RESUMEN
Ischemic stroke is one of the most frequent causes of injury in the central nervous system which may lead to multiorgan dysfunction, including in the lung. The aim of this study was to investigate whether brain ischemia/reperfusion with or without mechanical ventilation leads to lung injury. Male Sprague-Dawley rats were assigned to four groups: Sham, 1-h brain ischemia (MCAO)/24-h reperfusion (I/R), mechanical ventilation with moderate tidal volume (MTV), and I/R+MTV. The pulmonary capillary permeability (Kfc) was measured in the isolated perfused lung. Mean arterial blood pressure (MAP), heart rate (HR), blood-gas variables, histopathological parameters, lung glutathione peroxidase, and TNF-α were measured. Kfc in the I/R, MTV, and I/R+MTV groups were higher than that in the Sham group. In the I/R, MTV, and I/R+MTV groups, arterial partial pressures of oxygen and the arterial partial pressure of oxygen/fraction of inspired oxygen ratios were lower, whereas arterial partial pressures of carbon dioxide were higher than those in the Sham group. The histopathological score in the I/R group was more than that in the Sham group, and in the MTV and I/R+MTV groups were higher than those in the Sham and I/R groups. Furthermore, there were stepwise rises in TNF-α in the I/R, MTV, and I/R+MTV groups, respectively. There was no significant difference in MAP between groups. However, HR in the MTV group was higher than that in the Sham group. Brain ischemia/reperfusion leads to pulmonary capillary endothelial damage and the impairment of gas exchange in the alveolar-capillary barrier, which is exacerbated by mechanical ventilation with moderate tidal volume partially linked to inflammatory reactions.
Asunto(s)
Daño por Reperfusión/fisiopatología , Respiración Artificial/efectos adversos , Volumen de Ventilación Pulmonar/fisiología , Lesión Pulmonar Inducida por Ventilación Mecánica/fisiopatología , Animales , Pulmón/fisiopatología , Masculino , Ratas , Ratas Sprague-Dawley , Daño por Reperfusión/sangre , Factor de Necrosis Tumoral alfa/sangre , Lesión Pulmonar Inducida por Ventilación Mecánica/sangreRESUMEN
BACKGROUND: Gelsolin is an actin-scavenger controlling the tissue damage from actin in the blood. Gelsolin levels in circulation drops when tissue damage and corresponding actin release is pronounced due to catabolic conditions. The purpose of this study was to determine if low plasma gelsolin independently predicts a reduced chance of weaning from ventilator-demanding respiratory failure in critically ill patients within 28 days from admission. RESULTS: This cohort study included 746 critically ill patients with ventilator-demanding respiratory failure from the randomized clinical trial, "Procalcitonin And Survival Study (PASS)." Primary end point was successful weaning from mechanical ventilation within 28 days. We used multivariable Cox regression adjusted for age, sepsis, PaO2/FiO2 ratio and other known and suspected predictors of persistent respiratory failure. Follow-up was complete.For medical patients, baseline-gelsolin below the 25th percentile independently predicted a 40% lower chance of successful weaning within 28 days (HR 0.60, 95% CI 0.46-0.79, Pâ=â0.0002); among surgical patients this end point was not predicted. Low gelsolin levels predicted chance of being "alive and out of intensive care at day 14" for both medical and surgical patients (HR 0.69, 95% CI 0.54-0.89, Pâ=â0.004). Gelsolin levels did not predict 28 day mortality for surgical or medical patients. CONCLUSIONS: Low levels of serum gelsolin independently predict a decreased chance of successful weaning from ventilator within 28 days among medical intensive care patients. This finding has implications for identifying patients who need individualized intervention early in intensive care course to prevent unfavorable lung prognosis in acute respiratory failure. TRIAL REGISTRATION: This is a substudy to the PASS, Clinicaltrials.gov ID: NCT00271752, first registered January 1, 2006.
Asunto(s)
Lesión Pulmonar Aguda/sangre , Gelsolina/sangre , Insuficiencia Respiratoria/sangre , Lesión Pulmonar Inducida por Ventilación Mecánica/sangre , Lesión Pulmonar Aguda/terapia , Anciano , Enfermedad Crítica , Femenino , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Insuficiencia Respiratoria/terapia , Lesión Pulmonar Inducida por Ventilación Mecánica/terapiaRESUMEN
In patients requiring ventilator support, mechanical ventilation (MV) may induce acute lung injury (ventilator-induced lung injury [VILI]). VILI is associated with substantial morbidity and mortality in mechanically ventilated patients with and without acute respiratory distress syndrome. At the cellular level, VILI induces necrotic cell death. However, the contribution of necroptosis, a programmed form of necrotic cell death regulated by receptor-interacting protein-3 kinase (RIPK3) and mixed-lineage kinase domain-like pseudokinase (MLKL), to the development of VILI remains unexplored. Here, we show that plasma levels of RIPK3, but not MLKL, were higher in patients with MV (i.e., those prone to VILI) than in patients without MV (i.e., those less likely to have VILI) in two large intensive care unit cohorts. In mice, RIPK3 deficiency, but not MLKL deficiency, ameliorated VILI. In both humans and mice, VILI was associated with impaired fatty acid oxidation (FAO), but in mice this association was not observed under conditions of RIPK3 deficiency. These findings suggest that FAO-dependent RIPK3 mediates pathogenesis of acute lung injury.
Asunto(s)
Proteínas Quinasas/sangre , Proteínas Quinasas/deficiencia , Proteína Serina-Treonina Quinasas de Interacción con Receptores/sangre , Proteína Serina-Treonina Quinasas de Interacción con Receptores/deficiencia , Respiración Artificial/efectos adversos , Lesión Pulmonar Inducida por Ventilación Mecánica/sangre , Anciano , Animales , Líquido del Lavado Bronquioalveolar/química , Muerte Celular/genética , Estudios de Cohortes , Ácidos Grasos/metabolismo , Femenino , Humanos , Unidades de Cuidados Intensivos , Masculino , Ratones , Persona de Mediana Edad , Oxidación-Reducción , Proteínas Quinasas/genética , Proteínas Quinasas/metabolismo , Proteína Serina-Treonina Quinasas de Interacción con Receptores/genética , Proteína Serina-Treonina Quinasas de Interacción con Receptores/metabolismo , Lesión Pulmonar Inducida por Ventilación Mecánica/fisiopatologíaRESUMEN
PURPOSE OF REVIEW: Despite major improvement in ventilation strategies, hospital mortality and morbidity of the acute respiratory distress syndrome (ARDS) remain high. A lot of therapies have been shown to be ineffective for established ARDS. There is a growing interest in strategies aiming at avoiding development and progression of ARDS. RECENT FINDINGS: Recent advances in this field have explored identification of patients at high-risk, nonspecific measures to limit the risks of inflammation, infection and fluid overload, prevention strategies of ventilator-induced lung injury and patient self-inflicted lung injury, and pharmacological treatments. SUMMARY: There is potential for improvement in the management of patients admitted to intensive care unit to reduce ARDS incidence. Apart from nonspecific measures, prevention of ventilator-induced lung injury and patient self-inflicted lung injury are of major importance.
Asunto(s)
Cuidados Críticos , Progresión de la Enfermedad , Respiración Artificial/métodos , Síndrome de Dificultad Respiratoria/fisiopatología , Lesión Pulmonar Inducida por Ventilación Mecánica/prevención & control , Corticoesteroides/uso terapéutico , Antiinflamatorios no Esteroideos/uso terapéutico , Aspirina/uso terapéutico , Biomarcadores/sangre , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Respiración Artificial/efectos adversos , Síndrome de Dificultad Respiratoria/sangre , Síndrome de Dificultad Respiratoria/terapia , Medición de Riesgo , Lesión Pulmonar Inducida por Ventilación Mecánica/sangreRESUMEN
Current evidence indicates that conventional mechanical ventilation often leads to lung inflammatory response and oxidative stress, while lung-protective ventilation (LPV) minimizes the risk of ventilator-associated lung injury (VALI). This study evaluated the effects of LPV on relief of pulmonary injury, inflammatory response, and oxidative stress among patients undergoing craniotomy. Sixty patients undergoing craniotomy received either conventional mechanical (12 mL/kg tidal volume [VT] and 0 cm H2O positive end-expiratory pressure [PEEP]; CV group) or protective lung (6 mL/kg VT and 10 cm H2O PEEP; PV group) ventilation. Hemodynamic variables, lung function indexes, and inflammatory and oxidative stress markers were assessed. The PV group exhibited greater dynamic lung compliance and lower respiratory index than the CV group during surgery (P < 0.05). The PV group exhibited higher plasma interleukin- (IL-) 10 levels and lower plasma malondialdehyde and nitric oxide and bronchoalveolar lavage fluid, IL-6, IL-8, tumor necrosis factor-α, IL-10, malondialdehyde, nitric oxide, and superoxide dismutase levels (P < 0.05) than the CV group. There were no significant differences in hemodynamic variables, blood loss, liquid input, urine output, or duration of mechanical ventilation between the two groups (P > 0.05). Patients receiving LPV during craniotomy exhibited low perioperative inflammatory response, oxidative stress, and VALI.
Asunto(s)
Craneotomía , Lesión Pulmonar Inducida por Ventilación Mecánica/prevención & control , Adolescente , Adulto , Anciano , Citocinas/sangre , Femenino , Hemodinámica , Humanos , Masculino , Malondialdehído/sangre , Persona de Mediana Edad , Óxido Nítrico/sangre , Respiración Artificial/efectos adversos , Superóxido Dismutasa/sangre , Lesión Pulmonar Inducida por Ventilación Mecánica/sangre , Lesión Pulmonar Inducida por Ventilación Mecánica/parasitologíaRESUMEN
Neutrophil gelatinaseassociated lipocalin (NGAL) is a 25kDa protein of the lipocalin superfamily and its presence was initially observed in activated neutrophils. It has previously been demonstrated that the expression of NGAL is markedly increased in stimulated epithelia, and is important in the innate immunological response to various pathophysiological conditions, including infection, cancer, inflammation and kidney injury. The present study constructed a ventilatorassociated lung injury model in mice. NGAL mRNA and protein expression levels in lung tissue were detected using reverse transcriptionquantitative polymerase chain reaction and western blotting, respectively. In addition, NGAL protein levels in bronchoalveolar lavage fluid and serum were measured via western blotting. The results of the present study suggested that NGAL expression increased under all mechanical ventilation treatments. The increase was most prominent in the high peak inflation pressure and highvolume mechanical ventilation groups, where there was the greatest extent of lung injury. In addition, NGAL expression increased in a timedependent manner under highvolume mechanical ventilation, consistent with the degree of lung injury. These findings suggested that NGAL may serve as a potential novel biomarker in ventilatorassociated lung injury.
Asunto(s)
Biomarcadores , Lipocalina 2/metabolismo , Lesión Pulmonar Inducida por Ventilación Mecánica/metabolismo , Animales , Modelos Animales de Enfermedad , Expresión Génica , Lipocalina 2/sangre , Lipocalina 2/genética , Masculino , Ratones , Transporte de Proteínas , ARN Mensajero/genética , ARN Mensajero/metabolismo , Lesión Pulmonar Inducida por Ventilación Mecánica/sangre , Lesión Pulmonar Inducida por Ventilación Mecánica/genética , Lesión Pulmonar Inducida por Ventilación Mecánica/patologíaRESUMEN
Inappropriate mechanical ventilation (MV) can result in ventilator-induced lung injury (VILI). Probing mechanisms of VILI and searching for effective methods are current areas of research focus on VILI. The present study aimed to probe into mechanisms of endothelial microparticles (EMPs) in VILI and the protective effects of Tetramethylpyrazine (TMP) against VILI. In this study, C57BL/6 and TLR4KO mouse MV models were used to explore the function of EMPs associated with p21 activated kinases-4 (PAK-4) in VILI. Both the C57BL/6 and TLR4 KO groups were subdivided into a mechanical ventilation (MV) group, a TMP + MV group, and a control group. After four hours of high tidal volume (20 ml/kg) MV, the degree of lung injury and the protective effects of TMP were assessed. VILI inhibited the cytoskeleton-regulating protein of PAK4 and was accompanied by an increased circulating EMP level. The intercellular junction protein of ß-catenin was also decreased accompanied by a thickening alveolar wall, increased lung W/D values, and neutrophil infiltration. TMP alleviated VILI via decreasing circulating EMPs, stabilizing intercellular junctions, and alleviating neutrophil infiltration.
Asunto(s)
Micropartículas Derivadas de Células/metabolismo , Lesión Pulmonar/sangre , Respiración Artificial/efectos adversos , Lesión Pulmonar Inducida por Ventilación Mecánica/sangre , Quinasas p21 Activadas/sangre , Animales , Líquido del Lavado Bronquioalveolar , Adhesión Celular , Citoesqueleto/metabolismo , Modelos Animales de Enfermedad , Endotelio Vascular/metabolismo , Endotelio Vascular/patología , Pulmón/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Microscopía Confocal , Microscopía Fluorescente , Neutrófilos/citología , Neutrófilos/metabolismo , Pirazinas/química , Pruebas de Función Respiratoria , Volumen de Ventilación Pulmonar , Receptor Toll-Like 4/genética , beta Catenina/metabolismoRESUMEN
Despite mechanical ventilation being a very important life-saving intervention, ventilator-induced lung injury (VILI) is related with inflammatory effects and causes high mortality. Our previous study demonstrated that the interleukin-33 (IL-33) cytokine pathway is a biomarker of VILI. The purpose of this study was to further explore the effects of hydrocortisone sodium succinate (HC) on pro-inflammatory IL-33 activation by VILI. The rats were intubated and received ventilation at 20 cmH2O of inspiratory pressure (PC20) by a G5 ventilator for 4 h as a control group, and an intervention group received the same inspiratory pressure as well as treated with HC at 1 mg/kg at the third hour of ventilation (PC20+HC). The hemodynamic and respiratory data showed similar changes in the two groups that were exposed to VILI. The pathophysiological results showed that the HC treatment attenuated the VILI severity. Treatment of HC increased IL-33 expression in the bronchoalveolar lavage fluid (BALF). These results demonstrated that IL-33 is involved in VILI processing and HC treatment attenuated IL-33 involvement in inflammatory activation in VILI. In conclusion, IL-33 may play an important role in VILI.
Asunto(s)
Antiinflamatorios/uso terapéutico , Hidrocortisona/uso terapéutico , Interleucina-33/sangre , Lesión Pulmonar Inducida por Ventilación Mecánica/tratamiento farmacológico , Animales , Antiinflamatorios/farmacología , Líquido del Lavado Bronquioalveolar/química , Hemodinámica/efectos de los fármacos , Hidrocortisona/farmacología , Masculino , Ratas Wistar , Lesión Pulmonar Inducida por Ventilación Mecánica/sangre , Lesión Pulmonar Inducida por Ventilación Mecánica/fisiopatologíaRESUMEN
INTRODUCTION: The benefits of prone position ventilation are well demonstrated in the severe forms of acute respiratory distress syndrome, but not in the milder forms. We investigated the effects of prone position on arterial blood gases, lung inflammation, and histology in an experimental mild acute lung injury (ALI) model. METHODS: ALI was induced in Wistar rats by intraperitoneal Escherichia coli lipopolysaccharide (LPS, 5 mg/kg). After 24 h, the animals with PaO2/FIO2 between 200 and 300 mmHg were randomized into 2 groups: prone position (n = 6) and supine position (n = 6). Both groups were compared with a control group (n = 5) that was ventilated in the supine position. All of the groups were ventilated for 1 h with volume-controlled ventilation mode (tidal volume = 6 ml/kg, respiratory rate = 80 breaths/min, positive end-expiratory pressure = 5 cmH2O, inspired oxygen fraction = 1) RESULTS: Significantly higher lung injury scores were observed in the LPS-supine group compared to the LPS-prone and control groups (0.32 ± 0.03; 0.17 ± 0.03 and 0.13 ± 0.04, respectively) (p < 0.001), mainly due to a higher neutrophil infiltration level in the interstitial space and more proteinaceous debris that filled the airspaces. Similar differences were observed when the gravity-dependent lung regions and non-dependent lung regions were analyzed separately (p < 0.05). The BAL neutrophil content was also higher in the LPS-supine group compared to the LPS-prone and control groups (p < 0.05). There were no significant differences in the wet/dry ratio and gas exchange levels. CONCLUSIONS: In this experimental extrapulmonary mild ALI model, prone position ventilation for 1 h, when compared with supine position ventilation, was associated with lower lung inflammation and injury.
Asunto(s)
Lesión Pulmonar Aguda/prevención & control , Lipopolisacáridos , Pulmón/patología , Neumonía/prevención & control , Respiración con Presión Positiva/métodos , Posición Prona , Lesión Pulmonar Inducida por Ventilación Mecánica/prevención & control , Lesión Pulmonar Aguda/sangre , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/patología , Animales , Modelos Animales de Enfermedad , Inyecciones Intraperitoneales , Pulmón/fisiopatología , Masculino , Infiltración Neutrófila , Neumonía/sangre , Neumonía/inducido químicamente , Neumonía/patología , Respiración con Presión Positiva/efectos adversos , Ratas Wistar , Frecuencia Respiratoria , Posición Supina , Volumen de Ventilación Pulmonar , Lesión Pulmonar Inducida por Ventilación Mecánica/sangre , Lesión Pulmonar Inducida por Ventilación Mecánica/inducido químicamente , Lesión Pulmonar Inducida por Ventilación Mecánica/patologíaRESUMEN
BACKGROUND: Several biological markers of lung injury are predictors of morbidity and mortality in patients with acute respiratory distress syndrome (ARDS). Some lung-protective ventilation strategies, such as low tidal volume, are associated with a significant decrease in plasma biomarker levels compared to the high tidal volume ventilation strategy. The primary objective of this study was to test whether the institution of high-frequency percussive ventilation (HFPV) to patients with respiratory distress after smoke inhalation injury influenced initial biomarker levels of lung injury (just before and after using percussive ventilation). MATERIALS AND METHODS: A prospective observational cohort study was conducted in the intensive care unit of the Brussels Burn Center. Fifteen intubated, mechanically ventilated patients with minor burns and ARDS following smoke inhalation were enrolled in our study. Physiologic data and serum samples were collected before intubation and at four different time points within the first 48h after intubation to measure the concentration of interleukin (IL)-6, IL-8, and tumor necrosis factor-α (TNF alpha). The differences in biomarker levels before and after starting HFPV were analyzed using repeated measure analysis of variance and a paired t test with correction for multiple comparisons. RESULTS: Before starting HFPV under endotracheal intubation, all biological markers (IL-6, IL-8, and TNF alpha) were elevated in the spontaneously breathing patients with acute lung injury (ALI). After intubation and institution of a positive pressure ventilation with HFPV (tidal volume 5.6-6.6ml/kg per ideal body weight), none of the biological markers were increased significantly at either an early (3±2h) or a later point in time. However, the levels of IL-8 had decreased significantly after intubation at a later point in time. During the post-intubation period, the PaO2/FiO2 (partial pressure of arterial oxygen/fraction of the inspired oxygen) ratio increased significantly and the plateau airway pressure decreased significantly. CONCLUSION: Levels of IL-6, IL-8, and TNF alpha are elevated in spontaneously ventilating patients with minor burns and ARDS following smoke exposition prior to endotracheal intubation. The institution of HFPV with percussive positive pressure ventilation enhances blood oxygenation and could not further increase the initial levels of these biological markers of lung injury after smoke inhalation injury.
Asunto(s)
Ventilación de Alta Frecuencia/métodos , Interleucina-6/sangre , Interleucina-8/sangre , Síndrome de Dificultad Respiratoria/terapia , Lesión por Inhalación de Humo/terapia , Factor de Necrosis Tumoral alfa/sangre , Adulto , Biomarcadores/sangre , Unidades de Quemados , Quemaduras/complicaciones , Quemaduras/terapia , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Respiración con Presión Positiva , Estudios Prospectivos , Síndrome de Dificultad Respiratoria/sangre , Síndrome de Dificultad Respiratoria/etiología , Lesión por Inhalación de Humo/sangre , Lesión por Inhalación de Humo/complicaciones , Volumen de Ventilación Pulmonar , Lesión Pulmonar Inducida por Ventilación Mecánica/sangre , Lesión Pulmonar Inducida por Ventilación Mecánica/prevención & control , Adulto JovenRESUMEN
INTRODUCTION: Endothelial cell injury is an important component of acute lung injury. Platelet-endothelial cell adhesion molecule-1 (PECAM1) is a transmembrane protein that connects endothelial cells to one another and can be detected as a soluble, truncated protein (sPECAM1) in serum. We hypothesized that injurious mechanical ventilation (MV) leads to shedding of PECAM1 from lung endothelial cells resulting in increasing sPECAM1 levels in the systemic circulation. METHODS: We studied 36 Sprague-Dawley rats in two prospective, randomized, controlled studies (healthy and septic) using established animal models of ventilator-induced lung injury. Animals (n = 6 in each group) were randomized to spontaneous breathing or two MV strategies: low tidal volume (VT) (6 ml/kg) and high-VT (20 ml/kg) on 2 cmH2O of positive end-expiratory pressure (PEEP). In low-VT septic animals, 10 cmH2O of PEEP was applied. We performed pulmonary histological and physiological evaluation and measured lung PECAM1 protein content and serum sPECAM1 levels after four hours ventilation period. RESULTS: High-VT MV caused severe lung injury in healthy and septic animals, and decreased lung PECAM1 protein content (P < 0.001). Animals on high-VT had a four- to six-fold increase of mean sPECAM1 serum levels than the unventilated counterpart (35.4 ± 10.4 versus 5.6 ± 1.7 ng/ml in healthy rats; 156.8 ± 47.6 versus 35.6 ± 12.6 ng/ml in septic rats) (P < 0.0001). Low-VT MV prevented these changes. Levels of sPECAM1 in healthy animals on high-VT MV paralleled the sPECAM1 levels of non-ventilated septic animals. CONCLUSIONS: Our findings suggest that circulating sPECAM1 may represent a promising biomarker for the detection and monitoring of ventilator-induced lung injury.
Asunto(s)
Molécula-1 de Adhesión Celular Endotelial de Plaqueta/sangre , Lesión Pulmonar Inducida por Ventilación Mecánica/sangre , Lesión Pulmonar Inducida por Ventilación Mecánica/patología , Animales , Biomarcadores/sangre , Biomarcadores/metabolismo , Pulmón/metabolismo , Pulmón/patología , Masculino , Estudios Prospectivos , Distribución Aleatoria , Ratas , Ratas Sprague-DawleyRESUMEN
BACKGROUND: Extracorporeal (EC) carbon dioxide (CO(2)) removal (ECCO(2)R) may be a powerful alternative to ventilation, possibly avoiding the need for mechanical ventilation and endotracheal intubation. We previously reported how an infusion of lactic acid before a membrane lung (ML) effectively enhances ECCO(2)R. We evaluated an innovative ECCO(2)R technique based on ventilation of acidified dialysate. METHODS: Four swine were sedated, mechanically ventilated, and connected to a venovenous dialysis circuit (blood flow, 250 ml/min). The dialysate was recirculated in a closed loop circuit including a ML (gas flow, 10 liters/min) and then returned to the dialyzer. In each animal, 4 different dialysis flows (DF) of 200, 400, 600, and 800 ml/min were evaluated with and without lactic acid infusion (2.5 mEq/min); the sequence was completed 3 times. At the end of each step, we measured the volume of CO(2)R by the ML (V(co2)ML) and collected blood and dialysate samples for gas analyses. RESULTS: Acid infusion substantially increased V(co2)ML, from 33 ± 6 ml/min to 86 ± 7 ml/min. Different DFs had little effect on V(co2)ML, which was only slightly reduced at DF 200 ml/min. The partial pressure of CO(2) of blood passing through the dialysis filter changed from 60.9 ± 3.6 to 37.1 ± 4.8 mm Hg without acidification and to 32.5 ± 5.3 mm Hg with acidification, corresponding to a pH increase of 0.18 ± 0.03 and 0.03 ± 0.04 units, respectively. CONCLUSIONS: Ventilation of acidified dialysate efficiently increased ECCO(2)R of an amount corresponding to 35% to 45% of the total CO(2) production of an adult man from a blood flow as low as 250 ml/min.
Asunto(s)
Dióxido de Carbono/sangre , Soluciones para Diálisis/farmacología , Oxigenación por Membrana Extracorpórea/métodos , Diálisis Renal/efectos adversos , Respiración Artificial/métodos , Lesión Pulmonar Inducida por Ventilación Mecánica/terapia , Animales , Soluciones para Diálisis/química , Modelos Animales de Enfermedad , Concentración de Iones de Hidrógeno , Porcinos , Lesión Pulmonar Inducida por Ventilación Mecánica/sangreRESUMEN
BACKGROUND: Global metabolic profiling using quantitative nuclear magnetic resonance spectroscopy (MRS) and mass spectrometry (MS) is useful for biomarker discovery. The objective of this study was to discover biomarkers of acute lung injury induced by mechanical ventilation (ventilator-induced lung injury [VILI]), by using MRS and MS. METHODS: Male Sprague-Dawley rats were subjected to two ventilatory strategies for 2.5 h: tidal volume 9 ml/kg, positive end-expiratory pressure 5 cm H2O (control, n = 14); and tidal volume 25 ml/kg and positive end-expiratory pressure 0 cm H2O (VILI, n = 10). Lung tissue, bronchoalveolar lavage fluid, and serum spectra were obtained by high-resolution magic angle spinning and H-MRS. Serum spectra were acquired by high-performance liquid chromatography coupled to quadupole-time of flight MS. Principal component and partial least squares analyses were performed. RESULTS: Metabolic profiling discriminated characteristics between control and VILI animals. As compared with the controls, animals with VILI showed by MRS higher concentrations of lactate and lower concentration of glucose and glycine in lung tissue, accompanied by increased levels of glucose, lactate, acetate, 3-hydroxybutyrate, and creatine in bronchoalveolar lavage fluid. In serum, increased levels of phosphatidylcholine, oleamide, sphinganine, hexadecenal and lysine, and decreased levels of lyso-phosphatidylcholine and sphingosine were identified by MS. CONCLUSIONS: This pilot study suggests that VILI is characterized by a particular metabolic profile that can be identified by MRS and MS. The metabolic profile, though preliminary and pending confirmation in larger data sets, suggests alterations in energy and membrane lipids.SUPPLEMENTAL DIGITAL CONTENT IS AVAILABLE IN THE TEXT.
Asunto(s)
Metabolómica/métodos , Lesión Pulmonar Inducida por Ventilación Mecánica/metabolismo , Lesión Pulmonar Inducida por Ventilación Mecánica/patología , Animales , Biomarcadores/sangre , Líquido del Lavado Bronquioalveolar , Cromatografía Líquida de Alta Presión/métodos , Modelos Animales de Enfermedad , Análisis de los Mínimos Cuadrados , Pulmón/metabolismo , Pulmón/patología , Espectroscopía de Resonancia Magnética/métodos , Masculino , Espectrometría de Masas/métodos , Proyectos Piloto , Respiración con Presión Positiva/métodos , Análisis de Componente Principal , Ratas , Ratas Sprague-Dawley , Respiración Artificial/efectos adversos , Volumen de Ventilación Pulmonar/fisiología , Lesión Pulmonar Inducida por Ventilación Mecánica/sangreRESUMEN
PURPOSE OF REVIEW: The article provides an overview of efforts to identify and validate biomarkers in acute respiratory distress syndrome (ARDS) and a discussion of the challenges confronting researchers in this area. RECENT FINDINGS: Although various putative biomarkers have been investigated in ARDS, the data have been largely disappointing and the 'troponin' of ARDS remains elusive. Establishing a relationship between measurable biological processes and clinical outcomes is vital to advancing clinical trials in ARDS and expanding our arsenal of treatments for this complex syndrome. SUMMARY: This article summarizes the current status of ARDS biomarker research and provides a framework for future investigation.
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Respiración Artificial/efectos adversos , Síndrome de Dificultad Respiratoria/terapia , Lesión Pulmonar Inducida por Ventilación Mecánica/terapia , Biomarcadores/sangre , Femenino , Humanos , Molécula 1 de Adhesión Intercelular/sangre , Interleucina-6/sangre , Interleucina-8/sangre , Masculino , Mucina-1/sangre , Inhibidor 1 de Activador Plasminogénico/sangre , Receptor para Productos Finales de Glicación Avanzada/sangre , Investigación , Síndrome de Dificultad Respiratoria/sangre , Factor de Necrosis Tumoral alfa/sangre , Factor A de Crecimiento Endotelial Vascular/sangre , Lesión Pulmonar Inducida por Ventilación Mecánica/sangre , Proteínas de Transporte Vesicular/sangre , Factor de von Willebrand/metabolismoRESUMEN
INTRODUCTION: The principal mechanisms of ventilator induced lung injury (VILI) have been investigated in numerous animal studies. However, prospective data on the effect of old age on VILI are limited. Under the hypothesis that susceptibility to VILI is increased in old age, we investigated the pulmonary and extrapulmonary effects of mechanical ventilation with high tidal volume (VT) in old compared to young adult animals. INTERVENTIONS: Old (19.1±3.0 months) and young adult (4.4±1.3 months) male Wistar rats were anesthetized and mechanically ventilated (positive end-expiratory pressure 5 cmH2O, fraction of inspired oxygen 0.4, respiratory rate 40/minute) with a tidal volume (VT) of either 8, 16 or 24 ml/kg for four hours. RESULTS: Compared to young adult animals, high VT (24 ml/kg body weight) caused more lung injury in old animals as indicated by decreased oxygenation (arterial oxygen tension (PaO2): 208±3 vs. 131±20 mmHg; P<0.05), increased lung wet-to-dry-weight ratio (5.61±0.29 vs. 7.52±0.27; P<0.05), lung lavage protein (206±52 mg/l vs. 1,432±101; P<0.05) and cytokine (IL-6: 856±448 vs. 3,283±943 pg/ml; P<0.05) concentration. In addition, old animals ventilated with high VT had more systemic inflammation than young animals (IL-1ß: 149±44 vs. 272±36 pg/ml; P<0.05--young vs. old, respectively). CONCLUSIONS: Ventilation with unphysiologically large tidal volumes is associated with more lung injury in old compared to young rats. Aggravated pulmonary and systemic inflammation is a key finding in old animals developing VILI.
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Envejecimiento/patología , Lesión Pulmonar Inducida por Ventilación Mecánica/patología , Factores de Edad , Envejecimiento/sangre , Animales , Susceptibilidad a Enfermedades/sangre , Susceptibilidad a Enfermedades/patología , Masculino , Proyectos Piloto , Distribución Aleatoria , Ratas , Ratas Wistar , Volumen de Ventilación Pulmonar/fisiología , Lesión Pulmonar Inducida por Ventilación Mecánica/sangre , Lesión Pulmonar Inducida por Ventilación Mecánica/etiologíaRESUMEN
BACKGROUND: Extremely preterm infants often receive mechanical ventilation (MV), which can contribute to bronchopulmonary dysplasia (BPD). However, the effects of MV alone on the extremely preterm lung and the lung's capacity for repair are poorly understood. AIM: To characterise lung injury induced by MV alone, and mechanisms of injury and repair, in extremely preterm lungs and to compare them with very preterm lungs. METHODS: Extremely preterm lambs (0.75 of term) were transiently exposed by hysterotomy and underwent 2 h of injurious MV. Lungs were collected 24 h and at 15 d after MV. Immunohistochemistry and morphometry were used to characterise injury and repair processes. qRT-PCR was performed on extremely and very preterm (0.85 of term) lungs 24 h after MV to assess molecular injury and repair responses. RESULTS: 24 h after MV at 0.75 of term, lung parenchyma and bronchioles were severely injured; tissue space and myofibroblast density were increased, collagen and elastin fibres were deformed and secondary crest density was reduced. Bronchioles contained debris and their epithelium was injured and thickened. 24 h after MV at 0.75 and 0.85 of term, mRNA expression of potential mediators of lung repair were significantly increased. By 15 days after MV, most lung injury had resolved without treatment. CONCLUSIONS: Extremely immature lungs, particularly bronchioles, are severely injured by 2 h of MV. In the absence of continued ventilation these injured lungs are capable of repair. At 24 h after MV, genes associated with injurious MV are unaltered, while potential repair genes are activated in both extremely and very preterm lungs.
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Pulmón/embriología , Nacimiento Prematuro/patología , Respiración Artificial/efectos adversos , Lesión Pulmonar Inducida por Ventilación Mecánica/embriología , Lesión Pulmonar Inducida por Ventilación Mecánica/patología , Cicatrización de Heridas , Animales , Análisis de los Gases de la Sangre , Peso Corporal , Bronquiolos/embriología , Bronquiolos/metabolismo , Bronquiolos/patología , Proliferación Celular , Colágeno/metabolismo , ADN/metabolismo , Elastina/metabolismo , Electrólitos/metabolismo , Sangre Fetal/metabolismo , Regulación del Desarrollo de la Expresión Génica , Pulmón/metabolismo , Pulmón/patología , Miofibroblastos/metabolismo , Miofibroblastos/patología , Necrosis , Tamaño de los Órganos , Nacimiento Prematuro/sangre , Nacimiento Prematuro/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Lesión Pulmonar Inducida por Ventilación Mecánica/sangre , Lesión Pulmonar Inducida por Ventilación Mecánica/genética , Cicatrización de Heridas/genéticaRESUMEN
BACKGROUND: High-frequency oscillatory ventilation (HFOV) at higher frequencies minimizes the tidal volume. However, whether increased frequencies during HFOV can reduce ventilator-induced lung injury remains unknown. METHODS: After the induction of acute respiratory distress syndrome in the model by repeated lavages, 24 adult sheep were randomly divided into four groups (n = 6): three HFOV groups (3, 6, and 9 Hz) and one conventional mechanical ventilation (CMV) group. Standard lung recruitments were performed in all groups until optimal alveolar recruitment was reached. After lung recruitment, the optimal mean airway pressure or positive end-expiratory pressure was determined with decremental pressure titration, 2 cm H2O every 10 min. Animals were ventilated for 4 h. RESULTS: After lung recruitment, sustained improvements in gas exchange and compliance were observed in all groups. Compared with the HFOV-3 Hz and CMV groups, the transpulmonary pressure and tidal volumes were statistically significantly lower in the HFOV-9 Hz group. The lung injury scores and wet/dry weight ratios were significantly reduced in the HFOV-9 Hz group compared with the HFOV-3 Hz and CMV groups. Expression of interleukin-1ß and interleukin-6 in the lung tissue, decreased significantly in the HFOV-9 Hz group compared with the HFOV-3 Hz and CMV groups. Malondialdehyde expression and myeloperoxidase activity in lung tissues in the HFOV-9 Hz group decreased significantly, compared with the HFOV-3 Hz and CMV groups. CONCLUSION: The use of HFOV at 9 Hz minimizes lung stress and tidal volumes, resulting in less lung injury and reduced levels of inflammatory mediators compared with the HFOV-3 Hz and CMV conditions.
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Ventilación de Alta Frecuencia/métodos , Síndrome de Dificultad Respiratoria/terapia , Lesión Pulmonar Inducida por Ventilación Mecánica/prevención & control , Animales , Modelos Animales de Enfermedad , Interleucina-1beta/sangre , Interleucina-6/sangre , Masculino , Malondialdehído/sangre , Peroxidasa/sangre , Respiración con Presión Positiva/métodos , Respiración Artificial/métodos , Síndrome de Dificultad Respiratoria/sangre , Ovinos , Volumen de Ventilación Pulmonar , Lesión Pulmonar Inducida por Ventilación Mecánica/sangreRESUMEN
In the search for a noninvasive and reliable rapid screening method to detect biomarkers, a metabolomics fingerprinting approach was developed and applied to rat serum samples using capillary electrophoresis coupled to an electrospray ionization-time of flight-mass spectrometer (CE-TOF-MS). An ultrafiltration method was used for sample pretreatment. To evaluate performance the method was validated with carnitine, choline, ornithine, alanine, acetylcarnitine, betaine, and citrulline, covering the entire electropherogram of pool of rat serum. The linearity for all metabolites was >0.99, with good recovery and precision. Approximately 34 compounds were also confirmed in the pool of rat serum. The method was successfully applied to real serum samples from rats with ventilator-induced lung injury, an experimental rat model for acute lung injury (ALI), giving a total of 1163 molecular features. By use of univariate and multivariate statistics 18 significant compounds were found, of which five were confirmed. The involvement of arginase and nitric oxide synthase has been proved for other lung diseases, meaning the increase of asymmetric dimethyl arginine (ADMA) and ornithine and the decrease of arginine found were in accordance with published literature. Ultimately this fingerprinting approach offers the possibility of identifying biomarkers that could be regularly screened for as part of routine disease control. In this way it might be possible to prevent the development of ALI in patients in critical care units.
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Biomarcadores/sangre , Electroforesis Capilar/métodos , Metaboloma , Espectrometría de Masa por Ionización de Electrospray/métodos , Lesión Pulmonar Inducida por Ventilación Mecánica/sangre , Lesión Pulmonar Inducida por Ventilación Mecánica/diagnóstico , Animales , Masculino , Ratas , Ratas Sprague-Dawley , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
BACKGROUND: Mesenchymal stromal cells (MSCs) have been demonstrated to attenuate acute lung injury when delivered by intravenous or intratracheal routes. The authors aimed to determine the efficacy of and mechanism of action of intratracheal MSC therapy and to compare their efficacy in enhancing lung repair after ventilation-induced lung injury with intravenous MSC therapy. METHODS: : After induction of anesthesia, rats were orotracheally intubated and subjected to ventilation-induced lung injury (respiratory rate 18(-1) min, P insp 35 cm H2O,) to produce severe lung injury. After recovery, animals were randomized to receive: (1) no therapy, n = 4; (2) intratracheal vehicle (phosphate-buffered saline, 300 µl, n = 8); (3) intratracheal fibroblasts (4 × 10 cells, n = 8); (4) intratracheal MSCs (4 × 10(6) cells, n = 8); (5) intratracheal conditioned medium (300 µl, n = 8); or (6) intravenous MSCs (4 × 10(6) cells, n = 4). The extent of recovery after acute lung injury and the inflammatory response was assessed after 48 h. RESULTS: Intratracheal MSC therapy enhanced repair after ventilation-induced lung injury, improving arterial oxygenation (mean ± SD, 146 ± 3.9 vs. 110.8 ± 21.5 mmHg), restoring lung compliance (1.04 ± 0.11 vs. 0.83 ± 0.06 ml · cm H2O(-1)), reducing total lung water, and decreasing lung inflammation and histologic injury compared with control. Intratracheal MSC therapy attenuated alveolar tumor necrosis factor-α (130 ± 43 vs. 488 ± 211 pg · ml(-1)) and interleukin-6 concentrations (138 ± 18 vs. 260 ± 82 pg · ml(-1)). The efficacy of intratracheal MSCs was comparable with intravenous MSC therapy. Intratracheal MSCs seemed to act via a paracine mechanism, with conditioned MSC medium also enhancing lung repair after injury. CONCLUSIONS: Intratracheal MSC therapy enhanced recovery after ventilation-induced lung injury via a paracrine mechanism, and was as effective as intravenous MSC therapy.
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Trasplante de Células Madre Mesenquimatosas/métodos , Lesión Pulmonar Inducida por Ventilación Mecánica/cirugía , Animales , Modelos Animales de Enfermedad , Interleucina-6/sangre , Intubación Intratraqueal , Pulmón/fisiopatología , Rendimiento Pulmonar , Oxígeno/sangre , Ratas , Ratas Sprague-Dawley , Tráquea , Resultado del Tratamiento , Factor de Necrosis Tumoral alfa/sangre , Lesión Pulmonar Inducida por Ventilación Mecánica/sangreRESUMEN
Enhanced intrapulmonary fibrin deposition as a result of abnormal broncho-alveolar fibrin turnover is a hallmark of acute respiratory distress syndrome (ARDS), pneumonia and ventilator-induced lung injury (VILI), and is important to the pathogenesis of these conditions. The mechanisms that contribute to alveolar coagulopathy are localized tissue factor-mediated thrombin generation, impaired activity of natural coagulation inhibitors and depression of bronchoalveolar urokinase plasminogen activator-mediated fibrinolysis, caused by the increase of plasminogen activator inhibitors. There is an intense and bidirectional interaction between coagulation and inflammatory pathways in the bronchoalveolar compartment. Systemic or local administration of anticoagulant agents (including activated protein C, antithrombin and heparin) and profibrinolytic agents (such as plasminogen activators) attenuate pulmonary coagulopathy. Several preclinical studies show additional anti-inflammatory effects of these therapies in ARDS and pneumonia.