María Elisa Quilez

Activation of the Wnt/β-Catenin Signaling Pathway by Mechanical Ventilation Is Associated with Ventilator-Induced Pulmonary Fibrosis in Healthy Lungs

Background Mechanical ventilation (MV) with high tidal volumes (VT) can cause or aggravate lung damage, so-called ventilator induced lung injury (VILI). The relationship between specific mechanical events in the lung and the cellular responses that result in VILI remains incomplete. Since activation of Wnt/β-catenin signaling has been suggested to be central to mechanisms of lung healing and fibrosis, we hypothesized that the Wnt/β-catenin signaling plays a role during VILI. Methodology/Principal Findings Prospective, randomized, controlled animal study using adult, healthy, male Sprague-Dawley rats. Animals (nu200a=u200a6/group) were randomized to spontaneous breathing or two strategies of MV for 4 hours: low tidal volume (VT) (6 mL/kg) or high VT (20 mL/kg). Histological evaluation of lung tissue, measurements of WNT5A, total β-catenin, non-phospho (Ser33/37/Thr41) β-catenin, matrix metalloproteinase-7 (MMP-7), cyclin D1, vascular endothelial growth factor (VEGF), and axis inhibition protein 2 (AXIN2) protein levels by Western blot, and WNT5A, non-phospho (Ser33/37/Thr41) β-catenin, MMP-7, and AXIN2 immunohistochemical localization in the lungs were analyzed. High-VT MV caused lung inflammation and perivascular edema with cellular infiltrates and collagen deposition. Protein levels of WNT5A, non-phospho (Ser33/37/Thr41) β-catenin, MMP-7, cyclin D1, VEGF, and AXIN2 in the lungs were increased in all ventilated animals although high-VT MV was associated with significantly higher levels of WNT5A, non-phospho (Ser33/37/Thr41) β-catenin, MMP-7, cyclin D1, VEGF, and AXIN2 levels. Conclusions/Significance Our findings demonstrate that the Wnt/β-catenin signaling pathway is modulated very early by MV in lungs without preexistent lung disease, suggesting that activation of this pathway could play an important role in both VILI and lung repair. Modulation of this pathway might represent a therapeutic option for prevention and/or management of VILI.

Organ crosstalk during acute lung injury, acute respiratory distress syndrome, and mechanical ventilation.

Purpose of reviewMultiple organ failure is the main cause of morbidity and mortality in acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) patients. Moreover, survivors of both ALI and ARDS often show significant neurocognitive decline at discharge. These data suggest a deleterious organ crosstalk between lungs and distal organs. This article reviews the recent literature concerning the role of this organ crosstalk during ALI, ARDS, and mechanical ventilation, especially focusing on brain–lung communication. Recent findingsNumerous pulmonary and extrapulmonary disorders could predispose critically ill patients to ALI and ARDS. Mechanical ventilation, although a lifesaving intervention, could contribute by modulating the mechanisms involved in the pathophysiology of lung damage and their impact on remote organs. Emerging clinical and experimental evidence supports the hypothesis of a multidirectional organ crosstalk between lungs and distal organs. SummaryOrgan crosstalk is an emerging area of research in lung disease in critically ill patients. The findings of these studies are clinically relevant and show the importance of an integrative approach in the management of critical patients. However, further studies are necessary to understand the complex interactions concurring in these pathologies.

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.

Early physiological and biological features in three animal models of induced acute lung injury

IntroductionCritically ill patients often develop acute lung injury (ALI) in the context of different clinical conditions. We aimed to explore differences in early local and systemic features in three experimental animal models of ALI.MethodsMechanically ventilated male Sprague–Dawley rats were randomized to high tidal volume (VT) ventilation (HVT) (nxa0=xa08, VT 24xa0ml/kg), massive brain injury (MBI) (nxa0=xa08, VT 8xa0ml/kg) or endotoxemia (LPS) (nxa0=xa08, VT 8xa0ml/kg). Each experimental group had its own control group of eight rats (VT 8xa0ml/kg). We measured arterial blood gases, mean arterial pressure, lung compliance, inflammatory mediators in plasma and their expression and gelatinase activity in the lungs after 3xa0h of injury.ResultsDespite maintaining relatively normal lung function without evidence of important structural changes, we observed altered lung and systemic inflammatory responses in all three experimental models. LPS triggered the most robust inflammatory response and HVT the lowest systemic proinflammatory response. The HVT group had higher Il6, Tnf and Cxcl2 mRNA in lungs than MBI animals. Metalloproteinase activity/expression and neutrophilic recruitment in the lungs were higher in HVT than in LPS or MBI.ConclusionsThe early responses to direct or remote lung insult in our three models of ALI captured different physiological and biological features that could lead to respiratory and/or multiorgan failure.

Interacción pulmón-cerebro en el paciente ventilado mecánicamente

Patients with acute lung injury or acute respiratory distress syndrome (ARDS) admitted to the ICU present neuropsychological alterations, which in most cases extend beyond the acute phase and have an important adverse effect upon quality of life. The aim of this review is to deepen in the analysis of the complex interaction between lung and brain in critically ill patients subjected to mechanical ventilation. This update first describes the neuropsychological alterations occurring both during the acute phase of ICU stay and at discharge, followed by an analysis of lung-brain interactions during mechanical ventilation, and finally explores the etiology and mechanisms leading to the neurological disorders observed in these patients. The management of critical patients requires an integral approach focused on minimizing the deleterious effects over the short, middle or long term.

0468. Cerebral effects of lateral trendelenburg vs semirecumbent position in an experimental model of ventilator-associated pneumonia

Bacterial Colonization (0.22 vs 2.27 and 2.31 log cfu/gr, p< 0.05) and VAP (0 vs 67 and 86 %, p< 0.05) were drastically reduced in TL position as compared to SR and SR-inv respectively. MAP was lower in SR and SRinv compared to TL position (80 and 73 vs 90 mmHg, p< 0.05). At the brain level, pigs in TL position presented high score of petequial hemorrhage (2.6 vs 1 and 1.5, p< 0.05), and higher levels of immunopositive cells to caspase (6.3 vs 2.5 and 1.7, p< 0.05) and TUNEL (5.17 vs 1 and 2.72, p< 0.05) in the dentate gyrus in the hippocampus, both indicators of apoptosis, in comparison with groups SR and SR-inv respectively. Conclusions In this pig model of MV, TL position prevents pulmonary colonization and VAP development, but enhances cerebral hemorrhage, and increased apoptosis in the hippocampus. These alterations in the brain could be related with the increase in MAP observed in TL position. More studies to evaluate risks and benefits of TL position are needed.