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[This corrects the article DOI: 10.1371/journal.pone.0244532.].
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BACKGROUND: The first cases of coronavirus disease (COVID-19) in Brazil were diagnosed in February 2020. Our Emergency Department (ED) was designated as a COVID-19 exclusive service. We report our first 500 confirmed COVID-19 pneumonia patients. METHODS: From 14 March to 16 May 2020, we enrolled all patients admitted to our ED that had a diagnosis of COVID-19 pneumonia. Infection was confirmed via nasopharyngeal swabs or tracheal aspirate PCR. The outcomes included hospital discharge, invasive mechanical ventilation, and in-hospital death, among others. RESULTS: From 2219 patients received in the ED, we included 506 with confirmed COVID-19 pneumonia. We found that 333 patients were discharged home (65.9%), 153 died (30.2%), and 20 (3.9%) remained in the hospital. A total of 300 patients (59.3%) required ICU admission, and 227 (44.9%) needed invasive ventilation. The multivariate analysis found age, number of comorbidities, extension of ground glass opacities on chest CT and troponin with a direct relationship with all-cause mortality, whereas dysgeusia, use of angiotensin converting enzyme inhibitor or angiotensin-ii receptor blocker and number of lymphocytes with an inverse relationship with all-cause mortality. CONCLUSIONS: This was a sample of severe patients with COVID-19, with 59.2% admitted to the ICU and 41.5% requiring mechanical ventilator support. We were able to ascertain the outcome in majority (96%) of patients. While the overall mortality was 30.2%, mortality for intubated patients was 55.9%. Multivariate analysis agreed with data found in other studies although the use of angiotensin converting enzyme inhibitor or angiotensin-ii receptor blocker as a protective factor could be promising but would need further studies. TRIAL REGISTRATION: The study was registered in the Brazilian registry of clinical trials: RBR-5d4dj5.
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COVID-19/mortalidade , COVID-19/terapia , Idoso , Brasil/epidemiologia , COVID-19/epidemiologia , Estudos de Coortes , Serviço Hospitalar de Emergência , Feminino , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Estações do AnoRESUMO
OBJECTIVE: To investigate the role of coronary driving pressure (CDP) in myocardial microcirculatory blood flow during sepsis. We hypothesised that in septic shock there is an impaired autoregulation of microcirculation, and blood flow is totally dependent on CDP. We analysed the effect of lipopolysaccharide (LPS)-induced shock on myocardial microcirculation, separating subendocardial and epicardial areas. We then studied the effect of CDP increases using noradrenaline (NOR) or metaraminol (Aramine [ARA]) on myocardial microcirculation and function, and we analysed the effect of volume infusion on CDP and myocardial function. DESIGN AND SETTING: Endotoxaemia was induced in male Wistar rats by an intraperitoneal injection of LPS 10 mg/kg. Animals were divided into a control (CT) group, an LPS-injected group, and an LPS-injected group treated with saline fluid, NOR or ARA. MAIN OUTCOME MEASURES: Ninety minutes later, a haemodynamic evaluation was performed. NOR or ARA were used to manage the mean arterial pressure (MAP) and CDP, and we inserted a catheter into the left ventricle to measure cardiac parameters. To measure blood flow in the myocardium and other organs, microspheres were introduced into the left ventricle using an infusion pump. RESULTS: After LPS treatment, left ventricular (LV) systolic function (dP/dt max) and diastolic function (dP/dt min) decreased by 34% and 15%, respectively, and load-independent indices (LV contractility in ejection phase and dP/dt max÷end-diastolic volume) were reduced. The CDP was also reduced (by 58%) in the endotoxaemic rats. Myocardial blood flow was reduced (by 80%) in animals with an MAP≤65 mmHg. NOR increased the CDP (LPS, 38 mmHg [SEM, 2 mmHg]; LPS+NOR, 59 mmHg [SEM, 3 mmHg]) and microcirculatory perfusion (LPS, 2 mL/min/g tissue [SEM, 0.6 mL/min/g]; LPS+NOR, 6.2 mL/min/g [SEM, 0.8 mL/min/g]). ARA was also effective in improve microcirculation but saline volume infusion was ineffective in improving CDP or myocardial function. CDP showed a significant correlation with subendocardial blood flow. CONCLUSIONS: Myocardial blood flow in the LV subendocardium and the right ventricle decreases in endotoxaemic rats. Increasing CDP improves myocardial blood flow and function. Thus, in endotoxaemia, microcirculatory blood flow is pressure dependent, suggesting that it may be beneficial to treat patients with sepsis using a higher CDP.
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Vasos Coronários/fisiopatologia , Coração/fisiopatologia , Choque Séptico/fisiopatologia , Animais , Circulação Coronária/fisiologia , Endotoxemia/fisiopatologia , Hemodinâmica/fisiologia , Masculino , Metaraminol/farmacologia , Microcirculação/fisiologia , Norepinefrina/farmacologia , Ratos , Ratos Wistar , Função Ventricular Esquerda/fisiologiaRESUMO
OBJECTIVE: To evaluate the hemodynamic and metabolic effects of terlipressin and naloxone in cardiac arrest. METHODS: Cardiac arrest in rats was induced by asphyxia and maintained for 3.5 minutes. Animals were then resuscitated and randomized into one of six groups: placebo (n = 7), epinephrine (0.02 mg/kg; n = 7), naloxone (1 mg/kg; n = 7) or terlipressin, of which three different doses were tested: 50 µg/kg (TP50; n = 7), 100 µg/kg (TP100; n = 7) and 150 µg/kg (TP150; n = 7). Hemodynamic variables were measured at baseline and at 10 (T10), 20 (T20), 30 (T30), 45 (T45) and 60 (T60) minutes after cardiac arrest. Arterial blood samples were collected at T10, T30 and T60. RESULTS: The mean arterial pressure values in the TP50 group were higher than those in the epinephrine group at T10 (165 vs. 112 mmHg), T20 (160 vs. 82 mmHg), T30 (143 vs. 66 mmHg), T45 (119 vs. 67 mmHg) and T60 (96 vs. 66.8 mmHg). The blood lactate level was lower in the naloxone group than in the epinephrine group at T10 (5.15 vs. 10.5 mmol/L), T30 (2.57 vs. 5.24 mmol/L) and T60 (2.1 vs. 4.1 mmol/L). CONCLUSIONS: In this rat model of asphyxia-induced cardiac arrest, terlipressin and naloxone were effective vasopressors in cardiopulmonary resuscitation and presented better metabolic profiles than epinephrine. Terlipressin provided better hemodynamic stability than epinephrine.
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Epinefrina/farmacologia , Parada Cardíaca/tratamento farmacológico , Lipressina/análogos & derivados , Modelos Animais , Naloxona/farmacologia , Vasoconstritores/farmacologia , Animais , Pressão Arterial/efeitos dos fármacos , Asfixia/complicações , Reanimação Cardiopulmonar , Epinefrina/metabolismo , Parada Cardíaca/etiologia , Parada Cardíaca/fisiopatologia , Hemodinâmica/efeitos dos fármacos , Lipressina/metabolismo , Lipressina/farmacologia , Masculino , Naloxona/metabolismo , Distribuição Aleatória , Ratos , Ratos Wistar , Valores de Referência , Reprodutibilidade dos Testes , Terlipressina , Fatores de Tempo , Vasoconstritores/metabolismoRESUMO
Prosthetic mesh implants are commonly used to correct abdominal wall defects. However, success of the procedure is conditioned by an adequate inflammatory response to the device. We hypothesized that nitric oxide produced by nitric oxide synthase 2 (NOS2) and MMP-2 and -9 participate in response induced by mesh implants in the abdominal wall and, consequently, affect the outcome of the surgical procedure. In the first step, temporal inflammatory markers profile was evaluated. Polypropylene meshes were implanted in the peritoneal side of the abdominal wall of C57Black mice. After 2, 4, 7, 15, and 30 days, tissues around the mesh implant were collected and inflammatory markers were analyzed. In the second step, NOS2 activity was inhibited with nitro-L-arginine methyl ester (L-NAME). Samples were collected after 15 days (when inflammation was reduced), and the inflammatory and tissue remodeling markers were investigated. Polypropylene mesh implant induced a pro-inflammatory environment mediated by intense MMP-2 and -9 activities, NO release, and interleukin-1ß production peaking in 7 days and gradually decreasing after 15 days. NOS2 inhibition increased MMP-2 activity and resulted in a higher visceral adhesion incidence at the mesh implantation site when compared with non-treated animals that underwent the same procedure. We conclude that NOS2-derived NO is crucial for adequate response to polypropylene mesh implant integration in the peritoneum. NO deficiency results in an imbalance between extracellular matrix deposition/degradation contributing to visceral adhesions incidence.
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Inflamação/etiologia , Metaloproteinase 2 da Matriz/imunologia , Óxido Nítrico Sintase Tipo II/imunologia , Peritônio/cirurgia , Polipropilenos/efeitos adversos , Próteses e Implantes/efeitos adversos , Telas Cirúrgicas/efeitos adversos , Animais , Inibidores Enzimáticos/farmacologia , Matriz Extracelular/imunologia , Inflamação/imunologia , Interleucina-1beta/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/imunologia , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Peritônio/imunologia , Polipropilenos/imunologiaRESUMO
BACKGROUND: Renal dysfunction is associated with increased mortality in patients with decompensated heart failure. However, interventions targeted to prevention in this setting have been disappointing. We investigated the effects of hypertonic saline solution (HSS) for prevention of renal dysfunction in decompensated heart failure. METHODS: In a double-blind randomized trial, patients with decompensated heart failure were assigned to receive three-day course of 100mL HSS (NaCl 7.5%) twice daily or placebo. Primary end point was an increase in serum creatinine of 0.3mg/dL or more. Main secondary end point was change in biomarkers of renal function, including serum levels of creatinine, cystatin C, neutrophil gelatinase-associated lipocalin-NGAL and the urinary excretion of aquaporin 2 (AQP2), urea transporter (UT-A1), and sodium/hydrogen exchanger 3 (NHE3). RESULTS: Twenty-two patients were assigned to HSS and 12 to placebo. Primary end point occurred in two (10%) patients in HSS group and six (50%) in placebo group (relative risk 0.3; 95% CI 0.09-0.98; P=0.01). Relative to baseline, serum creatinine and cystatin C levels were lower in HSS as compared to placebo (P=0.004 and 0.03, respectively). NGAL level was not statistically different between groups, however the urinary expression of AQP2, UT-A1 and NHE3 was significantly higher in HSS than in placebo. CONCLUSIONS: HSS administration attenuated heart failure-induced kidney dysfunction as indicated by improvement in both glomerular and tubular defects, a finding with important clinical implications. HSS modulated the expression of tubular proteins involved in regulation of water and electrolyte homeostasis.
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Hidratação/métodos , Insuficiência Cardíaca/terapia , Nefropatias/prevenção & controle , Nefropatias/fisiopatologia , Solução Salina Hipertônica/administração & dosagem , Adulto , Idoso , Método Duplo-Cego , Feminino , Insuficiência Cardíaca/epidemiologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Nefropatias/epidemiologia , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: To evaluate the hemodynamic and metabolic effects of terlipressin and naloxone in cardiac arrest. METHODS: Cardiac arrest in rats was induced by asphyxia and maintained for 3.5 minutes. Animals were then resuscitated and randomized into one of six groups: placebo (n = 7), epinephrine (0.02 mg/kg; n = 7), naloxone (1 mg/kg; n = 7) or terlipressin, of which three different doses were tested: 50 µg/kg (TP50; n = 7), 100 µg/kg (TP100; n = 7) and 150 µg/kg (TP150; n = 7). Hemodynamic variables were measured at baseline and at 10 (T10), 20 (T20), 30 (T30), 45 (T45) and 60 (T60) minutes after cardiac arrest. Arterial blood samples were collected at T10, T30 and T60. RESULTS: The mean arterial pressure values in the TP50 group were higher than those in the epinephrine group at T10 (165 vs. 112 mmHg), T20 (160 vs. 82 mmHg), T30 (143 vs. 66 mmHg), T45 (119 vs. 67 mmHg) and T60 (96 vs. 66.8 mmHg). The blood lactate level was lower in the naloxone group than in the epinephrine group at T10 (5.15 vs. 10.5 mmol/L), T30 (2.57 vs. 5.24 mmol/L) and T60 (2.1 vs. 4.1 mmol/L). CONCLUSIONS: In this rat model of asphyxia-induced cardiac arrest, terlipressin and naloxone were effective vasopressors in cardiopulmonary resuscitation and presented better metabolic profiles than epinephrine. Terlipressin provided better hemodynamic stability than epinephrine. .
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Animais , Masculino , Ratos , Epinefrina/farmacologia , Parada Cardíaca/tratamento farmacológico , Lipressina/análogos & derivados , Modelos Animais , Naloxona/farmacologia , Vasoconstritores/farmacologia , Pressão Arterial/efeitos dos fármacos , Asfixia/complicações , Reanimação Cardiopulmonar , Epinefrina/metabolismo , Parada Cardíaca/etiologia , Parada Cardíaca/fisiopatologia , Hemodinâmica/efeitos dos fármacos , Lipressina/metabolismo , Lipressina/farmacologia , Naloxona/metabolismo , Distribuição Aleatória , Ratos Wistar , Valores de Referência , Reprodutibilidade dos Testes , Fatores de Tempo , Vasoconstritores/metabolismoRESUMO
PURPOSE: Metabolic disturbances are quite common in critically ill patients. Glycemic control appears to be an important adjuvant therapy in such patients. In addition, disorders of lipid metabolism are associated with worse prognoses. The purpose of this study was to investigate the effects that two different glycemic control protocols have on lipid profile and metabolism. METHODS: We evaluated 63 patients hospitalized for severe sepsis or septic shock, over the first 72 h of intensive care. Patients were randomly allocated to receive conservative glycemic control (target range 140180 mg/dl) or intensive glycemic control (target range 80110 mg/dl). Serum levels of lowdensity lipoprotein, high-density lipoprotein, triglycerides, total cholesterol, free fatty acids, and oxidized low-density lipoprotein were determined. RESULTS: In both groups, serum levels of low-density lipoprotein, high-density lipoprotein, and total cholesterol were below normal, whereas those of free fatty acids, triglycerides, and oxidized lowdensity lipoprotein were above normal. At 4 h after admission, free fatty acid levels were higher in the conservative group than in the intensive group, progressively decreasing in both groups until hour 48 and continuing to decrease until hour 72 only in the intensive group. Oxidized low-density lipoprotein levels were elevated in both groups throughout the study period. CONCLUSIONS: Free fatty acids respond to intensive glycemic control and, because of their high toxicity, can be a therapeutic target in patients with sepsis.
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Glicemia/análise , Dislipidemias/complicações , Dislipidemias/prevenção & controle , Sepse/sangue , APACHE , Colesterol/sangue , Colorimetria , Ensaio de Imunoadsorção Enzimática , Ácidos Graxos não Esterificados/sangue , Feminino , Humanos , Lipoproteínas HDL/sangue , Lipoproteínas LDL/sangue , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Estatísticas não Paramétricas , Triglicerídeos/sangueRESUMO
Prosthetic meshes are commonly used to correct abdominal wall defects. However, the inflammatory reaction induced by these devices in the peritoneum is not completely understood. We hypothesized that nitric oxide (NO), produced by nitric oxide synthase 2 (NOS2) may modulate the response induced by mesh implants in the abdominal wall and, consequently, affect the outcome of the surgical procedure. Polypropylene meshes were implanted in the peritoneal side of the abdominal wall in wild-type and NOS2-deficient (NOS2(-/-)) mice. After 15 days tissues around the mesh implant were collected, and inflammatory markers (the cytokine interleukin 1ß (IL-1ß) and NO) and tissue remodeling (collagen and metalloproteinases (MMP) 2 and 9) were analyzed. The lack of NOS2-derived NO induced a higher incidence of visceral adhesions at the mesh implantation site compared with wild-type mice that underwent the same procedure (P<0.05). Additionally, higher levels of IL-1ß were present in the mesh-implanted NOS2(-/-) animals compared with control and wild-type mice. Mesh implantation induced collagen I and III deposition, but in smaller amounts in NOS2(-/-) mice. MMP-9 activity after the surgical procedure was similarly increased in both groups. Conversely, MMP-2 activity was unchanged in mesh-implanted wild-type mice, but was significantly increased in NOS2(-/-) mice (P<0.01), due to decreased S-nitrosylation of the enzyme in these animals. We conclude that NOS2-derived NO is crucial for an adequate response to and integration of polypropylene mesh implants in the peritoneum. NO deficiency results in a prolonged inflammatory reaction to the mesh implant, and reduced collagen deposition may contribute to an increased incidence of visceral adhesions.
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Parede Abdominal/cirurgia , Colágeno/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Óxido Nítrico/metabolismo , Polipropilenos/metabolismo , Telas Cirúrgicas , Aderências Teciduais/metabolismo , Parede Abdominal/patologia , Animais , Materiais Biocompatíveis/metabolismo , Inflamação/imunologia , Inflamação/patologia , Interleucina-1beta/metabolismo , Masculino , Teste de Materiais , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Próteses e Implantes , Distribuição Aleatória , Aderências Teciduais/patologia , Cicatrização/fisiologiaRESUMO
Laser phototherapy emerges as an alternative or auxiliary therapy for acute ischemic stroke, traumatic brain injury, degenerative brain disease, spinal cord injury, and peripheral nerve regeneration, but its effects are still controversial. We have previously found that laser phototherapy immunomodulates the response to focal brain damage. Following direct cortical cryogenic injury the effects of laser phototherapy on inflammation and repair was assessed after cryogenic injury (CI) to the central nervous system (CNS) of rats. The laser phototherapy was carried out with a 780 nm AlGaAs diode laser. The irradiation parameters were: power of 40 mW, beam area of 0.04 cm(2), energy density of 3 J/cm(2) (3s) in two points (0.12 J per point). Two irradiations were performed at 3 h-intervals, in contact mode. Rats (20 non-irradiated - controls and 20 irradiated) were used. The wound healing in the CNS was followed in 6 h, 1, 7 and 14 days after the last irradiation. The size of the lesions, the neuron cell viability percentages and the amount of positive GFAP labeling were statistically compared by ANOVA complemented by Tukey's test (p<0.05). The distribution of lymphocytes, leukocytes and macrophages were also analyzed. CI created focal lesions in the cortex represented by necrosis, edema, hemorrhage and inflammatory infiltrate. The most striking findings were: lased lesions showed smaller tissue loss than control lesions in 6 h. During the first 24 h the amount of viable neurons was significantly higher in the lased group. There was a remarkable increase in the amount of GFAP in the control group by 14 days. Moreover, the lesions of irradiated animals had fewer leukocytes and lymphocytes in the first 24 h than controls. Considering the experimental conditions of this study it was concluded that laser phototherapy exerts its effect in wound healing following CI by controlling the brain damage, preventing neuron death and severe astrogliosis that could indicate the possibility of a better clinical outcome.
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Isquemia Encefálica/fisiopatologia , Isquemia Encefálica/radioterapia , Temperatura Baixa/efeitos adversos , Terapia com Luz de Baixa Intensidade , Cicatrização/efeitos da radiação , Animais , Isquemia Encefálica/etiologia , Isquemia Encefálica/patologia , Sobrevivência Celular/efeitos da radiação , Leucócitos/imunologia , Leucócitos/efeitos da radiação , Masculino , Neuroglia/patologia , Neuroglia/efeitos da radiação , Neurônios/patologia , Neurônios/efeitos da radiação , Ratos , Ratos WistarRESUMO
Sepsis induces a systemic inflammatory response leading to tissue damage and cell death. LPS tolerance affects inflammatory response. To comprehend potential new mechanisms of immune regulation in endotoxemia, we examined macrophage mRNA expression by macroarray affected by LPS tolerance. LPS tolerance was induced with subcutaneous administration of 1 mg/kg/day of LPS over 5 days. Macrophages were isolated from the spleen and the expression of 1200 genes was quantitatively analyzed by the macroarray technique. The tolerant group displayed relevant changes in the expression of 84 mRNA when compared to naïve mice. A functional group of genes related to cell death regulation was identified. PARP-1, caspase 3, FASL and TRAIL genes were confirmed by RT-PCR to present lower expression in tolerant mice. In addition, reduced expression of the pro-inflammatory genes TNF-α and IFN-γ in the tolerant group was demonstrated. Following this, animals were challenged with polymicrobial sepsis. Flow cytometry analysis showed reduced necrosis and apoptosis in macrophages from the tolerant group compared to the naïve group. Finally, a survival study showed a significant reduction in mortality in the tolerant group. Thus, in the current study we provide evidence for the selective reprogramming of the gene expression of cell death pathways during LPS tolerance and link these changes to protection from cell death and enhanced survival rates.
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Apoptose , Expressão Gênica , Macrófagos/citologia , Macrófagos/imunologia , Sepse/imunologia , Animais , Linhagem da Célula , Células Cultivadas , Citocinas/genética , Lipopolissacarídeos/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Sepse/genéticaRESUMO
Signal transduction through the surface molecule CD40 is critical for cellular activation in immunoinflammatory states such as sepsis. The mechanisms regulating this pathway are not completely understood. Because CD40 displays potentially regulatory cysteine residues and CD40 is probably exposed to NO in the inflammatory milieu, we hypothesized that S-nitrosylation, the interaction of NO with cysteines residues, acts as a post-translational modification on CD40, coregulating the signaling activity and, therefore, the level of cellular activation. As assessed by the biotin switch and the reduction/chemiluminescence S-nitrosylation detection techniques, CD40 was found to be S-nitrosylated endogenously and upon exposure to NO donors in both human and murine macrophages. S-nitrosylation of CD40 was associated with milder activation by its ligand (CD40L), leading to reduced in vitro cytokine (IL-1beta, IL-12, and TNF-alpha) production, which was reversed in the presence of inhibitors of NO synthesis. S-nitrosylated CD40 was found in resting RAW 246.7 macrophages and BALB/c mice peritoneal macrophages, turning into the denitrosylated state upon in vitro or systemic exposure, respectively, to LPS. Moreover, monocytes from patients with sepsis displayed denitrosylated CD40 in contrast to the CD40 S-nitrosylation measured in healthy individuals. Finally, in an attempt to explain how S-nitrosylation regulates CD40 activation, we demonstrate that NO affects the redistribution of CD40 on the cell surface, which is a requirement for optimal signal transduction. Our results support a novel post-translational regulatory mechanism in which the CD40 signal may be, at least in part, dependent on cellular activation-induced receptor denitrosylation.
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Antígenos CD40/metabolismo , Endotoxemia/imunologia , Inflamação/fisiopatologia , Óxido Nítrico/metabolismo , Sepse/imunologia , Transdução de Sinais/imunologia , Adulto , Idoso , Animais , Ligante de CD40/metabolismo , Linhagem Celular , Citocinas/biossíntese , Regulação para Baixo , Endotoxemia/metabolismo , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , Pessoa de Meia-Idade , Doadores de Óxido Nítrico/metabolismo , Processamento de Proteína Pós-Traducional , Sepse/metabolismoRESUMO
Extensive lymphocyte apoptosis may be an important cause of immune suppression in sepsis. Here we investigated the effect of LPS tolerance on lymphocyte apoptosis in an experimental model of polymicrobial infection. Tolerance was induced by the injection of lipopolysaccharide (1.0mg/kg/subcutaneously) once a day for 5 days. Macroarray analysis of mRNA isolated from T-(CD4) lymphocytes was used to identify genes that are differentially expressed during LPS tolerance. In addition, assessment of the expression of apoptosis-associated lymphocyte gene products and apoptotic events was performed on the 8th day; 6h after the terminal challenge with polymicrobial infection or high-dose LPS administration. Survival studies with polymicrobial infection were also conducted. LPS tolerance induced a broad reprogramming of cell death pathways, including a suppression of receptor-mediated and mitochondrial apoptotic pathways, inflammatory caspases, alternate apoptotic pathways, as well as reduced expression of genes involved in necrosis. These alterations led to a marked resistance of lymphocytes against cell death during the subsequent period of sepsis. In addition, LPS tolerance produced an increased differentiation of T-lymphocytes to T(H)1 and T(H)2, with a T(H)1 differentiation predominance. Thus, in the current study we provide an evidence for a marked reprogramming of gene expression of multiple cell death pathways during LPS tolerance. These alterations may play a significant role in the observed protection of the animals from a subsequent lethal polymicrobial sepsis challenge.
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Apoptose/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Regulação da Expressão Gênica/efeitos dos fármacos , Tolerância Imunológica/imunologia , Lipopolissacarídeos/farmacologia , Animais , Apoptose/imunologia , Linfócitos T CD4-Positivos/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/imunologia , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Análise de Sequência com Séries de Oligonucleotídeos , RNA Mensageiro/biossíntese , RNA Mensageiro/imunologia , Sepse/imunologia , Sepse/metabolismo , Sepse/prevenção & controleRESUMO
1. We recently demonstrated that hypertonic saline reduces inflammation and mortality in acute pancreatitis. The present study investigated the effects of hypertonic saline in metalloproteinase (MMP) regulation and pancreatitis-associated hepatic injury. 2. Wistar rats were divided into four groups: (i) control, not subjected to insult or treatment; (ii) no treatment (NT), induction of pancreatitis (retrograde infusion of 2.5% sodium taurocholate (1.0 mL/kg)), but no further treatment; (iii) normal saline (NS), induction of pancreatitis and treatment with normal saline (0.9% NaCl, 34 mL/kg, i.v. bolus, 1 h after the induction of pancreatitis); and (iv) hypertonic saline (HS), induction of pancreatitis and treatment with hypertonic saline (7.5% NaCl, 4 mL/kg administered over a period of 5 min, 1 h after the induction of pancreatitis). In all four groups, 4, 12 and 24 h after the induction of pancreatitis, liver tissue samples were assayed to determine levels of MMP-2, MMP-9, 47 kDa heat shock protein (HSP47) and collagen (Type I and III). 3. Compared with the control group, MMP-9 expression and activity was increased twofold in the NS and NT groups 4 and 12 h after the induction of pancreatitis, but remained at basal levels in the HS group. In contrast, MMP-2 expression was increased twofold 12 h after the induction of pancreatitis only in the NS group, whereas the expression of HSP47 was increased 4 h after the induction of pancreatitis in the NS and NT groups. Greater extracellular matrix remodelling occurred in the NS and NT groups compared with the HS group, probably as a result of the hepatic wound-healing response to repeated injury. However, the collagen content in hepatic tissue remained at basal levels in the HS group. 4. In conclusion, the results of the present study indicate that hypertonic saline is hepatoprotective and reduces hepatic remodelling, maintaining the integrity of the hepatic extracellular matrix during pancreatitis. Hypertonic saline-mediated regulation of MMP expression may have clinical relevance in pancreatitis-associated liver injury.
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Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Hepatopatias/tratamento farmacológico , Fígado/efeitos dos fármacos , Fígado/enzimologia , Pancreatite/tratamento farmacológico , Traumatismo por Reperfusão/tratamento farmacológico , Solução Salina Hipertônica/administração & dosagem , Animais , Colágeno/metabolismo , Proteínas de Choque Térmico HSP47/metabolismo , Fígado/metabolismo , Hepatopatias/complicações , Hepatopatias/enzimologia , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Pancreatite/complicações , Pancreatite/metabolismo , Ratos , Ratos Wistar , Traumatismo por Reperfusão/genética , Solução Salina Hipertônica/farmacologia , Ácido TaurocólicoRESUMO
BACKGROUND: Obesity is associated with increased sympathetic activity and higher mortality. Treatment of this condition is often frustrating. Roux-en-Y gastric bypass is the most effective technique nowadays for treatment of obesity. The aim of the present study is to assess the effects of this surgery on the cardiac autonomic activity, including the influence of gender and age, through heart rate variability (HRV) analysis. METHODS: The study group consisted of 71 obese patients undergoing gastric bypass. Time domain measures of HRV, obtained from 24-h Holter recordings, were evaluated before and 6 months after surgery, and the results were compared. Percentage of interval differences of successive normal sinus beats greater than 50 ms (pNN50) and square root of the mean squared differences of successive normal sinus beat intervals (rMSSD) was used to estimate the short-term components of HRV, related to the parasympathetic activity. Standard deviation of intervals between all normal sinus beats (SDNN) was related to overall HRV. RESULTS: SDNN, pNN50, and rMSSD showed significant increase 6 months after surgery (p<0.001, p=0.001 and p=0.002, respectively). Men presented a greater increase of SDNN than women (p=0.006) during the follow-up. There was a difference in rMSSD evolution for age groups (p=0.002). Only younger patients presented significant increase of rMSSD. CONCLUSION: Overall HRV increased 6 months after surgery; this increase was more evident in men. Cardiac parasympathetic activity increased also, but in younger patients only.
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Sistema Nervoso Autônomo/fisiopatologia , Derivação Gástrica , Obesidade Mórbida/fisiopatologia , Obesidade Mórbida/cirurgia , Nó Sinoatrial/fisiopatologia , Adolescente , Adulto , Fatores Etários , Índice de Massa Corporal , Estudos de Coortes , Feminino , Frequência Cardíaca/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Fatores Sexuais , Circunferência da Cintura , Redução de Peso/fisiologia , Adulto JovemAssuntos
Anticoagulantes/uso terapêutico , Benzimidazóis/uso terapêutico , Enoxaparina/uso terapêutico , Complicações Pós-Operatórias/prevenção & controle , Piridinas/uso terapêutico , Tromboembolia Venosa/prevenção & controle , Anticoagulantes/economia , Artroplastia de Quadril , Análise Custo-Benefício , Dabigatrana , Humanos , Flebografia , Tromboembolia Venosa/diagnóstico por imagemRESUMO
Sepsis, a leading cause of death worldwide, involves proinflammatory responses and inefficient bacterial clearance. Phagocytic cells play a crucial part in the prevention of sepsis by clearing bacteria through host innate receptors. Here we show that the FcRgamma adaptor, an immunoreceptor tyrosine-based activation motif (ITAM)-bearing signal transduction subunit of the Fc receptor family, has a deleterious effect on sepsis. FcRgamma(-/-) mice show increased survival during peritonitis, owing to markedly increased E. coli phagocytosis and killing and to lower production of the proinflammatory cytokine tumor necrosis factor (TNF)-alpha. The FcRgamma-associated receptor that inhibits E. coli phagocytosis is FcgammaRIII (also called CD16), and its absence protects mice from sepsis. FcgammaRIII binds E. coli, and this interaction induces FcRgamma phosphorylation, recruitment of the tyrosine phosphatase SHP-1 and phosphatidylinositide-3 kinase (PI3K) dephosphorylation. Decreased PI3K activity inhibits E. coli phagocytosis and increases TNF-alpha production through Toll-like receptor 4. We identified the phagocytic receptor negatively regulated by FcRgamma on macrophages as the class A scavenger receptor MARCO. E. coli-FcgammaRIII interaction induces the recruitment of SHP-1 to MARCO, thereby inhibiting E. coli phagocytosis. Thus, by binding FcgammaRIII, E. coli triggers an inhibitory FcRgamma pathway that both impairs MARCO-mediated bacterial clearance and activates TNF-alpha secretion.
Assuntos
Infecções por Escherichia coli/imunologia , Mediadores da Inflamação/fisiologia , Fagocitose/imunologia , Receptores de IgG/fisiologia , Sepse/imunologia , Transdução de Sinais/imunologia , Animais , Células da Medula Óssea/imunologia , Células da Medula Óssea/metabolismo , Células da Medula Óssea/patologia , Linhagem Celular , Células Cultivadas , Infecções por Escherichia coli/metabolismo , Infecções por Escherichia coli/microbiologia , Escherichia coli K12/imunologia , Mediadores da Inflamação/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Proteína Tirosina Fosfatase não Receptora Tipo 6/fisiologia , Receptores de IgG/deficiência , Receptores de IgG/genética , Receptores Imunológicos/antagonistas & inibidores , Receptores Imunológicos/fisiologia , Sepse/metabolismo , Sepse/microbiologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
OBJECTIVES: Severe acute pancreatitis (AP) is characterized by hemodynamic alterations and a systemic inflammatory response, leading to a high mortality rate. Treatment of hemorrhagic shock with hypertonic saline solutions significantly reduces mortality through an improvement in the hemodynamic conditions and possibly by an anti-inflammatory effect. Therefore, hypertonic solutions could be effective in AP. METHODS: Wistar rats were divided in 4 groups: group C, control, without AP; group NT, AP, without treatment; group NS, treatment with normal saline solution (NaCl 0.9%) 1 hour after AP; group HTS, treatment with hypertonic saline solution (NaCl 7.5%) 1 hour after AP. AP was induced by injection of 2.5% sodium taurocholate into the pancreatic duct. Mean arterial blood pressure (MAP) and heart rate were recorded at 0 and 2, 4, 24, and 48 hours after AP. After induction of AP, animals were killed at 2, 12, 24, and 48 hours for serum amylase, interleukin (IL)-6, and IL-10 analysis, pancreatic tissue culture and histologic analysis, oxidation and phosphorylation of liver mitochondria, pulmonary myeloperoxidase activity (MPO), and mortality study. RESULTS: In animals of groups NS and NT, a significant decrease of MAP was observed 48 hours after AP (NS: 91 +/- 3 mm Hg; NT: 89 +/- 3 mm Hg) compared with baseline (C: 105 +/- 2 mm Hg) and to HTS group (HTS: 102 +/- 2 mm Hg; P < 0.05). In animals of group NT, NS, and HTS, serum IL-6 and IL-10 levels were significantly higher at 2 hours after AP compared with the control group. However, IL-6 levels at 12 hours after AP and IL-10 levels at 2 and 12 hours after AP were significant lower in group HTS compared with NS and NT groups (P < 0.05). In group HTS, a decrease of pulmonary MPO activity and of pancreatic infection was observed 24 hours after AP compared with NT and NS groups (P < 0.05). A significant reduction on pancreatic acinar necrosis and mitochondrial dysfunction was observed after 48 hours of AP in animals of group HTS compared with groups NT and NS (P < 0.05). A significant reduction on mortality was observed in HTS (0/14) compared with NS (6/17; 35%) and NT (7/20; 35%). CONCLUSIONS: The administration of hypertonic saline solution in experimental AP attenuated hemodynamic alterations, decreased inflammatory cytokines, diminished systemic lesions and pancreatic acinar necrosis, prevented pancreatic infection, and reduced the mortality rate.
Assuntos
Pancreatite/terapia , Solução Salina Hipertônica/uso terapêutico , Doença Aguda , Animais , Pressão Sanguínea , Modelos Animais de Doenças , Frequência Cardíaca , Inflamação/prevenção & controle , Pancreatite/fisiopatologia , Ratos , Ratos WistarRESUMO
To determine the effects of Tityus serrulatus scorpion toxin on lung compliance and resistance, ionic equilibrium and acid-base balance over time in anesthetized and mechanically ventilated rats, we measured air flow, tracheal and esophageal pressure. Lung volume was obtained by electronic integration of airflow signal. Arterial blood samples were collected through a catheter at baseline (before) and 5, 15, 30 and 60 min after scorpion toxin injection for arterial blood gases, bicarbonate, and alkali reserve levels as well as for, sodium, potassium, magnesium, glucose, lactate, hematocrit, and osmolality analysis. Injection of the gamma fraction of the T. serrulatus scorpion venom in rats under mechanical ventilatory support leads to a continuous decrease in lung compliance secondary to pulmonary edema, but no change in airway resistance. The changes in arterial blood gases characterizing metabolic acidosis were accompanied by an increase in arterial lactate and glucose values, suggesting a scorpion toxin-induced lactic acidosis, in association with poor tissue perfusion (hypotension and low cardiac output). Moreover, scorpion toxin injection resulted in hyperosmolality, hyperkalemia, hypermagnesemia and an increase in hematocrit. The experiments have shown a clinically relevant animal model to study severe scorpion envenoming and may help to better understand the scorpion envenoming syndrome.
Assuntos
Equilíbrio Ácido-Base/efeitos dos fármacos , Eletrólitos/sangue , Complacência Pulmonar/efeitos dos fármacos , Venenos de Escorpião/toxicidade , Resistência das Vias Respiratórias/efeitos dos fármacos , Álcalis/sangue , Animais , Bicarbonatos/sangue , Glicemia/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Dióxido de Carbono/sangue , Débito Cardíaco/efeitos dos fármacos , Hematócrito , Concentração de Íons de Hidrogênio , Lactatos/sangue , Ratos , Escorpiões , Fatores de Tempo , Resistência Vascular/efeitos dos fármacosRESUMO
It has been widely recognized that the hippocampus and striatum are clearly more susceptible to oxidative stress than the remaining brain regions. However, the mechanism involved is not known. The activities of the antioxidant enzymes CuZn-superoxide dismutase (SOD), Mn-SOD and catalase were measured in the hippocampus and striatum and the results were compared to cortex and cerebellum (less susceptible to oxidative stress) after 3 h of a global transient ischemia/reperfusion. CuZn-SOD activities were reduced in all brain regions, but mainly in the hippocampus and striatum. Mn-SOD activity was lowered in the striatum, whereas catalase activity was reduced in the hippocampus and striatum. Our findings indicate that in the earlier phase of ischemia/reperfusion the decay in activities of catalase and SOD may be related with the high susceptibility of the hippocampus and striatum to oxidative damage.