Josefina López-Aguilar

Injurious mechanical ventilation affects neuronal activation in ventilated rats

IntroductionSurvivors of critical illness often have significant long-term brain dysfunction, and routine clinical procedures like mechanical ventilation (MV) may affect long-term brain outcome. We aimed to investigate the effect of the increase of tidal volume (Vt) on brain activation in a rat model.MethodsMale Sprague Dawley rats were randomized to three groups: 1) Basal: anesthetized unventilated animals, 2) low Vt (LVt): MV for three hours with Vt 8 ml/kg and zero positive end-expiratory pressure (ZEEP), and 3) high Vt (HVt) MV for three hours with Vt 30 ml/kg and ZEEP. We measured lung mechanics, mean arterial pressure (MAP), arterial blood gases, and plasma and lung levels of cytokines. We used immunohistochemistry to examine c-fos as a marker of neuronal activation. An additional group of spontaneously breathing rats was added to discriminate the effect of surgical procedure and anesthesia in the brain.ResultsAfter three hours on LVt, PaO2 decreased and PaCO2 increased significantly. MAP and compliance remained stable in MV groups. Systemic and pulmonary inflammation was higher in MV rats than in unventilated rats. Plasma TNFα was significantly higher in HVt than in LVt. Immunopositive cells to c-fos in the retrosplenial cortex and thalamus increased significantly in HVt rats but not in LVt or unventilated rats.ConclusionsMV promoted brain activation. The intensity of the response was higher in HVt animals, suggesting an iatrogenic effect of MV on the brain. These findings suggest that this novel cross-talking mechanism between the lung and the brain should be explored in patients undergoing MV.

Utilidad de las maniobras de reclutamiento (contra)

En los pacientes con SDRA se observa una reduccion del volumen pulmonar y el area de parenquima pulmonar util para realizar el intercambio de gases. La aplicacion de un patron ventilatorio adecuado que incluya la aplicacion de PEEP puede restituir el aireamiento de zonas pulmonares colapsadas y garantizar una distribucion mas homogenea del aire en el pulmon; a pesar de ello, los patrones de heterogeneidad observados en los pacientes con SDRA responden de forma diversa a la ventilacion con PEEP. El uso de maniobras de reclutamiento (MR) se ha propuesto como tratamiento adjunto a la ventilacion mecanica para reexpandir el tejido pulmonar colapsado que se observa en el SDRA. Sin embargo, no esta claro que las MR sean utiles cuando los pacientes se ventilan con PEEP elevada o cuando estan afectos de fibrosis, alteraciones de la caja toracica o alteraciones de la volemia, entre otras afecciones. De la misma manera, a la hora de tomar una decision acerca de las MR, hay que considerar no solo su efectividad a corto o largo plazo y su reversibilidad, sino tambien que las MR pueden no estar exentas de efectos adversos derivados de las elevadas presiones que se alcanzan. Entre ellos destacan la posibilidad de barotrauma y alteraciones hemodinamicas como la dificultad del retorno venoso y la disminucion del volumen sistolico y el flujo aortico, asi como la posibilidad de translocacion bacteriana a la circulacion sistemica u otros organos. Este articulo analiza los efectos derivados del uso de MR como tratamiento adyuvante en los pacientes con SDRA, frente a su efectividad y el beneficio potencial, asi como las diversas interacciones con diversos trastornos relacionados con el SDRA.

Early activation of pro-fibrotic WNT5A in sepsis-induced acute lung injury

IntroductionThe mechanisms of lung repair and fibrosis in the acute respiratory distress syndrome (ARDS) are poorly known. Since the role of WNT/β-catenin signaling appears to be central to lung healing and fibrosis, we hypothesized that this pathway is activated very early in the lungs after sepsis.MethodsWe tested our hypothesis using a three-step experimental design: (1) in vitro lung cell injury model with human bronchial epithelial BEAS-2B and lung fibroblasts (MRC-5) cells exposed to endotoxin for 18 hours; (2) an animal model of sepsis-induced ARDS induced by cecal ligation and perforation, and (3) lung biopsies from patients who died within the first 24 hours of septic ARDS. We examined changes in protein levels of target genes involved in the Wnt pathway, including WNT5A, non-phospho (Ser33/37/Thr41) β-catenin, matrix metalloproteinase-7 (MMP7), cyclin D1, and vascular endothelial growth factor (VEGF) by Western blotting and immunohistochemistry. Finally, we validated the main gene targets of this pathway in experimental animals and human lungs.ResultsProtein levels of WNT5A, non-phospho (Ser33/37/Thr41) β-catenin, total β-catenin, MMP7, cyclin D1, and VEGF increased after endotoxin stimulation in BEAS-2B and MRC-5 cells. Lungs from septic animals and from septic humans demonstrated acute lung inflammation, collagen deposition, and marked increase of WNT5A and MMP7 protein levels.ConclusionsOur findings suggest that the WNT/β-catenin signaling pathway is activated very early in sepsis-induced ARDS and could play an important role in lung repair and fibrosis. Modulation of this pathway might represent a potential target for treatment for septic and ARDS patients.

Endotoxin-induced lung alveolar cell injury causes brain cell damage

Sepsis is the most common cause of acute respiratory distress syndrome, a severe lung inflammatory disorder with an elevated morbidity and mortality. Sepsis and acute respiratory distress syndrome involve the release of inflammatory mediators to the systemic circulation, propagating the cellular and molecular response and affecting distal organs, including the brain. Since it has been reported that sepsis and acute respiratory distress syndrome contribute to brain dysfunction, we investigated the brain-lung crosstalk using a combined experimental in vitro airway epithelial and brain cell injury model. Conditioned medium collected from an in vitro lipopolysaccharide-induced airway epithelial cell injury model using human A549 alveolar cells was subsequently added at increasing concentrations (no conditioned, 2%, 5%, 10%, 15%, 25%, and 50%) to a rat mixed brain cell culture containing both astrocytes and neurons. Samples from culture media and cells from mixed brain cultures were collected before treatment, and at 6 and 24 h for analysis. Conditioned medium at 15% significantly increased apoptosis in brain cell cultures 24 h after treatment, whereas 25% and 50% significantly increased both necrosis and apoptosis. Levels of brain damage markers S100 calcium binding protein B and neuron-specific enolase, interleukin-6, macrophage inflammatory protein-2, as well as matrix metalloproteinase-9 increased significantly after treating brain cells with ≥2% conditioned medium. Our findings demonstrated that human epithelial pulmonary cells stimulated with bacterial lipopolysaccharide release inflammatory mediators that are able to induce a translational clinically relevant and harmful response in brain cells. These results support a brain-lung crosstalk during sepsis and sepsis-induced acute respiratory distress syndrome.

Do sedation and analgesia contribute to long-term cognitive dysfunction in critical care survivors?

Deep sedation during stay in the Intensive Care Unit (ICU) may have deleterious effects upon the clinical and cognitive outcomes of critically ill patients undergoing mechanical ventilation. Over the last decade a vast body of literature has been generated regarding different sedation strategies, with the aim of reducing the levels of sedation in critically ill patients. There has also been a growing interest in acute brain dysfunction, or delirium, in the ICU. However, the effect of sedation during ICU stay upon long-term cognitive deficits in ICU survivors remains unclear. Strategies for reducing sedation levels in the ICU do not seem to be associated with worse cognitive and psychological status among ICU survivors. Sedation strategy and management efforts therefore should seek to secure the best possible state in the mechanically ventilated patient and lower the prevalence of delirium, in order to prevent long-term cognitive alterations.

Erratum to: Injurious mechanical ventilation affects neuronal activation in ventilated rats

Unfortunately, the original version of this article [1] contained an error. Affiliation no. 5 had been omitted to be included for the first author, Maria Elisa Quilez. This has now been corrected. The full list of affiliations for the first author are: Maria Elisa Quilez1,2,5 1 CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III. C/ Sinesio Delgado 6, Madrid, 28029, Spain 2 Critical Care Center, Corporacio Sanitaria Parc Tauli, Institut Universitari, Esfera UAB. Parc Tauli sn. Sabadell, 08208, Spain 5 Universitat Autonoma de Barcelona. Campus de la UAB, Bellaterra, 08193, Spain