a crucial role played by endothelial dysfunction secondarily igniting cardiovascular, pulmonary, and renal complications, investigational focus has extended toward endothelial glycocalyx. This delicate coating of cells, including the vascular endothelium, regulates permeability, leukocyte traffic, nitric oxide production, and coagulation, and harbors diverse growth and survival factors. In this brief overview, we discuss the metabolic signatures of sepsis as they relate to the loss of glycocalyx integrity and highlight the contribution of several proteases, heparanase, and hyaluronidase to the shedding of glycocalyx. Clinical manifestations of glycocalyx degradation in unraveling acute respiratory distress syndrome and the cardiovascular, microcirculatory, and renal complications of sepsis are concisely presented. Finally, we list therapeutic strategies for preventing the degradation of, and for restoration of, the glycocalyx.


Assuntos
Endotélio Vascular/patologia , Endotoxemia/patologia , Glicocálix/metabolismo , Sepse/patologia , Animais , Endotélio Vascular/metabolismo , Endotoxemia/metabolismo , Humanos , Sepse/metabolismo
3.
PLoS One ; 15(2): e0228727, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32012200

RESUMO

Increased endothelial permeability is central to the pathogenesis of sepsis and leads to organ dysfunction and death but the endogenous mechanisms that drive increased endothelial permeability are not completely understood. We previously reported that cell-free hemoglobin (CFH), elevated in 80% of patients with sepsis, increases lung microvascular permeability in an ex vivo human lung model and cultured endothelial cells. In this study, we augmented a murine model of polymicrobial sepsis with elevated circulating CFH to test the hypothesis that CFH increases microvascular endothelial permeability by inducing endothelial apoptosis. Mice were treated with an intraperitoneal injection of cecal slurry with or without a single intravenous injection of CFH. Severity of illness, mortality, systemic and lung inflammation, endothelial injury and dysfunction and lung apoptosis were measured at selected time points. We found that CFH added to CS increased sepsis mortality, plasma inflammatory cytokines as well as lung apoptosis, edema and inflammation without affecting large vessel reactivity or vascular injury marker concentrations. These results suggest that CFH is an endogenous mediator of increased endothelial permeability and apoptosis in sepsis and may be a promising therapeutic target.


Assuntos
Apoptose , Permeabilidade Capilar , Hemoglobinas/metabolismo , Pulmão/irrigação sanguínea , Pulmão/patologia , Sepse/metabolismo , Sepse/patologia , Animais , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Feminino , Humanos , Inflamação/patologia , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo , Sepse/microbiologia
4.
Int J Infect Dis ; 92: 218-225, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31962181

RESUMO

BACKGROUND: To provide better management of Fournier's gangrene, mortality-associated comorbidities and common etiologies were identified. METHODS: A systematic search was conducted using 12 databases, followed by meticulous screening to select relevant articles. Meta-analysis and meta-regression (for possible cofounders) were both done for all possible outcomes. RESULTS: Out of 1186 reports screened, 38 studies were finally included in the systematic review and meta-analysis. A higher risk of mortality was detected in patients with diabetes, heart disease, renal failure, and kidney disease, with risk ratios (RR) and 95% confidence intervals (95% CI) of 0.72 (0.59-0.89), 0.39 (0.24-0.62), 0.41 (0.27-0.63), and 0.34 (95% CI 0.16-0.73), respectively. However, there was no association between mortality rates and comorbid hypertension, lung disease, liver disease, or malignant disease (p > 0.05). The highest mortality rates were due to sepsis (76%) and multiple organ failure (66%), followed by respiratory (19.4%), renal (18%), cardiovascular (15.7%), and hepatic (5%) mortality. CONCLUSIONS: Modifications to the Fournier's Gangrene Severity Index (FGSI) are recommended, in order to include comorbidities as an important prognostic tool for FG mortality. Close monitoring of the patients, with special interest given to the main causes of mortality, is an essential element of the management process.


Assuntos
Gangrena de Fournier/epidemiologia , Índice de Gravidade de Doença , Causas de Morte , Comorbidade , Gangrena de Fournier/complicações , Gangrena de Fournier/mortalidade , Humanos , Prognóstico , Estudos Retrospectivos , Sepse/patologia , Taxa de Sobrevida
5.
PLoS One ; 15(1): e0228020, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31990941

RESUMO

BACKGROUND: Limited data is available to describe clinical characteristics, long-term outcomes, healthcare resource use and the attributable costs of invasive meningococcal disease (IMD) in Germany. We aimed to examine demographic and clinical characteristics as well as healthcare resource use and related costs. METHODS: We conducted a retrospective cohort study based on the InGef database in patients with IMD between 2009 and 2015. Cases were identified based on hospital main discharge diagnoses of IMD. Demographics, clinical characteristics, 30-day and 1-year mortality as well as IMD-related complications and sequelae in IMD cases were examined. In addition, short and long-term costs and healthcare resource use in IMD cases were analyzed and compared to an age- and sex-matched control group without IMD. RESULTS: The study population comprised 164 IMD cases between 2009 and 2015. The mean length of the IMD-related hospitalization was 13 days and 38% of all cases presented with meningitis only, 35% with sepsis only, 16% with both and 11% with other IMD. The 30-day and one-year mortality were 4.3% and 5.5%, respectively. Approximately 13% of IMD cases had documented IMD-related complications at hospital discharge and 24% suffered from sequelae during follow-up. The IMD-related hospitalization was associated with mean costs of € 9,620 (standard deviation: € 22,197). The difference of mean costs between IMD cases and matched non-IMD controls were € 267 in the first month and € 1,161 from one month to one year after discharged from IMD-related hospitalization. During the later follow-up period, the mean overall costs and costs associated with individual healthcare sectors were also higher for IMD cases without reaching statistical significance. CONCLUSIONS: IMD resulted in severe complications and sequelae and was associated with extensive costs and increased healthcare resource use in Germany, especially in the first year after IMD diagnosis and due the IMD-related hospitalization.


Assuntos
Custos de Cuidados de Saúde/estatística & dados numéricos , Hospitalização/economia , Infecções Meningocócicas/economia , Sepse/economia , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Criança , Pré-Escolar , Efeitos Psicossociais da Doença , Bases de Dados Factuais , Feminino , Alemanha/epidemiologia , Hospitalização/estatística & dados numéricos , Humanos , Lactente , Masculino , Infecções Meningocócicas/epidemiologia , Infecções Meningocócicas/mortalidade , Infecções Meningocócicas/patologia , Pessoa de Meia-Idade , Neisseria meningitidis/crescimento & desenvolvimento , Neisseria meningitidis/patogenicidade , Estudos Retrospectivos , Sepse/epidemiologia , Sepse/mortalidade , Sepse/patologia , Análise de Sobrevida
6.
DNA Cell Biol ; 39(1): 105-117, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31794266

RESUMO

Septic cardiomyopathy (SC) is a rare and harmful cardiovascular disease with decreased left ventricular (LV) output and multiple organ failure, which poses a serious threat to human life. Despite the advances in SC, its diagnostic basis and treatment methods are limited, and the specific diagnostic biomarkers and its candidate regulatory targets have not yet been fully established. In this study, the GSE79962 gene expression profile was retrieved, with 20 patients with SC and 11 healthy donors as control. Weighted gene coexpression network analysis (WGCNA) was employed to investigate gene modules that were strongly correlated with clinical phenotypes. Blue module was found to be most significantly related to SC. Moreover, Gene Ontology (GO) functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed on the coexpression genes in blue module and showed that it was associated with metabolic pathways, oxidative phosphorylation, and cardiac muscle contraction. Furthermore, a total of 10 hub genes NDUFB5, TIMMDC1, VDAC3, COQ10A, MRPL16 (mitochondrial ribosomal protein L16), C3orf43, TMEM182, DLAT, NDUFA8, and PDHB (pyruvate dehydrogenase E1 beta subunit) in the blue module were identified at transcriptional level and further validated at translational level in myocardium of an lipopolysaccharide-induced septic cardiac dysfunction mouse model. Overall, the results of quantitative real-time polymerase chain reaction were consistent with most of the microarray analysis results. Intriguingly, we observed that the highest change was NDUFB5, TIMMDC1, and VDAC3. These identified and validated genes provided references that would advance the understanding of molecular mechanisms of SC. Taken together, using WGCNA, the hub genes NDUFB5, TIMMDC1, and VDAC3 might serve as potential biomarkers for diagnosis and/or therapeutic targets for precise treatment of SC in the future.


Assuntos
Cardiomiopatias/genética , Complexo I de Transporte de Elétrons/genética , Perfilação da Expressão Gênica/métodos , Proteínas de Transporte da Membrana Mitocondrial/genética , Sepse/genética , Canais de Ânion Dependentes de Voltagem/genética , Idoso , Animais , Cardiomiopatias/metabolismo , Cardiomiopatias/patologia , Biologia Computacional/métodos , Progressão da Doença , Complexo I de Transporte de Elétrons/metabolismo , Feminino , Ontologia Genética , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Subunidades Proteicas/genética , Subunidades Proteicas/metabolismo , Sepse/metabolismo , Sepse/patologia , Canais de Ânion Dependentes de Voltagem/metabolismo
7.
Life Sci ; 240: 117081, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31756342

RESUMO

BACKGROUND AND GOAL OF THE STUDY: Pulmonary inflammation, increased vascular permeability, and pulmonary edema, occur in response to primary pulmonary infections like pneumonia but are also evident in endotoxemia or sepsis. Mechanical ventilation augments pre-existing lung injury and inflammation resulting from exposure to microbial products. The objective of this study was to test the hypothesis that low-tidal-volume prevent ventilation induced lung injury in sepsis. MATERIALS AND METHODS: 10-12-week-old male C57BL/6N-mice received an intraperitoneal (i.p.) injection with equipotent dosages of LPS, 1668-thioate, 1612-thioate, or PBS. 120 min after injection, mice were randomized to low- (LV, 7 ± 1 ml/kg) or high-tidal-volume (HV, 25 ± 1 ml/kg) ventilation. Hemodynamic and ventilatory parameters were recorded and inflammatory markers were analyzed form BAL that was generated after 90 minute ventilation. RESULTS AND DISCUSSION: Arterial blood pressures declined during mechanical ventilation in all groups. pO2 decreased in LPS injected and CO2 increased in sham, LPS, and 1612-thioate administered mice at 45 min and in 1668-thioate injected mice after 90 minute LV ventilation compared to respective HV groups. BAL protein concentrations increased in HV ventilated and 1668- or 1612-thioat pre-treated mice. BAL TNF-α protein concentrations increased in both LPS- and 1668-thioate-injected and IL-1ß protein concentrations only in LPS-injected and HV ventilated mice. Most notably, no increased protein concentrations were observed in any of the LV ventilated groups. CONCLUSION: We conclude that low-tidal-volume ventilation may be a potential strategy for the prevention of ventilator induced lung injury in a murine model of systemic TLR agonist induced lung injury.


Assuntos
Inflamação/terapia , Sepse/terapia , Volume de Ventilação Pulmonar , Lesão Pulmonar Induzida por Ventilação Mecânica/prevenção & controle , Animais , Pressão Arterial , Líquido da Lavagem Broncoalveolar , Dióxido de Carbono/sangue , Hemodinâmica , Inflamação/complicações , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Oxigênio/sangue , Mecânica Respiratória , Sepse/complicações , Sepse/patologia , Lesão Pulmonar Induzida por Ventilação Mecânica/patologia
8.
Life Sci ; 241: 117051, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31733315

RESUMO

AIMS: Sepsis is a severe public health problem affecting millions of individuals, with global mortality rates caused by lower respiratory tract infections are approximately 2.38 million people a year die from respiratory failure caused by infection. Although ACE is known to contribute to damage in septicemia, the pathophysiological mechanisms of sepsis remain unclear. While mortality can be significantly reduced through effective and sensitive antibiotic therapy, antibiotic resistance restricts the use of these drugs, and the investigation of novel agents and targets is therefore essential. Our aim was to determine whether Perindopril (PER) has anti-inflammatory and antioxidant capable of preventing these adverse conditions resulting in injury in previous studies. MAIN METHODS: Sprague Dawley rats were randomly assigned into the control group, received oral saline solution alone for four days. the cecal ligation and puncture (CLP) group, underwent only cecal ligation and puncture induced sepsis, while the CLP + PER (2 mg/kg) underwent cecal ligation and puncture-induced sepsis together with oral administration of 2 mg/kg PER for four days before induction of sepsis. KEY FINDINGS: Malondialdehyde (MDA), tumor necrosis factor-alpha (TNF-α), Caspase-3 and nuclear factor kappa B (NF-kß/p65) levels increased in the CLP group. On the other hand, PER (2 mg/kg) oral administration to septic rats decreased MDA, TNF-α and increase glutathione (GSH) in the lung tissue. In addition, PER administration also decreased the lung tissue NF-κB and Caspase-3 immunopositivity against sepsis. SIGNIFICANCE: PER treatment may represent a promising means of preventing sepsis-induced lung injury via antioxidant and anti-inflammation effects.


Assuntos
Estresse Oxidativo/efeitos dos fármacos , Perindopril/farmacologia , Substâncias Protetoras/farmacologia , Sepse/prevenção & controle , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Ceco/cirurgia , Vesículas Extracelulares/efeitos dos fármacos , Feminino , Glutationa/metabolismo , Inflamação/tratamento farmacológico , Inflamação/etiologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Punções/efeitos adversos , Ratos Sprague-Dawley , Sepse/etiologia , Sepse/mortalidade , Sepse/patologia , Fator de Necrose Tumoral alfa/metabolismo
9.
Crit Care Clin ; 36(1): 41-54, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31733681

RESUMO

The diagnosis of sepsis, and especially its differentiation from sterile inflammation, may be challenging. The triggering receptor expressed on myeloid cells-1 is an amplifier of the innate immune response. Its soluble form is detectable in various biological fluids and can be used as a surrogate marker of triggering receptor expressed on myeloid cells-1 activation. In this article, we review the abundant literature evaluating the usefulness of soluble triggering receptor expressed on myeloid cells-1 for the diagnosis and the prognosis evaluation of sepsis or localized infections.


Assuntos
Biomarcadores/sangue , Células Mieloides/patologia , Sepse/sangue , Sepse/imunologia , Sepse/patologia , Receptor Gatilho 1 Expresso em Células Mieloides/sangue , Receptor Gatilho 1 Expresso em Células Mieloides/imunologia , Humanos , Imunidade Inata , Células Mieloides/imunologia , Prognóstico , Sepse/diagnóstico
10.
An Acad Bras Cienc ; 91(4): e20190434, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31800708

RESUMO

Sepsis is a life-threatening organ dysfunction induced by a disrupted host response to infecting pathogens. Inflammation and oxidative stress are intrinsically related to sepsis progression and organ failure. Vitamin B6 is an important cellular cofactor for metabolic processes and has anti-inflammatory and antioxidant properties. We aimed at evaluating the effect of vit B6 on inflammation and oxidative stress markers in the liver and lung of rats subjected to a relevant animal model of polymicrobial sepsis. Adult male Wistar rats were submitted to cecal ligation and perforation model and immediately after sepsis induction, vit B6 was administered as a single dose (600 mg/kg, subcutaneous). Twenty-four hours later, the lung and liver were harvest for neutrophil infiltration, oxidative markers to lipids and protein and antioxidant activity of endogenous enzyme. Vitamin B6 diminished neutrophil infiltration in both organs, oxidative markers in the liver and restored catalase activity levels in the lung of septic animals. Vitamin B6 exerts anti-inflammatory and antioxidant effects in peripheral organs after polymicrobial sepsis.


Assuntos
Antioxidantes/farmacologia , Inflamação/prevenção & controle , Fígado/patologia , Pulmão/patologia , Estresse Oxidativo/efeitos dos fármacos , Sepse/complicações , Vitamina B 6/farmacologia , Animais , Biomarcadores/metabolismo , Modelos Animais de Doenças , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Masculino , Ratos , Ratos Wistar , Sepse/patologia
12.
BMC Infect Dis ; 19(1): 968, 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31718563

RESUMO

BACKGROUND: This study investigated the clinical value of interleukin-6 (IL-6), pentraxin 3 (PTX3), and procalcitonin (PCT) in patients with sepsis and septic shock diagnosed according to the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). METHODS: Serum levels of IL-6, PTX3, and PCT were measured in 142 enrolled subjects (51 with sepsis, 46 with septic shock, and 45 as controls). Follow-up IL-6 and PTX3 levels were measured in patients with initial septic shock within 24 h of hospital discharge. Optimal cut-off values were determined for sepsis and septic shock, and prognostic values were evaluated. RESULTS: Serum IL-6 levels could discriminate sepsis (area under the curve [AUC], 0.83-0.94, P <  0.001; cut-off value, 52.60 pg/mL, 80.4% sensitivity, 88.9% specificity) from controls and could distinguish septic shock (AUC, 0.71-0.89; cut-off value, 348.92 pg/mL, 76.1% sensitivity, 78.4% specificity) from sepsis. Twenty-eight-day mortality was significantly higher in the group with high IL-6 (≥ 348.92 pg/mL) than in the group with low IL-6 (< 348.92 pg/mL) (P = 0.008). IL-6 was an independent risk factor for 28-day mortality among overall patients (hazard ratio, 1.0004; 95% confidence interval, 1.0003-1.0005; p = 0.024). In septic shock patients, both the initial and follow-up PTX3 levels were consistently significantly higher in patients who died than in those who recovered (initial p = 0.004; follow-up P <  0.001). CONCLUSIONS: The diagnostic and prognostic value of IL-6 was superior to those of PTX3 and PCT for sepsis and septic shock.


Assuntos
Proteína C-Reativa/análise , Interleucina-6/sangue , Pró-Calcitonina/sangue , Sepse/diagnóstico , Componente Amiloide P Sérico/análise , Choque Séptico/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Curva ROC , Fatores de Risco , Sensibilidade e Especificidade , Sepse/mortalidade , Sepse/patologia , Índice de Gravidade de Doença , Choque Séptico/mortalidade , Choque Séptico/patologia
13.
Int J Nanomedicine ; 14: 6779-6797, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31692534

RESUMO

Background: Sepsis is a life-threatening condition caused by dysregulated host responses to infection. Macrophages, which recognize microbial infections through identification of bacterial markers such as lipopolysaccharide (LPS), are crucial to the pathogenesis of sepsis-associated liver injury. However, the understanding of the SPIONs-mediated modulation of macrophage responses in LPS-induced sepsis and liver injury is limited. Materials and methods: Superparamagnetic iron oxide nanoparticles (SPIONs) of γ-Fe2O3 nanoparticles were prepared, and their morphology and magnetic properties were characterized. Results: Using a murine model of LPS-induced sepsis and liver injury, we found that SPIONs alleviated LPS-induced sepsis, preventing infiltration of inflammatory cells into the liver. SPIONs also increased the level of interleukin-10 (IL-10) in liver macrophages, while SPIONs's effect on LPS-induced sepsis was abrogated in IL-10-/- mice, indicating that the protective effect of SPIONs is dependent on IL-10+ macrophages. Moreover, SPIONs activated macrophage autophagy to increase IL-10 production, which was markedly attenuated by autophagy inhibition. Furthermore, SPIONs upregulated the expression of Caveolin-1 (Cav1) in macrophages, which plays a role in cellular uptake of metallic nanoparticles. Interestingly, activation of Cav1 and Notch1/HES1 signaling was involved in SPIONs-induced autophagy in both RAW 264.7 cells and bone marrow-derived macrophages (BMDMs). Our data reveal a novel mechanism for SPIONs -induced autophagy in macrophages, which occurs through activation of the Cav1-Notch1/HES1 signaling pathway, which promotes the production of IL-10 in macrophages, leading to inhibition of inflammation in LPS-induced sepsis and liver injury. Conclusion: Our results suggest that SPIONs may represent a potential therapeutic agent for the treatment of sepsis and sepsis-induced liver injury.


Assuntos
Autofagia/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Nanopartículas de Magnetita/uso terapêutico , Sepse/tratamento farmacológico , Animais , Autofagia/fisiologia , Caveolina 1/genética , Caveolina 1/metabolismo , Compostos Férricos/química , Compostos Férricos/farmacologia , Interleucina-10/metabolismo , Lipopolissacarídeos/toxicidade , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Macrófagos/metabolismo , Macrófagos/patologia , Nanopartículas de Magnetita/química , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células RAW 264.7 , Receptor Notch1/metabolismo , Sepse/metabolismo , Sepse/patologia , Fatores de Transcrição HES-1/metabolismo
14.
Biol Pharm Bull ; 42(10): 1641-1650, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31582652

RESUMO

Aquaporin-3 (AQP3) is expressed in various parts of the intestine, where it regulates the proliferation and migration of intestinal epithelial cells and the transport of glycerol and hydrogen peroxide. Our study aimed to investigate the effect on the expression of AQP3 of intestinal injury in septic mice and whether oral administration of glycerol can reduce intestinal epithelial injury and barrier disorder by acting as a partial substitute for the function of AQP3. We established a sepsis model by cecal ligation and perforation (CLP) in mice. Sepsis induced intestinal injury, as demonstrated by the disordered destruction of the morphology of the intestinal mucosa, time-dependent increases in Chiu's score (p < 0.05), significantly increased (p < 0.05) plasma concentrations of determination of the levels of diamine oxidase (DAO) and intestinal fatty acid-binding protein 2 (FABP2), and time-dependent downregulation of the expression of AQP3 and occluding (p < 0.05). While the administration of oral glycerol partially ameliorated the sepsis-induced injury of the intestinal mucosa, as shown by the partial recovery of the morphological structure, with decreased Chiu's score, decreased plasma concentrations of DAO and intestinal-type FABP2, upregulated expression of occludin and decreased mortality rate (Sepsis vs. Sepsis + Glycerol, p < 0.05). The results showed that the expression levels of AQP3 and occludin were downregulated after septic intestinal injury, while treatment with glycerol, which acts as a substitute for AQP3, partly ameliorated intestinal injury and improved the survival rate. This preliminary experiment suggests that AQP3 may protect the intestinal tract against the effects of sepsis.


Assuntos
Aquaporina 3/imunologia , Mucosa Intestinal/patologia , Ocludina/imunologia , Sepse/imunologia , Animais , Citocinas/imunologia , Regulação para Baixo , Glicerol/farmacologia , Glicerol/uso terapêutico , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/imunologia , Masculino , Camundongos Endogâmicos BALB C , Ocludina/genética , Sepse/tratamento farmacológico , Sepse/patologia
15.
Dis Markers ; 2019: 1089107, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31583025

RESUMO

The focus of sepsis has shifted from inflammation to organ dysfunction on the basis of a recent definition based on the sequential organ failure score (SOFA). A diagnostic and prognostic marker is necessary under this definition but is currently unknown. We enrolled 80 sepsis patients consecutively admitted to an intensive care unit through the emergency department and 80 healthy control patients who received routine health check-ups from August 2018 to January 2019. SEPSIS-3 criteria were used for the diagnosis of patients based on SOFA score ≥ 2 from the baseline along with evidence of infection. Concentrations of 28 cytokines, eight chemokines, and nine growth factors were measured on the day of diagnosis. Hierarchical cluster analysis was performed for molecules. The majority of infections were pneumonia (45% of patients) and urinary tract infections (40% of patients). Most of the measured molecules were increased in patients with sepsis. Area under receiver operating characteristic curve (AUROC) values were found to be as follows: hepatic growth factor (HGF), 0.899; interleukin-1 receptor antagonist (IL-1RA), 0.893; C-C motif ligand 5 (CCL5) 5, 0.887; C-X-C motif chemokine 10 (CXCL10), 0.851; CCL2, 0.840; and IL-6, 0.830. IL-1RA, IL-6, IL-8, IL-15, and CCL11 concentrations correlated with SOFA score with statistical significance. Prognosis multivariate analysis revealed an odds ratio of 0.968 for epidermal growth factor (EGF). Three clusters were formed, of which Clusters 2 and 3 were associated with nonsurvivors. Diagnosis of sepsis was performed using cytokines, chemokines, and growth factors. HGF revealed the highest diagnostic capability, and EGF predicted favorable prognosis among the tested molecules.


Assuntos
Citocinas/sangue , Fator de Crescimento de Hepatócito/sangue , Pneumonia/diagnóstico , Sepse/diagnóstico , Infecções Urinárias/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , Biomarcadores/sangue , Estudos de Casos e Controles , Fator de Crescimento Epidérmico/sangue , Feminino , Humanos , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Razão de Chances , Escores de Disfunção Orgânica , Pneumonia/sangue , Pneumonia/mortalidade , Pneumonia/patologia , Prognóstico , Curva ROC , Estudos Retrospectivos , Sepse/sangue , Sepse/mortalidade , Sepse/patologia , Análise de Sobrevida , Infecções Urinárias/sangue , Infecções Urinárias/mortalidade , Infecções Urinárias/patologia
16.
DNA Cell Biol ; 38(11): 1197-1206, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31618067

RESUMO

Researches establish an indispensable role of mitochondrial dysfunction in septic cardiomyopathy. We aimed to investigate the effects of long noncoding RNA (LncRNA) SOX2 overlapping transcript (SOX2OT) on mitochondrial dysfunction in septic cardiomyopathy. We observed an obvious overexpression of SOX2OT in septic hearts and cardiomyocytes. Knockdown of SOX2OT in mice recovered the reduced cardiac function, and improved the mitochondrial membrane potential impaired by lipopolysaccharide (LPS). SOX2OT overexpressed mice showed the opposite situation. In parallel, knockdown of SOX2OT in cardiomyocytes restored the mitochondrial membrane potential, along with reduced mitochondrial reactive oxygen species production induced by LPS, while overexpression of SOX2OT reversed these effects. Mechanistically, SOX2OT could regulate mitochondrial dysfunction in septic cardiomyopathy via SOX2. In general, SOX2OT contributed to mitochondrial dysfunction progression via inhibiting SOX2 expression in septic cardiomyopathy, which may provide a new insight for treatment of septic cardiomyopathy.


Assuntos
Cardiomiopatias , Mitocôndrias Cardíacas/fisiologia , Doenças Mitocondriais/genética , RNA Longo não Codificante/fisiologia , Sepse , Animais , Cardiomiopatias/genética , Cardiomiopatias/patologia , Cardiomiopatias/fisiopatologia , Células Cultivadas , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias Cardíacas/patologia , Doenças Mitocondriais/patologia , Ratos , Sepse/genética , Sepse/patologia , Sepse/fisiopatologia
17.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 50(4): 512-519, 2019 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-31642228

RESUMO

OBJECTIVE: To investigate the role of p38 mitogen-activated protein kinase (MAPK) signaling pathway in autophagy of neurons in hippocampus of sepsis rats. METHODS: A sepsis model was established by cecal ligation and puncture (CLP). SD rats were randomly divided into sham-operated group (sham group), model group (CLP group), vehicle-treated group (CLP+Veh group) and inhibitor-treated group (CLP+SB203580 group), and each group was divided into 3, 6, 12, 24 and 48 h subgroups. CLP+Veh group and CLP+SB203580 group were injected with 1% DMSO 5 µL and 0.1 mmol/L SB203580 5 µL respectively in the lateral ventricle, and CLP was established 30 min after injection. The sham group only turned over the cecum and closed the abdomen without other treatments. The vital signs of rats were monitored, including mean arterial pressure (MAP) and heart rate (HR). Neurobehavioral score was used to investigate the brain injury in rats. Histopathological changes in hippocampus of rats were observed by HE staining. The process of neuronal autophagy in hippocampal of rats was observed under transmission electron microscope (TEM). Western blot assay was performed to detect the expression of microtubule associated protein 1 light chain 3 (LC3)Ⅱ, LC3Ⅰ, selective autophagy adaptor protein p62/sequestosome-1 (p62/SQSTM1), MAPK-activated protein kinase 2 (MK-2) and phosphorylation MK-2 (p-MK-2) in the hippocampus. The expressions of LC3 and p62/SQSTM1 in hippocampal neurons of rats were observed by immunofluorescence. RESULTS: At different time points, MAP of CLP group was lower than sham group, while HR was higher than sham group, the change was most obvious at 12 h after molding; the neurobehavioral score of CLP group was the lowest; the histopathological changes in the hippocampus were obvious; and many autophagy vacuoles were observed under transmission electron microscope; compared with CLP group, the neurobehavioral score of CLP+SB203580 group increased; the pathological changes in the hippocampus improved; the inclusions in autophagy vacuoles were degraded under transmission electron microscopy; Western blot results showed:compared with sham group, expression of-LC3Ⅱ/LC3Ⅰ, p-MK-2/MK-2 increased, and p62/SQSTM1 decreased in hippocampal tissue of CLP group in rat, the former reaches its peak at 12 h, the latter bottomed out at 12 h. Compared with the other groups, at 12 h of modeling, the expression of LC3Ⅱ/LC3Ⅰ, p-MK-2/MK-2 was further increased, the expression of p62/SQSTM1 decreased further in hippocampal tissue of CLP+SB203580 group in rat (P < 0.05); immunofluorescence observation showed that localization and expression of LC3 and p62/SQSTM1 in NeuN were consistent with Western blot. CONCLUSION: Inhibition of p38 MAPK signaling pathway in sepsis rats can further activate autophagy and protect neurons in the hippocampus.


Assuntos
Autofagia , Sistema de Sinalização das MAP Quinases , Neurônios/citologia , Sepse/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Hipocampo/patologia , Imidazóis/farmacologia , Piridinas/farmacologia , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Sepse/patologia
18.
Dis Markers ; 2019: 8792640, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31612071

RESUMO

Background: Calreticulin has been identified to play a critical role in innate and adaptive immune responses. However, little is known about the role of calreticulin in sepsis with a characteristic of immune disorder. This study was aimed at investigating whether plasma calreticulin level increases in sepsis and its association with sepsis severity. Methods: This retrospective analysis evaluated sepsis patients who were admitted to the intensive care unit (ICU). Healthy subjects were also included as controls. Plasma samples were collected from the patients within 48 h after ICU admission as well as the healthy subjects. Plasma calreticulin levels were measured via the enzyme-linked immunosorbent assay. Results: In total, 127 sepsis patients and 40 healthy controls were included. Calreticulin was significantly increased in sepsis patients than in healthy controls. Furthermore, the level of plasma calreticulin was significantly higher in nonsurvivors than in survivors. Patients with calreticulin levels > 343.5 pg/ml showed lower cumulative survival than those with levels < 343.5 pg/ml. Conclusion: Calreticulin level was positively correlated with the severity of sepsis. High calreticulin level indicated poor prognosis of sepsis patients.


Assuntos
Calreticulina/sangue , Sepse/sangue , Sepse/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Humanos , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Prognóstico , Curva ROC , Estudos Retrospectivos , Sepse/mortalidade , Sepse/patologia , Índice de Gravidade de Doença , Análise de Sobrevida
19.
Int J Med Sci ; 16(8): 1149-1156, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31523178

RESUMO

Background Sepsis, a leading cause of death in intensive care units, is generally associated with vascular dysfunction. However, its pathophysiological process has not been fully clarified, lacking in-depth knowledge of its pathophysiological process may hinder the improvement of diagnosis and therapy for sepsis. Hence, as the key parts of the vascular wall, the interaction between endothelial cells (ECs) and smooth muscle cells (SMCs) under septic situation need to be further studied. Methods ECs and SMCs were co-cultured using Transwell plates. Lipopolysaccharide (LPS) was used to induce sepsis. A scratch-wound assay was used to assess cell migration, and western blotting was used to assess the level of redifferentiation of SMCs as well as the expression of PDGFR-ß and IQGAP1. Results Co-culture with ECs reduced the redifferentiation of SMCs induced by LPS (10 µg/ml), which was characterized by increased migration ability and decreased expression of contractile proteins (e.g., SM22 and α-SMA). The production of TNF-α could decrease the level of PDGFR-ß in SMCs. Treatment of SMCs with the PDGFR-ß inhibitor imatinib (5 µM) was able to counteract LPS-induced SMC redifferentiation and reduce IQGAP1 protein expression, especially when SMCs were co-cultured with ECs. Conclusion The phenotype of vascular SMCs co-cultured with ECs was modulated by IQGAP1 through the PDGFR-ß pathway, which may lead to vascular remodeling and homeostasis in LPS-induced intravascular injury. This pathway could be a novel target for the treatment of vascular damage.


Assuntos
Músculo Liso Vascular/citologia , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Proteínas Ativadoras de ras GTPase/metabolismo , Técnicas de Cocultura , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Endotélio Vascular/citologia , Humanos , Lipopolissacarídeos/toxicidade , Músculo Liso Vascular/efeitos dos fármacos , Fenótipo , Sepse/metabolismo , Sepse/patologia , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismo
20.
Oxid Med Cell Longev ; 2019: 1475729, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31531179

RESUMO

Intestinal dysmotility is a frequent complication during sepsis and plays an important role in the development of secondary infections and multiple organ failure. However, the central mechanisms underlying this process have not been well elucidated. Currently, effective therapies are still lacking for the treatment of sepsis-induced intestinal dysmotility. In this study, we found that the activation of IL-17 signaling within the muscularis propria might be associated with dysmotility of the small intestine during polymicrobial sepsis. Furthermore, we demonstrated that targeting IL-17A partially rescued the motility of the small intestine and alleviated interstitial cells of Cajal (ICC) injury during sepsis. The blockade of IL-17A suppressed the dominant sepsis-induced infiltration of M1-polarized macrophages into the muscularis. Additionally, impaired ICC survival may be associated with the oxidative stress injury induced by dominant infiltration of M1-polarized macrophages. Our findings reveal the important role of the IL-17 signaling pathway in the small intestine during sepsis and provide clues for developing a novel therapeutic strategy for treating gastrointestinal dysmotility during sepsis.


Assuntos
Motilidade Gastrointestinal/imunologia , Interleucina-17/imunologia , Células Intersticiais de Cajal/imunologia , Intestino Delgado/imunologia , Sepse/imunologia , Transdução de Sinais/imunologia , Animais , Feminino , Interleucina-17/antagonistas & inibidores , Células Intersticiais de Cajal/patologia , Intestino Delgado/lesões , Intestino Delgado/patologia , Masculino , Camundongos , Células RAW 264.7 , Sepse/patologia
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