RESUMEN
BACKGROUND: Transthoracic esophagectomy for cancer triggers a massive inflammatory reaction. The data whether a minimally invasive esophagectomy (MIE) leads to less pronounced inflammatory response compared to open right-sided transthoracic esophagectomy (OE) are scarce. The aim of this study was to evaluate the extent of the inflammatory reaction, represented by levels of the pro-inflammatory interleukins IL-6 and IL-8, the anti-inflammatory IL-1 RA and the chemokines CINC-1 and MCP-1 in the right pleural fluid and the blood from patients undergoing standard OE or MIE. METHODS: Pleural drainage fluid and blood was collected at five different time points during the first 72 h following surgery, and the concentrations of IL-6, IL-8, IL-1 RA, CINC-1 and MCP-1 were analyzed using enzyme-linked immune-sorbent assays in 24 patients undergoing MIE or OE. RESULTS: The groups were matched for cancer stage and comorbidities. Pro- and anti-inflammatory mediator levels in the pleural fluid were markedly increased at the end of surgery and on postoperative days 1-3. The pleural inflammatory response of all cyto- and chemokines was lower in the MIE group, reaching significance at some time points. Cyto- and chemokine response levels measured in the blood were overall lower compared to those in the pleural fluid. The chemokines CINC-1 and MCP-1 reacted less pronounced or not at all. Preoperative pulmonary comorbidity, postoperative pulmonary morbidity and length of surgery were associated with an increased reaction in selected mediators. CONCLUSIONS: The minimally invasive technique attenuates the inflammatory response, especially locally in the thoracic compartment. Length of procedure, preoperative pulmonary comorbidity and postoperative pulmonary complications are mirrored in an increase in individual inflammatory markers in the pleural fluid. The value of the chemokines CINC-1 and MCP-1 as markers of inflammation in the setting of esophagectomy is unclear.
Asunto(s)
Citocinas/biosíntesis , Neoplasias Esofágicas/cirugía , Esofagectomía , Procedimientos Quirúrgicos Mínimamente Invasivos , Pleura/inmunología , Anciano , Citocinas/sangre , Neoplasias Esofágicas/inmunología , Neoplasias Esofágicas/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/etiologíaRESUMEN
BACKGROUND: Postoperative cognitive complications are associated with substantial morbidity and mortality. Ketamine has been suggested to have neuroprotective effects in various settings. This systematic review evaluates the effects of intraoperative ketamine administration on postoperative delirium and postoperative cognitive dysfunction (POCD). METHODS: Medline, Embase and Central were searched to 4 March 2018 without date or language restrictions. We considered randomised controlled trials (RCTs) comparing intraoperative ketamine administration versus no intervention in adults undergoing surgery under general anaesthesia. Primary outcomes were postoperative delirium and POCD. Non-cognitive adverse events, mortality and length of stay were considered as secondary outcomes. Data were independently extracted. The quality of the evidence (GRADE approach) was assessed following recommendations from the Cochrane collaboration. Risk ratios were calculated for binary outcomes, mean differences for continuous outcomes. We planned to explore the effects of age, specific anaesthesia regimen, depth of anaesthesia and intraoperative haemodynamic events through subgroup analyses. RESULTS: Six RCTs were included. The incidence of postoperative delirium did not differ between groups (4 trials, 557 patients, RR 0.83, 95% CI [0.25, 2.80]), but patients receiving ketamine seemed at lower risk of POCD (3 trials, 163 patients, RR 0.34, 95% CI [0.15, 0.73]). However, both analyses presented limitations. Therefore, the quality of the evidence (GRADE) was deemed low (postoperative delirium) and very low (POCD). CONCLUSION: The effect of ketamine on postoperative delirium remains unclear but its administration may offer some protection towards POCD. Large, well-designed randomised trials are urgently needed to further clarify the efficacy of ketamine on neurocognitive outcomes.
Asunto(s)
Anestésicos Disociativos/uso terapéutico , Disfunción Cognitiva/prevención & control , Delirio/prevención & control , Cuidados Intraoperatorios/métodos , Ketamina/uso terapéutico , Complicaciones Posoperatorias/prevención & control , Anestésicos Disociativos/administración & dosificación , Humanos , Ketamina/administración & dosificaciónRESUMEN
Volatile anaesthetics such as sevoflurane attenuate inflammatory processes, thereby impacting patient outcome significantly. Their inhalative administration is, however, strictly limited to controlled environments such as operating theatres, and thus an intravenously injectable immunomodulatory drug would offer distinct advantages. As protective effects of volatile anaesthetics have been associated with the presence of trifluorinated carbon groups in their basic structure, in this study we investigated the water-soluble sevoflurane metabolite hexafluoro-2-propanol (HFIP) as a potential immunomodulatory drug in a rat model of endotoxic shock. Male Wistar rats were subjected to intravenous lipopolysaccharide (LPS) and thereafter were treated with HFIP. Plasma and tissue inflammatory mediators, neutrophil invasion, tissue damage and haemodynamic stability were the dedicated end-points. In an endotoxin-induced endothelial cell injury model, underlying mechanisms were elucidated using gene expression and gene reporter analyses. HFIP reduced the systemic inflammatory response significantly and decreased endotoxin-induced tissue damage. Additionally, the LPS-provoked drop in blood pressure of animals was resolved by HFIP treatment. Pathway analysis revealed that the observed attenuation of the inflammatory process was associated with reduced nuclear factor kappa B (NF-κΒ) activation and suppression of its dependent transcripts. Taken together, intravenous administration of HFIP exerts promising immunomodulatory effects in endotoxaemic rats. The possibility of intravenous administration would overcome limitations of volatile anaesthetics, and thus HFIP might therefore represent an interesting future drug candidate for states of severe inflammation.
Asunto(s)
Adyuvantes Inmunológicos/farmacología , Endotoxemia/prevención & control , Propanoles/farmacología , Choque Séptico/prevención & control , Animales , Células Cultivadas , Citocinas/genética , Citocinas/metabolismo , Modelos Animales de Enfermedad , Células Endoteliales/metabolismo , Endotoxemia/metabolismo , Ensayo de Inmunoadsorción Enzimática , Expresión Génica/efectos de los fármacos , Perfilación de la Expresión Génica , Humanos , Inflamación/sangre , Inflamación/metabolismo , Inflamación/prevención & control , Mediadores de Inflamación/sangre , Mediadores de Inflamación/metabolismo , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Modelos Lineales , Lipopolisacáridos/farmacología , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Masculino , Éteres Metílicos/metabolismo , Neutrófilos/efectos de los fármacos , Neutrófilos/metabolismo , Propanoles/metabolismo , Ratas Wistar , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Sevoflurano , Choque Séptico/sangre , Choque Séptico/inducido químicamenteRESUMEN
BACKGROUND: Growing evidence suggests a protective effect of volatile anaesthetics in ischaemia-reperfusion (I/R)-injury, and the accumulation of neutrophils is a crucial event. Pro-inflammatory cytokines carrying the C-X-C-motif including interleukin-8 (IL-8) and CXC-ligand 1 (CXCL1) activate CXC receptor-1 (CXCR1; stimulated by IL-8), CXC receptor-2 (CXCR2; stimulated by IL-8 and CXCL1), or both to induce CD11b-dependent neutrophil transmigration. Inhibition of CXCR1, CXCR2, or both reduces I/R-injury by preventing neutrophil accumulation. We hypothesized that interference with CXCR1/CXCR2 signalling contributes to the well-established beneficial effect of volatile anaesthetics in I/R-injury. METHODS: Isolated human neutrophils were stimulated with IL-8 or CXCL1 and exposed to volatile anaesthetics (sevoflurane/desflurane). Neutrophil migration was assessed using an adapted Boyden chamber. Expression of CD11b, CXCR1, and CXCR2 was measured by flow cytometry. Blocking antibodies against CXCR1/CXCR2/CD11b and phorbol myristate acetate were used to investigate specific pathways. RESULTS: Volatile anaesthetics reduced CD11b-dependent neutrophil transmigration induced by IL-8 by >30% and CD11b expression by 18 and 27% with sevoflurane/desflurane, respectively. This effect was independent of CXCR1/CXCR2 expression and CXCR1/CXCR2 endocytosis. Inhibition of CXCR1 signalling did not affect downregulation of CD11b with volatile anaesthetics. Blocking of CXCR2-signalling neutralized effects by volatile anaesthetics on CD11b expression. Specific stimulation of CXCR2 with CXCL1 was sufficient to induce upregulation of CD11b, which was impaired with volatile anaesthetics. No effect of volatile anaesthetics was observed with direct stimulation of protein kinase C located downstream of CXCR1/CXCR2. CONCLUSION: Volatile anaesthetics attenuate neutrophil inflammatory responses elicited by CXC cytokines through interference with CXCR2 signalling. This might contribute to the beneficial effect of volatile anaesthetics in I/R-injury.
Asunto(s)
Anestésicos por Inhalación/farmacología , Inflamación/sangre , Neutrófilos/efectos de los fármacos , Receptores de Interleucina-8B/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Adulto , Anestésicos por Inhalación/sangre , Desflurano , Femenino , Citometría de Flujo/métodos , Humanos , Isoflurano/análogos & derivados , Isoflurano/sangre , Isoflurano/farmacología , Masculino , Éteres Metílicos/sangre , Éteres Metílicos/farmacología , Persona de Mediana Edad , Receptores de Interleucina-8B/sangre , Sevoflurano , Adulto JovenRESUMEN
BACKGROUND: Matrix-metalloproteinases (MMP) and cancer cell invasion are crucial for solid tumour metastasis. Important signalling events triggered by inflammatory cytokines, such as tumour necrosis factor α (TNFα), include Src-kinase-dependent activation of Akt and focal adhesion kinase (FAK) and phosphorylation of caveolin-1. Based on previous studies where we demonstrated amide-type local anaesthetics block TNFα-induced Src activation in malignant cells, we hypothesized that local anaesthetics might also inhibit the activation and/or phosphorylation of Akt, FAK and caveolin-1, thus attenuating MMP release and invasion of malignant cells. METHODS: NCI-H838 lung adenocarcinoma cells were incubated with ropivacaine or lidocaine (1 nM-100 µM) in absence/presence of TNFα (20 ng ml(-1)) for 20 min or 4 h, respectively. Activation/phosphorylation of Akt, FAK and caveolin-1 were evaluated by Western blot, and MMP-9 secretion was determined by enzyme-linked immunosorbent assay. Tumour cell migration (electrical wound-healing assay) and invasion were also assessed. RESULTS: Ropivacaine (1 nM-100 µM) and lidocaine (1-100 µM) significantly reduced TNFα-induced activation/phosphorylation of Akt, FAK and caveolin-1 in NCI-H838 cells. MMP-9 secretion triggered by TNFα was significantly attenuated by both lidocaine and ropivacaine (half-maximal inhibitory concentration [IC50]=3.29×10(-6) M for lidocaine; IC50=1.52×10(-10) M for ropivacaine). The TNFα-induced increase in invasion was completely blocked by both lidocaine (10 µM) and ropivacaine (1 µM). CONCLUSIONS: At clinically relevant concentrations both ropivacaine and lidocaine blocked tumour cell invasion and MMP-9 secretion by attenuating Src-dependent inflammatory signalling events. Although determined entirely in vitro, these findings provide significant insight into the potential mechanism by which local anaesthetics might diminish metastasis.
Asunto(s)
Adenocarcinoma/patología , Amidas/farmacología , Anestésicos Locales/farmacología , Lidocaína/farmacología , Neoplasias Pulmonares/patología , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Adenocarcinoma/metabolismo , Adenocarcinoma/secundario , Adenocarcinoma del Pulmón , Caveolina 1/metabolismo , Movimiento Celular/efectos de los fármacos , Evaluación Preclínica de Medicamentos/métodos , Activación Enzimática/efectos de los fármacos , Proteína-Tirosina Quinasas de Adhesión Focal/metabolismo , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundario , Metaloproteinasa 9 de la Matriz/metabolismo , Invasividad Neoplásica , Proteínas de Neoplasias/metabolismo , Fosforilación/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ropivacaína , Células Tumorales Cultivadas , Factor de Necrosis Tumoral alfa/fisiologíaRESUMEN
Clinical and basic science studies have demonstrated the anti-inflammatory properties of local anaesthetics. Recent studies have begun to unravel molecular pathways linking inflammation and cancer. Regional anaesthesia is associated in some retrospective clinical studies with reduced risk of metastasis and increased long-term survival. The potential beneficial effects of regional anaesthesia have been attributed mainly to the inhibition of the neuroendocrine stress response to surgery and to the reduction in the requirements of volatile anaesthetics and opioids. Because cancer is linked to inflammation and local anaesthetics have anti-inflammatory effects, these agents may participate in reducing the risk of metastasis, but their mechanism of action is unknown. We demonstrated in vitro that amide local anaesthetics attenuate tumour cell migration as well as signalling pathways enhancing tumour growth and metastasis. This has provided the first evidence of a molecular mechanism by which regional anaesthesia might inhibit or reduce cancer metastases.
Asunto(s)
Anestesia de Conducción , Anestésicos Locales/farmacología , Metástasis de la Neoplasia/prevención & control , Lesión Pulmonar Aguda/tratamiento farmacológico , Animales , Antiinflamatorios/farmacología , Humanos , Inflamación/complicaciones , FN-kappa B/fisiología , Células Neoplásicas CirculantesRESUMEN
Dexamethasone has been found to reduce the incidence of high-altitude pulmonary oedema. Mechanisms explaining this effect still remain unclear. We assessed the effect of dexamethasone using established cell lines, including rat alveolar epithelial cells (AEC), pulmonary artery endothelial cells (RPAEC) and alveolar macrophages (MAC), in an environment of low oxygen, simulating a condition of alveolar hypoxia as found at high altitude. Inflammatory mediators and ion transporter expression were quantified. Based on earlier results, we hypothesized that hypoxic conditions trigger inflammation. AEC, RPAEC and MAC, pre-incubated for 1 h with or without dexamethasone (10(-7) mol/l), were subsequently exposed to mild hypoxia (5% O(2), or normoxia as control) for 24 h. mRNA and protein levels of cytokine-induced neutrophil chemoattractant-1, monocyte chemoattractant protein-1 and interleukin-6 were analysed. mRNA expression and functional activity of the apical epithelial sodium channel and basolateral Na(+)/K(+)-ATPase were determined using radioactive marker ions. In all three types of pulmonary cells hypoxic conditions led to an attenuated secretion of inflammatory mediators, which was even more pronounced in dexamethasone pretreated samples. Function of Na(+)/K(+)-ATPase was not significantly influenced by hypoxia or dexamethasone, while activity of epithelial sodium channels was decreased under hypoxic conditions. When pre-incubated with dexamethasone, however, transporter activity was partially maintained. These findings illustrate that long-term hypoxia does not trigger an inflammatory response. The ion transport across apical epithelial sodium channels under hypoxic conditions is ameliorated in cells treated with dexamethasone.
Asunto(s)
Células Epiteliales Alveolares/efectos de los fármacos , Células Epiteliales Alveolares/metabolismo , Dexametasona/farmacología , Inflamación/metabolismo , Canales Iónicos/metabolismo , Células Epiteliales Alveolares/inmunología , Animales , Hipoxia de la Célula , Supervivencia Celular/efectos de los fármacos , Células Endoteliales/efectos de los fármacos , Células Endoteliales/inmunología , Células Endoteliales/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Inflamación/inmunología , Mediadores de Inflamación/metabolismo , Macrófagos Alveolares/efectos de los fármacos , Macrófagos Alveolares/inmunología , Macrófagos Alveolares/metabolismo , RatasRESUMEN
Pulmonary oedema is a hallmark of acute lung injury (ALI), consisting of various degrees of water and proteins. Physiologically, sodium enters through apical sodium channels (ENaC) and is extruded basolaterally by a sodium-potassium-adenosine-triphosphatase pump (Na(+) /K(+) -ATPase). Water follows to maintain iso-osmolar conditions and to keep alveoli dry. We postulated that the volatile anaesthetic sevoflurane would impact oedema resolution positively in an in-vitro and in-vivo model of ALI. Alveolar epithelial type II cells (AECII) and mixed alveolar epithelial cells (mAEC) were stimulated with 20 µg/ml lipopolysaccharide (LPS) and co-exposed to sevoflurane for 8 h. In-vitro active sodium transport via ENaC and Na(+) /K(+) -ATPase was determined, assessing (22) sodium and (86) rubidium influx, respectively. Intratracheally applied LPS (150 µg) was used for the ALI in rats under sevoflurane or propofol anaesthesia (8 h). Oxygenation index (PaO(2) /FiO(2) ) was calculated and lung oedema assessed determining lung wet/dry ratio. In AECII LPS decreased activity of ENaC and Na(+) /K(+) -ATPase by 17·4% ± 13·3% standard deviation and 16·2% ± 13·1%, respectively. These effects were reversible in the presence of sevoflurane. Significant better oxygenation was observed with an increase of PaO(2) /FiO(2) from 189 ± 142 mmHg to 454 ± 25 mmHg after 8 h in the sevoflurane/LPS compared to the propofol/LPS group. The wet/dry ratio in sevoflurane/LPS was reduced by 21·6% ± 2·3% in comparison to propofol/LPS-treated animals. Sevoflurane has a stimulating effect on ENaC and Na(+) /K(+) -ATPase in vitro in LPS-injured AECII. In-vivo experiments, however, give strong evidence that sevoflurane does not affect water reabsorption and oedema resolution, but possibly oedema formation.
Asunto(s)
Lesión Pulmonar Aguda/patología , Pulmón/patología , Éteres Metílicos/farmacología , Alveolos Pulmonares/metabolismo , Edema Pulmonar/patología , Lesión Pulmonar Aguda/tratamiento farmacológico , Anestésicos/farmacología , Animales , Transporte Biológico Activo/efectos de los fármacos , Línea Celular , Supervivencia Celular/efectos de los fármacos , Lipopolisacáridos/farmacología , Pulmón/efectos de los fármacos , Masculino , Oxígeno/análisis , Alveolos Pulmonares/efectos de los fármacos , Edema Pulmonar/metabolismo , Ratas , Ratas Wistar , Síndrome de Dificultad Respiratoria/metabolismo , Rubidio/metabolismo , Sevoflurano , Sodio/metabolismo , Canales de Sodio/efectos de los fármacos , Isótopos de Sodio/metabolismo , ATPasa Intercambiadora de Sodio-Potasio/metabolismoAsunto(s)
Trasplante de Riñón , Propofol , Anestesia , Anestésicos , Anestésicos por Inhalación , Donadores Vivos , Éteres Metílicos , SevofluranoRESUMEN
Apoptotic cell death has been considered an underlying mechanism in acute lung injury. To evaluate the evidence of this process, apoptosis rate was determined in effector cells (alveolar macrophages, neutrophils) and target cells (tracheobronchial and alveolar epithelial cells) of the respiratory compartment upon exposure to hypoxia and endotoxin stimulation in vitro. Cells were exposed to 5% oxygen or incubated with lipopolysaccharide (LPS) for 4, 8 and 24 h, and activity of caspase-3, -8 and -9 was determined. Caspase-3 of alveolar macrophages was increased at all three time-points upon LPS stimulation, while hypoxia did not affect apoptosis rate at early time-points. In neutrophils, apoptosis was decreased in an early phase of hypoxia at 4 h. However, enhanced expression of caspase-3 activity was seen at 8 and 24 h. In the presence of LPS a decreased apoptosis rate was observed at 8 h compared to controls, while it was increased at 24 h. Tracheobronchial as well as alveolar epithelial cells experienced an enhanced caspase-3 activity upon LPS stimulation with no change of apoptosis rate under hypoxia. While increased apoptosis rate is triggered through an intrinsic and extrinsic pathway in alveolar macrophages, intrinsic signalling is activated in tracheobronchial epithelial cells. The exact pathway pattern in neutrophils and alveolar epithelial cells could not be determined. These data clearly demonstrate that upon injury each cell type experiences its own apoptosis pattern. Further experiments need to be performed to determine the functional role of these apoptotic processes in acute lung injury.
Asunto(s)
Lesión Pulmonar Aguda/patología , Apoptosis/fisiología , Sistema Respiratorio/citología , Animales , Apoptosis/efectos de los fármacos , Bronquios/citología , Camptotecina/farmacología , Caspasa 3/metabolismo , Caspasa 8/metabolismo , Caspasa 9/metabolismo , Hipoxia de la Célula/fisiología , Línea Celular , Células Cultivadas , Células Epiteliales/citología , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Humanos , Lipopolisacáridos/farmacología , Macrófagos Alveolares/citología , Macrófagos Alveolares/efectos de los fármacos , Macrófagos Alveolares/metabolismo , Masculino , Neutrófilos/citología , Neutrófilos/efectos de los fármacos , Neutrófilos/metabolismo , Alveolos Pulmonares/citología , Ratas , Ratas Wistar , Mucosa Respiratoria/citología , Organismos Libres de Patógenos Específicos , Tráquea/citologíaRESUMEN
Lidocaine, bupivacaine or ropivacaine are used routinely to manage perioperative pain. Sparse data exist evaluating the effects of local anaesthetics (LA) on fibroblasts, which are involved actively in wound healing. Therefore, we investigated the effects of the three LA to assess the survival, viability and proliferation rate of fibroblasts. Human fibroblasts were exposed to 0·3 mg/ml and 0·6 mg/ml of each LA for 2 days, followed by incubation with normal medium for another 1, 4 or 7 days (group 1). Alternatively, cells were incubated permanently with LA for 3, 6 or 9 days (group 2). Live cell count was assessed using trypan blue staining. Viability was measured by the tetrazolium bromide assay. Proliferation tests were performed with the help of the colorimetric bromodeoxyuridine assay. Production of reactive oxygen species (ROS) was determined, measuring the oxidation of non-fluorescent-2,7'-dichlorofluorescin. Treatment of cells with the three LA showed a concentration-dependent decrease of live cells, mitochondrial activity and proliferation rate. Group arrangement played a significant role for cell count and proliferation, while exposure time influenced viability. Among the analysed LA, bupivacaine showed the most severe cytotoxic effects. Increased production of ROS correlated with decreased viability of fibroblasts in lidocaine- and bupivacaine-exposed cells, but not upon stimulation with ropivacaine. This study shows a concentration-dependent cytotoxic effect of lidocaine, bupivacaine and ropivacaine on fibroblasts in vitro, with more pronounced effects after continuous incubation. A possible mechanism of cell impairment could be triggered by production of ROS upon stimulation with lidocaine and bupivacaine.
Asunto(s)
Anestésicos Locales/farmacología , Fibroblastos/citología , Fibroblastos/efectos de los fármacos , Amidas/farmacología , Apoptosis/efectos de los fármacos , Bupivacaína/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Fibroblastos/metabolismo , Humanos , Lidocaína/farmacología , Especies Reactivas de Oxígeno/metabolismo , RopivacaínaRESUMEN
Acute lung injury (ALI) is a well-defined inflammation whereby alveolar macrophages play a crucial role as effector cells. As shown previously in numerous experimental approaches, volatile anaesthetics might reduce the degree of injury in pre- or post-conditioning set-ups. Therefore, we were interested to evaluate the effect of the application of the volatile anaesthetic sevoflurane on alveolar macrophages regarding the expression of inflammatory mediators upon lipopolysaccharide (LPS) stimulation in vitro. Alveolar macrophages were stimulated with LPS. Two hours later, cells were exposed additionally to air (control) or to sevoflurane-containing air for 4, 6, 8, 12 or 24 h. Tumour necrosis factor (TNF)-alpha, cytokine-induced neutrophil chemoattractant-1 (CINC-1), macrophage-inflammatory protein-2 (MIP-2) and monocyte chemoattractant protein-1 (MCP-1) proteins were determined and chemotaxis assays were performed. To evaluate possible cellular signalling pathways phosphorylation of the kinases extracellular-regulated kinase (ERK) and Akt was assessed. In the early phase of sevoflurane post-conditioning expression of TNF-alpha, CINC-1, MIP-2 and MCP-1 was attenuated, leading to a diminished chemotaxis reaction for neutrophils. Phosphorylation of ERK seems to be a possible cellular mechanism in the sevoflurane-induced protection in vitro. Pharmacological post-conditioning of alveolar macrophages with sevoflurane immunmodulates the inflammatory response upon stimulation with endotoxin. This might be a possible option for a therapeutical approach in ALI.
Asunto(s)
Anestésicos por Inhalación/farmacología , Lipopolisacáridos/antagonistas & inhibidores , Proteínas Inflamatorias de Macrófagos/biosíntesis , Macrófagos Alveolares/efectos de los fármacos , Éteres Metílicos/farmacología , Lesión Pulmonar Aguda/metabolismo , Lesión Pulmonar Aguda/patología , Animales , Línea Celular , Quimiocina CCL2/biosíntesis , Quimiocina CXCL1/biosíntesis , Quimiocina CXCL2/biosíntesis , Quimiotaxis de Leucocito/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Lipopolisacáridos/farmacología , Macrófagos Alveolares/metabolismo , Ratas , Sevoflurano , Transducción de Señal/efectos de los fármacos , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Acute lung injury is a common complication in critically ill patients. The present study examined possible immunomodulating effects of the volatile anaesthetic sevoflurane on lipopolysaccharide (LPS)-stimulated alveolar epithelial cells (AEC) in vitro. Sevoflurane was applied after the onset of injury, simulating a "postconditioning" scenario. Rat AEC were stimulated with LPS for 2 h, followed by a 4-h co-exposure to a CO(2)/air mixture with sevoflurane 2.2 volume %; control cells were exposed to the CO(2)/air mixture only. Cytokine-induced neutrophil chemoattractant-1, monocyte chemoattractant protein-1, intercellular adhesion molecule-1, as well as the potential protective mediators inducible nitric oxide synthase (iNOS)2 and heat shock protein (HSP)-32, were analysed. Additionally, functional assays (chemotaxis, adherence and cytotoxicity assay) were performed. A significant reduction of inflammatory mediators in LPS-stimulated, sevoflurane-exposed AEC was found, leading to reduced chemotaxis, neutrophil adherence and neutrophil-induced AEC killing. While iNOS2 was increased in the sevoflurane group, blocking experiments with iNOS2 inhibitor did not affect sevoflurane-induced decrease of inflammatory mediators and AEC killing. Interestingly, sevoflurane treatment also resulted in an enhanced expression of HSP-32. The data presented in the current study provide strong evidence that anaesthetic postconditioning with sevoflurane mediates cytoprotection in the respiratory compartment in an in vitro model of acute lung injury.
Asunto(s)
Anestésicos/farmacología , Células Epiteliales/citología , Enfermedades Pulmonares/tratamiento farmacológico , Éteres Metílicos/farmacología , Alveolos Pulmonares/citología , Alveolos Pulmonares/patología , Enfermedad Aguda , Animales , Dióxido de Carbono/química , Modelos Animales de Enfermedad , Endotoxinas/metabolismo , Femenino , Técnicas In Vitro , Lipopolisacáridos/metabolismo , Lipopolisacáridos/farmacología , Lesión Pulmonar , Mycoplasma/metabolismo , Alveolos Pulmonares/metabolismo , Ratas , SevofluranoRESUMEN
The complement activation product, C5a, may play a key role in the acute inflammatory response. Polyclonal antibody to rat C5a was used to define the requirements for C5a in neutrophil-dependent inflammatory lung injury after systemic activation of complement by cobra venom factor (CVF) or after intrapulmonary deposition of IgG immune complexes. In the CVF model, intravenous infusion (but not intratracheal instillation) of anti-C5a produced a dose-dependent reduction in lung permeability and in lung content of myeloperoxidase. In C6-deficient rats, CVF infusion caused the same level of lung injury (measured by leak of 125I-albumin) as found in C6-sufficient rats. In the IgG immune complex model of lung injury, anti-C5a administered intratracheally (but not intravenously) reduced in a dose-dependent manner both the increase in lung vascular permeability as well as the buildup of lung myeloperoxidase. Treatment with anti-C5a greatly suppressed upregulation of lung vascular intercellular adhesion molecule-1 (ICAM-1). This was correlated with a substantial drop in levels of TNFalpha in bronchoalveolar fluids. These data demonstrate the requirement for C5a in the two models of injury. In the IgG immune complex model, C5a is required for the full production of TNFalpha and the corresponding upregulation of lung vascular ICAM-1.
Asunto(s)
Complemento C5a/fisiología , Inmunoglobulina G/farmacología , Inflamación/fisiopatología , Pulmón/fisiopatología , Neutrófilos/fisiología , Animales , Líquido del Lavado Bronquioalveolar/química , Quimiotaxis de Leucocito , Activación de Complemento , Complemento C5a/inmunología , Venenos Elapídicos/administración & dosificación , Venenos Elapídicos/toxicidad , Ensayo de Inmunoadsorción Enzimática , Humanos , Inmunoglobulina G/administración & dosificación , Inflamación/inmunología , Infusiones Intravenosas , Instilación de Medicamentos , Molécula 1 de Adhesión Intercelular/biosíntesis , Pulmón/efectos de los fármacos , Pulmón/patología , Peroxidasa/metabolismo , Conejos , Ratas , Tráquea , Factor de Necrosis Tumoral alfa/análisis , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
Leucocyte infiltration is known to play an important role in hypoxia-induced tissue damage. However, little information is available about hypoxia and interaction of effector (neutrophils) with target cells (alveolar epithelial cells, AEC; rat pulmonary artery endothelial cells, RPAEC). The goal of this study was to elucidate hypoxia-induced changes of effector-target cell interaction. AEC and RPAEC were exposed to 5% oxygen for 2-6 h. Intercellular adhesion molecule-1 (ICAM-1) expression was determined and cell adherence as well as cytotoxicity assays were performed. Nitric oxide and heat shock protein 70 (HSP70) production was assessed in target cells. Under hypoxic conditions enhanced ICAM-1 production was found in both cell types. This resulted in an increase of adherent neutrophils to AEC and RPAEC. The death rate of hypoxia-exposed target cells decreased significantly in comparison to control cells. Nitric oxide (NO) concentration was enhanced, as was production of HSP70 in AEC. Blocking NO production in target cells resulted in increased cytotoxicity in AEC and RPAEC. This study shows for the first time that target cells are more resistant to effector cells under hypoxia, suggesting hypoxia-induced cell protection. An underlying mechanism for this phenomenon might be the protective effect of increased levels of NO in target cells.
Asunto(s)
Endotelio Vascular/citología , Neutrófilos/fisiología , Alveolos Pulmonares/citología , Arteria Pulmonar/citología , Animales , Adhesión Celular/fisiología , Muerte Celular/fisiología , Hipoxia de la Célula/fisiología , Células Cultivadas , Endotelio Vascular/metabolismo , Células Epiteliales/metabolismo , Células Epiteliales/fisiología , Femenino , Proteínas HSP70 de Choque Térmico/metabolismo , Humanos , Molécula 1 de Adhesión Intercelular/biosíntesis , Molécula 1 de Adhesión Intercelular/genética , Molécula 1 de Adhesión Intercelular/metabolismo , Neutrófilos/metabolismo , Óxido Nítrico/biosíntesis , Alveolos Pulmonares/metabolismo , Arteria Pulmonar/metabolismo , ARN Mensajero/genética , Ratas , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Regulación hacia ArribaRESUMEN
Gastrointestinal malignancies largely contribute to cancer related deaths in the United States, with colorectal cancer representing the 3rd place of the ten leading entities of mortality due to cancer for both females and males. The majority of patients with GI tumors has to undergo surgery (either as a curative or palliative intervention) and are therefore also in need for a proper general and/or regional anesthesia. Recent findings have suggested that the type of anesthesia administered might have an impact on cancer recurrence and metastasis and thus this new field in the anesthesia world has become a largely studied topic. This review highlights current concepts and summarizes the evidence for an impact of the type of anesthesia on patient outcome after cancer surgery, suggesting the perioperative period might be a "window of opportunity" which should not be missed.
Asunto(s)
Analgésicos Opioides/uso terapéutico , Anestesia/métodos , Anestésicos por Inhalación/uso terapéutico , Anestésicos Intravenosos/uso terapéutico , Anestésicos Locales/uso terapéutico , Neoplasias Colorrectales/cirugía , Recurrencia Local de Neoplasia/epidemiología , Anestesia de Conducción/métodos , Transición Epitelial-Mesenquimal , Humanos , Inflamación , Metástasis de la Neoplasia , Células Neoplásicas Circulantes , Atención Perioperativa , Periodo Perioperatorio , Pronóstico , Factores de RiesgoRESUMEN
Increased responding to drug-associated stimuli (cue reactivity) and an inability to tolerate delayed gratification (reward impulsivity) have been implicated in the development and maintenance of drug addiction. Whereas data from animal studies suggest that both the dopamine and opioid system are involved in these two reward-related processes, their role in humans is less clear. Moreover, dopaminergic and opioidergic drugs have not been directly compared with regard to these functions, even though a deeper understanding of the underlying mechanisms might inform the development of specific treatments for elevated cue reactivity and reward impulsivity. In a randomized, double-blind, between-subject design we administered the selective dopamine D2/D3 receptor antagonist amisulpride (400 mg, n=41), the unspecific opioid receptor antagonist naltrexone (50 mg, n=40) or placebo (n=40) to healthy humans and measured cue-induced responding with a Pavlovian-instrumental transfer task and reward impulsivity with a delay discounting task. Mood was assessed using a visual analogue scale. Compared with placebo, amisulpride significantly suppressed cue-induced responding and reward impulsivity. The effects of naltrexone were similar, although less pronounced. Both amisulpride and naltrexone decreased average mood ratings compared with placebo. Our results demonstrate that a selective blockade of dopamine D2/D3 receptors reduces cue-induced responding and reward impulsivity in healthy humans. Antagonizing µ-opioid receptors has similar effects for cue-induced responding and to a lesser extent for reward impulsivity.
Asunto(s)
Señales (Psicología) , Descuento por Demora/efectos de los fármacos , Antagonistas de Dopamina/farmacología , Conducta Impulsiva/efectos de los fármacos , Naltrexona/farmacología , Antagonistas de Narcóticos/farmacología , Recompensa , Sulpirida/análogos & derivados , Amisulprida , Método Doble Ciego , Femenino , Voluntarios Sanos , Humanos , Masculino , Receptores de Dopamina D2 , Receptores de Dopamina D3/antagonistas & inhibidores , Receptores Opioides mu/antagonistas & inhibidores , Sulpirida/farmacología , Adulto JovenRESUMEN
STUDY OBJECTIVES: In the context of acute normovolemic hemodilution (ANH) recurarization, defined as significant decrease of train-of-four ratio (TOFR) during retransfusion of autologous blood withdrawn after induction of anesthesia, has been described for vecuronium and atracurium. The present study for the first time examined this risk for rocuronium and mivacurium. DESIGN: Prospective, randomized, unblinded clinical study. SETTING: University Hospital in Zurich/Switzerland. PATIENTS: 20 ASA physical status I and II patients undergoing general anesthesia for major maxillofacial surgery. INTERVENTIONS: Anesthesia was induced and maintained with propofol and remifentanil, and rocuronium (0.9 mg kg(-1)) or mivacurium (0.25 mg kg(-1)) was given to facilitate intubation. Thereafter, ANH was started with the removal of 500 mL autologous blood and the subsequent replacement by the same amount of 6% hydroxyethyl starch. The withdrawn blood was stored at 4 degrees C until retransfusion at the end of surgery. MEASUREMENTS: To estimate the risk of recurarization during retransfusion, the degree of recurarization during retransfusion of the autologous blood was assessed mechanomyographically. Plasma levels of rocuronium and mivacurium in the patients' plasma and the autologous blood were determined after its removal and before retransfusion. MAIN RESULTS: The TOFR before retransfusion was 0.97 (range: 0.96 to 0.98) for rocuronium (n = 10) and 0.98 (range: 0.96 to 1.0) for mivacurium (n = 8); n.s. During retransfusion, a slight, but statistically significant reduction of TOFR occurred in one patient in each group. In the mivacurium group, this recurarization occurred 10 minutes after the start of retransfusion; in the rocuronium group, it occurred 20 minutes after retransfusion. The plasma levels of rocuronium and mivacurium in the autologous blood did not change during storage. The plasma concentration of mivacurium in the autologous blood after its removal was 420 +/- 142 microg/L; before retransfusion, it was 384 +/- 147 microg/L. The respective concentrations for rocuronium were 2930 +/- 516 microg/L and 2660 +/- 464 microg/L. CONCLUSIONS: Recurarization during retransfusion may occur with both neuromuscular blocking drugs, mivacurium and rocuronium, when these drugs were injected before the removal of the autologous blood.
Asunto(s)
Androstanoles/administración & dosificación , Anestesia General , Transfusión de Sangre Autóloga/efectos adversos , Isoquinolinas/administración & dosificación , Bloqueo Neuromuscular , Fármacos Neuromusculares no Despolarizantes/administración & dosificación , Adulto , Androstanoles/farmacocinética , Hemodilución , Humanos , Isoquinolinas/farmacocinética , Mivacurio , Unión Neuromuscular/efectos de los fármacos , Unión Neuromuscular/fisiología , Fármacos Neuromusculares no Despolarizantes/farmacocinética , Estudios Prospectivos , Factores de Riesgo , Rocuronio , Transmisión Sináptica/efectos de los fármacosRESUMEN
Renal Fanconi syndrome occurs in about 1-5% of all children treated with Ifosfamide (Ifo) and impairment of renal phosphate reabsorption in about 20-30% of them. Pathophysiological mechanisms of Ifo-induced nephropathy are ill defined. The aim has been to investigate whether Ifo metabolites affect the type IIa sodium-dependent phosphate transporter (NaPi-IIa) in viable opossum kidney cells. Ifo did not influence viability of cells or NaPi-IIa-mediated transport up to 1 mM/24 h. Incubation of confluent cells with chloroacetaldehyde (CAA) and 4-hydroperoxyIfosfamide (4-OH-Ifo) led to cell death by necrosis in a concentration-dependent manner. At low concentrations (50-100 microM/24 h), cell viability was normal but apical phosphate transport, NaPi-IIa protein, and -mRNA expression were significantly reduced. Coincubation with sodium-2-mercaptoethanesulfonate (MESNA) prevented the inhibitory action of CAA but not of 4-OH-Ifo; DiMESNA had no effect. Incubation with Ifosfamide-mustard (Ifo-mustard) did alter cell viability at concentrations above 500 microM/24 h. At lower concentrations (50-100 microM/24 h), it led to significant reduction in phosphate transport, NaPi-IIa protein, and mRNA expression. MESNA did not block these effects. The effect of Ifo-mustard was due to internalization of NaPi-IIa. Cyclophosphamide-mustard (CyP-mustard) did not have any influence on cell survival up to 1000 microM, but the inhibitory effect on phosphate transport and on NaPi-IIa protein was the same as found after Ifo-mustard. In conclusion, CAA, 4-OH-Ifo, and Ifo- and CyP-mustard are able to inhibit sodium-dependent phosphate cotransport in viable opossum kidney cells. The Ifo-mustard effect took place via internalization and reduction of de novo synthesis of NaPi-IIa. Therefore, it is possible that Ifo-mustard plays an important role in pathogenesis of Ifo-induced nephropathy.
Asunto(s)
Acetaldehído/análogos & derivados , Ifosfamida/análogos & derivados , Ifosfamida/farmacología , Fosfatos/metabolismo , Mostazas de Fosforamida/farmacología , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo IIa/efectos de los fármacos , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo IIa/metabolismo , Acetaldehído/farmacología , Animales , Antineoplásicos Alquilantes , Transporte Biológico/efectos de los fármacos , Muerte Celular/efectos de los fármacos , Línea Celular , Relación Dosis-Respuesta a Droga , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/genética , Ifosfamida/metabolismo , Riñón/citología , Riñón/efectos de los fármacos , Riñón/metabolismo , Mesna/farmacología , Zarigüeyas , ARN Mensajero/genética , ARN Mensajero/metabolismo , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo IIa/genéticaRESUMEN
The animal model of inflammatory response induced by intratracheal application of lipopolysaccharide includes many typical features of acute lung injury or the acute respiratory distress syndrome. A number of experimental investigations have been performed to characterize the nature of this injury more effectively. In inflammatory conditions, hypoxia occurs frequently before and in parallel with pulmonary and non-pulmonary pathological events. This current study was designed to examine the in vivo effect of hypoxia as a potentially aggravating condition in endotoxin-induced lung injury. Lipopolysaccharide, 150 microg, was instilled intratracheally into rat lungs, and thereafter animals were exposed to either normoxia or hypoxia (10% oxygen). Lungs were collected 2, 4, 6 and 8 h later. Inflammatory response and tissue damage were evaluated by quantitative analysis of inflammatory cells and mediators, surfactant protein and vascular permeability. A significantly enhanced neutrophil recruitment was seen in lipopolysaccharide-animals exposed to hypoxia compared to lipopolysaccharide-animals under normoxia. This increased neutrophil accumulation was triggered by inflammatory mediators such as tumour necrosis factor-alpha and macrophage inflammatory protein-1beta, secreted by alveolar macrophages. Determination of vascular permeability and surfactant protein-B showed enhanced concentrations in lipopolysaccharide-lungs exposed to hypoxia, which was absent in animals previously alveolar macrophage-depleted. This study demonstrates that hypoxia aggravates lipopolysaccharide injury and therefore represents a second hit injury. The additional hypoxia-induced inflammatory reaction seems to be predominantly localized in the respiratory compartment, underlining the compartmentalized nature of the inflammatory response.