RESUMO
BACKGROUND: Currently, clinical indicators for evaluating endothelial permeability in sepsis are unavailable. Endothelium-derived extracellular vesicles (EDEVs) are emerging as biomarkers of endothelial injury. Platelet endothelial cell adhesion molecule (PECAM) and vascular endothelial (VE)-cadherin are constitutively expressed endothelial intercellular adhesion molecules that regulate intercellular adhesion and permeability. Herein, we investigated the possible association between EDEVs expressing intercellular adhesion molecules (PECAM+ or VE-cadherin+ EDEVs) and endothelial permeability and sepsis severity. METHODS: Human umbilical vein endothelial cells (HUVECs) were stimulated with tumor necrosis factor alpha (TNF-α) directly or after pretreatment with permeability-modifying reagents such as angiopoietin-1, prostacyclin, or vascular endothelial growth factor (VEGF) to alter TNF-α-induced endothelial hyperpermeability. Endothelial permeability was measured using the dextran assay or transendothelial electrical resistance. Additionally, a prospective cross-sectional observational study was conducted to analyze circulating EDEV levels in patients with sepsis. EDEVs were examined in HUVEC culture supernatants or patient plasma (nonsepsis, n = 30; sepsis, n = 30; septic shock, n = 42) using flow cytometry. The Wilcoxon rank-sum test was used for comparisons between 2 groups. Comparisons among 3 or more groups were performed using the Steel-Dwass test. Spearman's test was used for correlation analysis. Statistical significance was set at P < .05. RESULTS: TNF-α stimulation of HUVECs significantly increased EDEV release and endothelial permeability. Pretreatment with angiopoietin-1 or prostacyclin suppressed the TNF-α-induced increase in endothelial permeability and inhibited the release of PECAM+ and VE-cadherin+ EDEVs. In contrast, pretreatment with VEGF increased TNF-α-induced endothelial permeability and the release of PECAM+ and VE-cadherin+ EDEVs. However, pretreatment with permeability-modifying reagents did not affect the release of EDEVs expressing inflammatory stimulus-inducible endothelial adhesion molecules such as E-selectin, intracellular adhesion molecule-1, or vascular cell adhesion molecule-1. The number of PECAM+ EDEVs on admission in the septic-shock group (232 [124, 590]/µL) was significantly higher (P = .043) than that in the sepsis group (138 [77,267]/µL), with an average treatment effect of 98/µL (95% confidence interval [CI], 2-270/µL), and the number of VE-cadherin+ EDEVs in the septic-shock group (173 [76,339]/µL) was also significantly higher (P = .004) than that in the sepsis group (81 [42,159]/µL), with an average treatment effect (ATE) of 79/µL (95% CI, 19-171/µL); these EDEV levels remained elevated until day 5. CONCLUSIONS: EDEVs expressing intercellular adhesion molecules (PECAM+ or VE-cadherin+ EDEVs) may reflect increased endothelial permeability and could be valuable diagnostic and prognostic markers for sepsis.
Assuntos
Antígenos CD , Caderinas , Permeabilidade Capilar , Vesículas Extracelulares , Células Endoteliais da Veia Umbilical Humana , Sepse , Índice de Gravidade de Doença , Humanos , Vesículas Extracelulares/metabolismo , Sepse/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Masculino , Estudos Prospectivos , Antígenos CD/metabolismo , Feminino , Pessoa de Meia-Idade , Caderinas/metabolismo , Idoso , Fator de Necrose Tumoral alfa/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , Estudos Transversais , Células Cultivadas , Angiopoietina-1/metabolismo , Biomarcadores/metabolismo , Biomarcadores/sangue , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Endotélio Vascular/metabolismo , Epoprostenol/metabolismoRESUMO
BACKGROUND/AIMS: Adrenaline quickly inhibits the release of histamine from mast cells. Besides ß2-adrenergic receptors, several in vitro studies also indicate the involvement of α-adrenergic receptors in the process of exocytosis. Since exocytosis in mast cells can be detected electrophysiologically by the changes in the membrane capacitance (Cm), its continuous monitoring in the presence of drugs would determine their mast cell-stabilizing properties. METHODS: Employing the whole-cell patch-clamp technique in rat peritoneal mast cells, we examined the effects of adrenaline on the degranulation of mast cells and the increase in the Cm during exocytosis. We also examined the degranulation of mast cells in the presence or absence of α-adrenergic receptor agonists or antagonists. RESULTS: Adrenaline dose-dependently suppressed the GTP-γ-S-induced increase in the Cm and inhibited the degranulation from mast cells, which was almost completely erased in the presence of butoxamine, a ß2-adrenergic receptor antagonist. Among α-adrenergic receptor agonists or antagonists, high dose prazosin, a selective α1-adrenergic receptor antagonist, significantly reduced the ratio of degranulating mast cells and suppressed the increase in the Cm. Additionally, prazosin augmented the inhibitory effects of adrenaline on the degranulation of mast cells. CONCLUSION: This study provided electrophysiological evidence for the first time that adrenaline dose-dependently inhibited the process of exocytosis, confirming its usefulness as a potent mast cell-stabilizer. The pharmacological blockade of α1-adrenergic receptor by prazosin synergistically potentiated such mast cell-stabilizing property of adrenaline, which is primarily mediated by ß2-adrenergic receptors.
Assuntos
Degranulação Celular , Epinefrina , Exocitose , Mastócitos , Prazosina , Animais , Mastócitos/efeitos dos fármacos , Mastócitos/metabolismo , Mastócitos/citologia , Epinefrina/farmacologia , Ratos , Prazosina/farmacologia , Degranulação Celular/efeitos dos fármacos , Masculino , Exocitose/efeitos dos fármacos , Técnicas de Patch-Clamp , Antagonistas de Receptores Adrenérgicos alfa 1/farmacologia , Ratos WistarRESUMO
BACKGROUND: Esophagectomy is a high-risk procedure that can involve serious postoperative complications. There has been an increase in the number of minimally invasive esophagectomies (MIEs) being performed. However, the relationship between intraoperative management and postoperative complications in MIE remains unclear. METHODS: After the institutional review board approval, we enrolled 300 patients who underwent MIE at Tohoku University Hospital between April 2016 and March 2021. The relationships among patient characteristics, intraoperative and perioperative factors, and postoperative complications were retrospectively analyzed. The primary outcome was the relationship between intraoperative fluid volume and anastomotic leakage, and the secondary outcomes included the associations between other perioperative factors and postoperative complications. RESULTS: Among 300 patients, 28 were excluded because of missing data; accordingly, 272 patients were included in the final analysis. The median [interquartile range] operative duration was 599 [545-682] minutes; total intraoperative infusion volume was 3,747 [3,038-4,399] mL; total infusion volume per body weight per hour was 5.48 [4.42-6.73] mL/kg/h; and fluid balance was + 2,648 [2,015-3,263] mL. The postoperative complications included anastomotic leakage in 68 (25%) patients, recurrent nerve palsy in 91 (33%) patients, pneumonia in 62 (23%) patients, cardiac arrhythmia in 13 (5%) patients, acute kidney injury in 5 (2%) patients, and heart failure in 5 (2%) patients. The Cochrane-Armitage trend test indicated significantly increased anastomotic leakage among patients with a relatively high total infusion volume (P = 0.0085). Moreover, anastomotic leakage was associated with male sex but not with peak serum lactate levels. Patients with a longer anesthesia duration or recurrent nerve palsy had a significantly higher incidence of postoperative pneumonia than those without. Further, the incidence of postoperative pneumonia was not associated with the operative duration, total infusion volume, or fluid balance. The operative duration and blood loss were related to the total infusion volume. Acute kidney injury was not associated with the total infusion volume or serum lactate levels. CONCLUSIONS: Among patients who underwent MIE, the total infusion volume was positively correlated with the incidence of anastomotic leakage. Further, postoperative pneumonia was associated with recurrent nerve palsy but not total infusion volume or fluid balance.
Assuntos
Neoplasias Esofágicas , Esofagectomia , Pneumonia , Humanos , Masculino , Fístula Anastomótica/epidemiologia , Fístula Anastomótica/etiologia , Fístula Anastomótica/cirurgia , Neoplasias Esofágicas/cirurgia , Esofagectomia/efeitos adversos , Esofagectomia/métodos , Lactatos , Procedimentos Cirúrgicos Minimamente Invasivos/efeitos adversos , Procedimentos Cirúrgicos Minimamente Invasivos/métodos , Paralisia/complicações , Pneumonia/epidemiologia , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Tetralogy of Fallot (TOF) is a complex cyanotic congenital heart disease. As most patients with TOF undergo palliative or radical surgical repair during childhood, cardiac surgery under cardiopulmonary bypass (CPB) for adult survivors with unrepaired TOF is exceedingly rare. CASE PRESENTATION: A 41-year-old woman with unrepaired TOF, pulmonary atresia (PA), and major aortopulmonary collateral arteries (MAPCAs) developed acute infectious endocarditis (IE). As vegetation gradually increased despite intravenous antibiotic administration, she was scheduled for urgent aortic valve replacement under CPB. Pulmonary blood flow was primarily provided by the MAPCAs originating from the descending aorta. Intra-aortic balloon occlusion for MAPCAs was performed to ensure a bloodless surgical field. Aortic valve replacement was successful. CONCLUSION: An adult with uncorrected TOF developed acute IE and subsequently had successful cardiac surgery under CPB. Understanding TOF physiology with PA and MAPCAs, particularly pulmonary blood flow through MAPCAs, is crucial.
RESUMO
In mechanically ventilated severe acute respiratory distress syndrome patients, spontaneous inspiratory effort generates more negative pressure in the dorsal lung than in the ventral lung. The airflow caused by this pressure difference is called pendelluft, which is a possible mechanisms of patient self-inflicted lung injury. This study aimed to use computer simulation to understand how the endotracheal tube and insufficient ventilatory support contribute to pendelluft. We established two models. In the invasive model, an endotracheal tube was connected to the tracheobronchial tree with 34 outlets grouped into six locations: the right and left upper, lower, and middle lobes. In the non-invasive model, the upper airway, including the glottis, was connected to the tracheobronchial tree. To recreate the inspiratory effort of acute respiratory distress syndrome patients, the lower lobe pressure was set at -13 cmH2O, while the upper and middle lobe pressure was set at -6.4 cmH2O. The inlet pressure was set from 10 to 30 cmH2O to recreate ventilatory support. Using the finite volume method, the total flow rates through each model and toward each lobe were calculated. The invasive model had half the total flow rate of the non-invasive model (1.92 L/s versus 3.73 L/s under 10 cmH2O, respectively). More pendelluft (gas flow into the model from the outlets) was observed in the invasive model than in the non-invasive model. The inlet pressure increase from 10 to 30 cmH2O decreased pendelluft by 11% and 29% in the invasive and non-invasive models, respectively. In the invasive model, a faster jet flowed from the tip of the endotracheal tube toward the lower lobes, consequently entraining gas from the upper and middle lobes. Increasing ventilatory support intensifies the jet from the endotracheal tube, causing a venturi effect at the bifurcation in the tracheobronchial tree. Clinically acceptable ventilatory support cannot completely prevent pendelluft.
Assuntos
Baías , Síndrome do Desconforto Respiratório , Humanos , Simulação por Computador , Traqueia , Intubação IntratraquealRESUMO
Background: von Willebrand factors (vWFs), hemostatic factors, are produced as large multimers and are shear stress-dependently cleaved to become the appropriate size. A reduction in vWF large multimers develops in various conditions including the use of extracorporeal life support, which can cause excessive-high shear stress in the blood flow and result in hemostatic disorders. The objective of this prospective study was to investigate the impact of venovenous extracorporeal membrane oxygenation (VV ECMO) use on the status of vWF large multimers and hemostatic disorders during single lung transplantation (SLT). Methods: We prospectively enrolled 12 patients who underwent SLT at our center. Among them, seven patients were supported by VV ECMO intraoperatively (ECMO group) and the remaining five patients underwent SLT without ECMO support (control group). The vWF large multimer index (%) was defined as the ratio of the large multimer proportion in total vWF (vWF large multimer ratio) derived from a patient's plasma to that from standard human plasma. Results: The vWF large multimer index at the end of the surgery was significantly lower in the ECMO group than in the control group (112.6% vs. 75.8%, respectively; P<0.05). The intraoperative blood loss and the amounts of intraoperative transfusion products in the ECMO group tended to be greater than those in the control group; however, the differences were not significant. Conclusions: During SLT, the use of VV ECMO caused a decrease in the vWF large multimer index. The short duration of time of VV ECMO use in our study did not significantly affect the intra- and postoperative outcomes including blood loss, blood transfusion, and re-exploration thoracotomy for bleeding. Nevertheless, to comprehensively evaluate the actual influence of this decrease in the vWF large multimer index on intra- and postoperative outcomes, a multicenter larger-scale study is warranted.
RESUMO
The endotracheal tubes (ETTs) used for children have a smaller inner diameter. Accordingly, the resistance across ETT (RETT) is higher. Theoretically, shortening the ETTs can decrease total airway resistance (Rtotal), because Rtotal is sum of RETT and patient's airway resistance. However, the effectiveness of ETT shortening for mechanical ventilation in the clinical setting has not been reported. We assessed the effectiveness of shortening a cuffed ETT for decreasing Rtotal, and increasing tidal volume (TV), and estimated the RETT/Rtotal ratio in children. In anesthetized children in a constant pressure-controlled ventilation setting, Rtotal and TV were measured with a pneumotachometer before and after shortening a cuffed ETT. In a laboratory experiment, the pressure gradient across the original length, shortened length, and the slip joint alone of the ETT were measured. We then determined the RETT/Rtotal ratio using the above results. The clinical study included 22 children. The median ETT percent shortening was 21.7%. Median Rtotal was decreased from 26 to 24 cmH2O/L/s, and median TV was increased by 6% after ETT shortening. The laboratory experiment showed that ETT length and the pressure gradient across ETT are linearly related under a certain flow rate, and approximately 40% of the pressure gradient across the ETT at its original length was generated by the slip joint. Median RETT/Rtotal ratio were calculated as 0.69. The effectiveness of ETT shortening on Rtotal and TV was very limited, because the resistance of the slip joint was very large.
Assuntos
Resistência das Vias Respiratórias , Intubação Intratraqueal , Humanos , Criança , Volume de Ventilação Pulmonar , Intubação Intratraqueal/métodos , Respiração Artificial , PulmãoRESUMO
OBJECTIVES: Standard bilateral lung transplantation (BLT) is not feasible for patients with pulmonary arterial hypertension (PAH) complicated with a giant pulmonary arterial aneurysm (PAA). This study aimed to describe the outcomes of BLT with pulmonary artery reconstruction (PAR) using donor aorta for such patients. METHODS: This is a retrospective single-centre study reviewing PAH patients with a PAA who received BLT with PAR using donor aorta from January 2010 through December 2020. We compared the characteristics and short- and long-term outcomes of recipients receiving PAR (PAR group) with those who had no PAA and received standard BLT (non-PAR group). RESULTS: Nineteen adult PAH patients underwent cadaveric lung transplantation during the study period. Among them, 5 patients with a giant PAA (median pulmonary artery trunk diameter, 69.9 mm) underwent BLT with PAR using donor aorta and the others received standard BLT. Although the operation time tended to be longer in the PAR group compared with the non-PAR group (1239 vs 958 mins, P = 0.087), 90-day mortality (PAR group: 0% vs non-PAR group: 14.3%, P > 0.99), and 5-year survival rate (PAR group: 100% vs non-PAR group: 85.7%, P = 0.74) was comparable between the groups. No dilatation, constriction or infection of the aortic grafts were recorded during the study period with a median follow-up time of 94 months in the PAR group. CONCLUSIONS: Lung transplantation with PAR using donor aorta is a valid surgical option for PAH patients complicated with a giant PAA.
Assuntos
Aneurisma , Hipertensão Pulmonar , Transplante de Pulmão , Hipertensão Arterial Pulmonar , Adulto , Humanos , Hipertensão Pulmonar/complicações , Hipertensão Pulmonar/cirurgia , Artéria Pulmonar/cirurgia , Estudos Retrospectivos , Aneurisma/complicações , Aneurisma/cirurgia , Hipertensão Pulmonar Primária Familiar , AortaRESUMO
OBJECTIVES: The clinical use of less-invasive devices that calculate the cardiac output from arterial pressure waveform is increasing. The authors aimed to evaluate the accuracy and characteristics of the systemic vascular resistance index (SVRI) of the cardiac index measured by 2 less-invasive devices, fourth-generation FloTrac (CIFT) and LiDCOrapid (CILR), compared with the intermittent thermodilution technique, using a pulmonary artery catheter (CITD). DESIGN: This was a prospective observational study. SETTING: This study was conducted at a single university hospital. PARTICIPANTS: Twenty-nine adult patients undergoing elective cardiac surgery. INTERVENTIONS: Elective cardiac surgery was used as an intervention. MEASUREMENTS AND MAIN RESULTS: Hemodynamic parameters, CIFT, CILR, and CITD, were measured after the induction of general anesthesia, at the start of cardiopulmonary bypass, after completion of weaning from cardiopulmonary bypass, 30 minutes after weaning, and at sternal closure (135 measurements in total). The CIFT and CILR had moderate correlations with CITD (r = 0.62 and 0.58, respectively). Compared with CITD, CIFT, and CILR had a bias of -0.73 and -0.61 L/min/m2, limit of agreement of -2.14-to-0.68 L/min/m2 and -2.42-to-1.20 L/min/m2, and percentage error of 39.9% and 51.2%, respectively. Subgroup analysis for evaluating SVRI characteristics showed that the percentage errors of CIFT and CILR were 33.9% and 54.5% in low SVRI (<1,200 dyne×s/cm5/m), 37.6% and 47.9% in moderate SVRI (1,200-1,800 dyne×s/cm5/m), 49.3% and 50.6% in high SVRI (>1,800 dyne·s/cm5/m2), respectively. CONCLUSIONS: The accuracy of CIFT or CILR was not clinically acceptable for cardiac surgery. Fourth-generation FloTrac was unreliable in high SVRI. LiDCOrapid was inaccurate across a broad range of SVRI, and minimally affected by SVRI.
Assuntos
Procedimentos Cirúrgicos Cardíacos , Monitorização Intraoperatória , Adulto , Humanos , Monitorização Intraoperatória/métodos , Débito Cardíaco , Resistência Vascular , Hemodinâmica , Procedimentos Cirúrgicos Cardíacos/métodos , Termodiluição/métodos , Reprodutibilidade dos TestesRESUMO
OBJECTIVES: The objective of the present study was to examine the effect of venovenous (VV) extracorporeal membrane oxygenation (ECMO) use on the haemodynamics during single lung transplantation (SLT) and postoperative course. METHODS: Forty-seven patients who underwent SLT for end-stage lung diseases in our lung transplant centre between January 2010 and December 2019 were included in this study. The recipients were divided into 3 groups according to the type of intraoperative ECMO. No type of ECMO was intra-operatively used in the patients of the no use of ECMO (NO ECMO) group. The patients in the venoarterial (VA) and VV ECMO groups were put on VA and VV ECMO during the surgery, respectively. The data were compared among the 3 groups. RESULTS: There were 13 SLT cases in the NO ECMO group, 23 SLT cases in the VA ECMO group and 11 SLT cases in the VV ECMO group. Re-exploration for bleeding was performed in 3 (13.0%) recipients in the VA ECMO group. No recipients required re-exploration in the other groups. In the NO ECMO group, systolic pulmonary arterial pressure (PAP) was significantly elevated during the main pulmonary artery clamp on the SLT side and it was decreased in the VA ECMO group because of the bypass flow. Interestingly, systolic PAP was significantly decreased in the VV ECMO group as well. CONCLUSIONS: VV ECMO decreases the PAP during SLT, which could be a choice for extracorporeal life support during lung transplant surgery for patients, even those with pulmonary hypertension.
Assuntos
Oxigenação por Membrana Extracorpórea , Hipertensão Pulmonar , Transplante de Pulmão , Pressão Sanguínea , Oxigenação por Membrana Extracorpórea/efeitos adversos , Hemodinâmica , Humanos , Transplante de Pulmão/efeitos adversos , Estudos RetrospectivosRESUMO
Fluid mechanics show that high-density gases need more energy while flowing through a tube. Thus, high-density anesthetic gases consume more energy to flow and less energy for lung inflation during general anesthesia. However, its impact has not been studied. Therefore, this study aimed to investigate the effects of high-density anesthetic gases on tidal volume in laboratory and clinical settings. In the laboratory study, a test lung was ventilated at the same pressure-controlled ventilation with 22 different gas compositions (density range, 1.22-2.27 kg/m3) using an anesthesia machine. A pneumotachometer was used to record the tidal volume of the test lung and the respiratory gas composition; it showed that the tidal volume of the test lung decreased as the respiratory gas density increased. In the clinical study, the change in tidal volume per body weight, accompanied by gas composition change (2% sevoflurane in oxygen and with 0-30-60% of N2O), was recorded in 30 pediatric patients. The median tidal volume per body weight decreased by 10% when the respiratory gas density increased from 1.41 kg/m3 to 1.70 kg/m3, indicating a significant between-group difference (P < 0.0001). In both settings, an increase in respiratory gas density decreased the tidal volume during pressure-controlled ventilation, which could be explained by the fluid dynamics theory. This study clarified the detailed mechanism of high-density anesthetic gas reduced the tidal volume during mechanical ventilation and revealed that this phenomenon occurs during pediatric anesthesia, which facilitates further understanding of the mechanics of ventilation during anesthesia practice and respiratory physiology.
Assuntos
Anestésicos Inalatórios , Respiração Artificial , Peso Corporal , Criança , Humanos , Pulmão , Volume de Ventilação Pulmonar/fisiologiaAssuntos
Obstrução das Vias Respiratórias , Aneurisma , Complexo de Eisenmenger , Oxigenação por Membrana Extracorpórea , Transplante de Pulmão , Obstrução das Vias Respiratórias/diagnóstico por imagem , Obstrução das Vias Respiratórias/etiologia , Obstrução das Vias Respiratórias/cirurgia , Aneurisma/complicações , Aneurisma/diagnóstico por imagem , Aneurisma/cirurgia , Complexo de Eisenmenger/complicações , Complexo de Eisenmenger/diagnóstico por imagem , Complexo de Eisenmenger/cirurgia , Humanos , Artéria Pulmonar/diagnóstico por imagem , Artéria Pulmonar/cirurgiaRESUMO
Although single-lung transplant on the side with better lung function is challenging in patients with significantly asymmetrical lung function between the right and left sides, it sometimes can be a realistic option because of the recipient's condition and from the viewpoint of organ sharing. We report our experience with a successful case of single-lung transplant on the side with a pulmonary perfusion ratio of 89%. The transplant was performed with the patient under central venoarterial extracorporeal membrane oxygenation through a clamshell incision, and the patient had an acceptable short- and long-term outcome with a remarkable improvement of lung function.
Assuntos
Bronquiolite Obliterante/diagnóstico , Transplante de Pulmão , Insuficiência Respiratória/cirurgia , Adulto , Bronquiolite Obliterante/etiologia , Oxigenação por Membrana Extracorpórea , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Masculino , Qualidade de Vida , Testes de Função Respiratória , Insuficiência Respiratória/etiologia , Resultado do TratamentoRESUMO
BACKGROUND: Adrenaline quickly inhibits the release of histamine from mast cells. Besides ß 2-adrenergic receptors, several in vitro studies also indicate the involvement of α-adrenergic receptors in the process of exocytosis. Since exocytosis in mast cells can be detected electrophysiologically by the changes in the membrane capacitance (Cm), its continuous monitoring in the presence of drugs would determine their mast cell-stabilizing properties. METHODS: Employing the whole-cell patch-clamp technique in rat peritoneal mast cells, we examined the effects of adrenaline on the degranulation of mast cells and the increase in the Cm during exocytosis. We also examined the degranulation of mast cells in the presence or absence of α-adrenergic receptor agonists or antagonists. RESULTS: Adrenaline dose-dependently suppressed the GTP-γ-S-induced increase in the Cm and inhibited the degranulation from mast cells, which was almost completely erased in the presence of butoxamine, a ß 2-adrenergic receptor antagonist. Among α-adrenergic receptor agonists or antagonists, high-dose prazosin, a selective α 1-adrenergic receptor antagonist, significantly reduced the ratio of degranulating mast cells and suppressed the increase in the Cm. Additionally, prazosin augmented the inhibitory effects of adrenaline on the degranulation of mast cells. CONCLUSIONS: This study provided electrophysiological evidence for the first time that adrenaline dose-dependently inhibited the process of exocytosis, confirming its usefulness as a potent mast cell stabilizer. The pharmacological blockade of α 1-adrenergic receptor by prazosin synergistically potentiated such mast cell-stabilizing property of adrenaline, which is primarily mediated by ß 2-adrenergic receptors.
Assuntos
Epinefrina/metabolismo , Prazosina/farmacologia , Receptores Adrenérgicos alfa 1/metabolismo , Animais , Eletrofisiologia , Exocitose/efeitos dos fármacos , Humanos , Masculino , Mastócitos/efeitos dos fármacos , Mastócitos/fisiologia , Ratos , Ratos Wistar , Receptores Adrenérgicos alfa 1/genéticaRESUMO
BACKGROUND: Delayed rectifier K+-channel, Kv1.3, is most predominantly expressed in T-lymphocytes and macrophages. In such leukocytes, Kv1.3-channels play pivotal roles in the activation and proliferation of cells, promoting cellular immunity. Since leukocyte-derived cytokines stimulate fibroblasts to produce collagen fibers in inflamed kidneys, Kv1.3-channels expressed in leukocytes would contribute to the progression of tubulointerstitial renal fibrosis. METHODS: Male Sprague-Dawley rats that underwent unilateral ureteral obstruction (UUO) were used at 1, 2, or 3 weeks after the operation. We examined the histological features of the kidneys and the leukocyte expression of Kv1.3-channels. We also examined the therapeutic effects of a selective channel inhibitor, margatoxin, on the progression of renal fibrosis and the proliferation of leukocytes within the cortical interstitium. RESULTS: In rat kidneys with UUO, progression of renal fibrosis and the infiltration of leukocytes became most prominent at 3 weeks after the operation, when Kv1.3-channels were overexpressed in proliferating leukocytes. In the cortical interstitium of margatoxin-treated UUO rat kidneys, immunohistochemistry revealed reduced expression of fibrosis markers. Additionally, margatoxin significantly decreased the numbers of leukocytes and suppressed their proliferation. CONCLUSIONS: This study clearly demonstrated that the numbers of T-lymphocytes and macrophages were markedly increased in UUO rat kidneys with longer postobstructive days. The overexpression of Kv1.3-channels in leukocytes was thought to be responsible for the proliferation of these cells and the progression of renal fibrosis. This study strongly suggested the therapeutic usefulness of targeting lymphocyte Kv1.3-channels in the treatment of renal fibrosis.
Assuntos
Nefropatias/imunologia , Canal de Potássio Kv1.3/imunologia , Macrófagos/imunologia , Linfócitos T/imunologia , Obstrução Ureteral/imunologia , Animais , Modelos Animais de Doenças , Sistemas de Liberação de Medicamentos , Fibrose , Nefropatias/tratamento farmacológico , Nefropatias/patologia , Macrófagos/patologia , Masculino , Ratos , Ratos Sprague-Dawley , Linfócitos T/patologia , Obstrução Ureteral/tratamento farmacológico , Obstrução Ureteral/patologiaRESUMO
OBJECTIVE: To identify the outcome of patients with sepsis using high-frequency blood pressure data. MATERIALS AND METHODS: This retrospective observational study was conducted at a university hospital ICU (derivation study) and at two urban hospitals (validation study) with data from adult sepsis patients who visited the centers during the same period. The area under the curve (AUC) of blood pressure falling below threshold was calculated. The predictive 90-day mortality (primary endpoint) area under threshold (AUT) and critical blood pressure were calculated as the maximum area under the curve of the receiver operating characteristic curve (AUCROC) and the threshold minus average AUT (derivation study), respectively. For the validation study, the derived 90-day mortality AUCROC (using critical blood pressure) was compared with Sequential Organ Failure Assessment (SOFA), Simplified Acute Physiology Score (SAPS) II, Acute Physiology and Chronic Health Evaluation (APACHE) II, and APACHE III. RESULTS: Derivation cohort (N = 137): the drop area from the mean blood pressure of 70 mmHg at 24-48 hours most accurately predicted 90-day mortality [critical blood pressure, 67.8 mmHg; AUCROC, 0.763; 95% confidence interval (CI), 0.653-0.890]. Validation cohort (N = 141): the 90-day mortality AUCROC (0.776) compared with the AUCROC for SOFA (0.711), SAPSII (0.771), APACHE II (0.745), and APACHE III (0.710) was not significantly different from the critical blood pressure 67.8 mmHg (P = 0.420). CONCLUSION: High-frequency arterial blood pressure data of the period and extent of blood pressure depression can be useful in predicting the clinical outcomes of patients with sepsis.
Assuntos
Pressão Arterial , Sepse/mortalidade , Sepse/fisiopatologia , APACHE , Adulto , Idoso , Área Sob a Curva , Feminino , Humanos , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Prognóstico , Curva ROC , Estudos RetrospectivosRESUMO
Circulating endothelial microparticles (EMPs) are considered to be markers of endothelial injury, and lung microvascular endothelial cells express higher levels of angiotensin-converting enzyme (ACE). The aim of this study is to examine whether the number of ACE+ microvascular EMPs could be a prognostic marker for the development of acute respiratory distress syndrome (ARDS) in septic patients.The numbers of EMPs and ACE+ EMPs in the culture supernatant from human microvascular endothelial cells, as well as in the blood of mouse lung injury models and septic patients (n=82), were examined using flow cytometry.ACE+ EMPs in the culture supernatant from pulmonary microvascular endothelial cells increased after exposure to an inflammatory stimulus. In the mouse lung injury models, the circulating ACE+ EMPs and ACE+ EMP/EMP ratio were higher than in the controls (p<0.001). The ACE+ EMP/EMP ratio was correlated with the wet/dry lung ratio (rs=0.775, p<0.001). The circulating ACE+ EMPs and ACE+ EMP/EMP ratio on admission were significantly increased in septic patients who developed ARDS compared with septic patients who did not (p<0.001).Therefore, circulating ACE+ EMPs may be a prognostic marker for the development of ARDS in the septic patients.
Assuntos
Lesão Pulmonar Aguda/metabolismo , Micropartículas Derivadas de Células/metabolismo , Células Endoteliais/metabolismo , Peptidil Dipeptidase A/metabolismo , Síndrome do Desconforto Respiratório/metabolismo , Choque Séptico/metabolismo , Idoso , Animais , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Síndrome do Desconforto Respiratório/etiologia , Sepse/complicações , Sepse/metabolismo , Choque Séptico/complicaçõesRESUMO
BACKGROUND/AIMS: Voltage-dependent potassium channels (Kv1.3) are predominantly expressed in lymphocyte plasma membranes. These channels are critical for the activation and proliferation of lymphocytes. Since second-generation antihistamines are lipophilic and exert immunomodulatory effects, they are thought to affect the lymphocyte Kv1.3-channel currents. METHODS: Using the patch-clamp whole-cell recording technique in murine thymocytes, we tested the effects of second-generation antihistamines, such as cetirizine, fexofenadine, azelastine, and terfenadine, on the channel currents and the membrane capacitance. RESULTS: These drugs suppressed the peak and the pulse-end currents of the channels, although the effects of azelastine and terfenadine on the peak currents were more marked than those of cetirizine and fexofenadine. Both azelastine and terfenadine significantly lowered the membrane capacitance. Since these drugs did not affect the process of endocytosis in lymphocytes, they were thought to have interacted directly with the plasma membranes. CONCLUSIONS: Our study revealed for the first time that second-generation antihistamines, including cetirizine, fexofenadine, azelastine, and terfenadine, exert suppressive effects on lymphocyte Kv1.3-channels. The efficacy of these drugs may be related to their immunomodulatory mechanisms that reduce the synthesis of inflammatory cytokine.
Assuntos
Antagonistas dos Receptores Histamínicos H1/farmacologia , Imunomodulação/efeitos dos fármacos , Canal de Potássio Kv1.3/metabolismo , Potenciais da Membrana/efeitos dos fármacos , Timócitos/metabolismo , Animais , Masculino , Camundongos , Técnicas de Patch-ClampRESUMO
In the original publication, Fig. 3 has been incorrectly published. The correct version of Fig. 3 is given in this Correction.