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1.  Effects of anesthetic regimes on inflammatory responses in a rat model of acute lung injury 
Intensive care medicine  2012;38(9):1548-1555.
Gamma amino butyric acid (GABA) is the major inhibitory neurotransmitter through activation of GABA receptors. Volatile anesthetics activate type A (GABAA) receptors resulting in inhibition of synaptic transmission. Lung epithelial cells have been recently found to express GABAA receptors that exert anti-inflammatory properties. We hypothesized that the volatile anesthetic sevoflurane (SEVO) attenuates lung inflammation through activation of lung epithelial GABAA receptors.
Sprague-Dawley rats were anesthetized with SEVO or ketamine/xylazine (KX). Acute lung inflammation was induced by intratracheal instillation of endotoxin, followed by mechanical ventilation for 4 h at a tidal volume of 15 mL/kg without positive end-expiratory pressure (two-hit lung injury model). To examine the specific effects of GABA, healthy human bronchial epithelial cells (BEAS-2B) were challenged with endotoxin in the presence and absence of GABA with and without addition of the GABAA receptor antagonist picrotoxin.
Anesthesia with SEVO improved oxygenation and reduced pulmonary cytokine responses compared to KX. This phenomenon was associated with increased expression of the π subunit of GABAA receptors and glutamic acid decarboxylase (GAD). The endotoxin-induced cytokine release from BEAS-2B cells was attenuated by the treatment with GABA, which was reversed by the administration of picrotoxin.
Anesthesia with SEVO suppresses pulmonary inflammation thus protects the lung from the two-hit injury. The anti-inflammatory effect of SEVO is likely due to activation of pulmonary GABAA signaling pathways.
PMCID: PMC4896809  PMID: 22711173 CAMSID: cams2911
volatile anesthetics; mechanical ventilation; inflammation
2.  Inhibition of poly(adenosine diphosphate-ribose) polymerase attenuates ventilator-induced lung injury 
Anesthesiology  2008;108(2):261-268.
Mechanical ventilation can induce organ injury associated with overwhelming inflammatory responses. Excessive activation of poly(adenosine diphosphate-ribose) polymerase enzyme following massive DNA damage may aggravate inflammatory responses. We thus hypothesized that the pharmacological inhibition of poly(adenosine diphosphate-ribose) polymerase by PJ-34 will attenuate ventilator-induced lung injury.
Anesthetized rats were subjected to intratracheal instillation of lipopolysaccharide at a dose of 6 mg/kg. The animals were then randomized to receive mechanical ventilation at either low tidal volume (6 mL/kg) with 5 cmH2O positive end-expiratory pressure or high tidal volume (15 mL/kg) with zero positive end-expiratory pressure, in the presence and absence of intravenous administration of PJ-34.
The high tidal volume ventilation resulted in an increase in poly (adenosine diphosphate-ribose) polymerase activity in the lung. The treatment with PJ-34 maintained a greater oxygenation and a lower airway plateau pressure than the vehicle control group. This was associated with a decreased level of interleukin-6, active plasminogen activator inhibitor-1 in the lung, attenuated leukocyte lung transmigration and reduced pulmonary edema and apoptosis. The administration of PJ-34 also decreased the systemic levels of tumor necrosis factor-α and interleukin-6, and attenuated the degree of apoptosis in the kidney.
The pharmacological inhibition of poly(adenosine diphosphate-ribose) polymerase reduces ventilator-induced lung injury and protects kidney function.
PMCID: PMC4894820  PMID: 18212571 CAMSID: cams3638
3.  ATF3 Protects Pulmonary Resident Cells from Acute and Ventilator-Induced Lung Injury by Preventing Nrf2 Degradation 
Antioxidants & Redox Signaling  2015;22(8):651-668.
Aims: Ventilator-induced lung injury (VILI) contributes to mortality in patients with acute respiratory distress syndrome, the most severe form of acute lung injury (ALI). Absence of activating transcription factor 3 (ATF3) confers susceptibility to ALI/VILI. To identify cell-specific ATF3-dependent mechanisms of susceptibility to ALI/VILI, we generated ATF3 chimera by adoptive bone marrow (BM) transfer and randomized to inhaled saline or lipopolysacharide (LPS) in the presence of mechanical ventilation (MV). Adenovirus vectors to silence or overexpress ATF3 were used in primary human bronchial epithelial cells and murine BM-derived macrophages from wild-type or ATF3-deficient mice. Results: Absence of ATF3 in myeloid-derived cells caused increased pulmonary cellular infiltration. In contrast, absence of ATF3 in parenchymal cells resulted in loss of alveolar-capillary membrane integrity and increased exudative edema. ATF3-deficient macrophages were unable to limit the expression of pro-inflammatory mediators. Knockdown of ATF3 in resident cells resulted in decreased junctional protein expression and increased paracellular leak. ATF3 overexpression abrogated LPS induced membrane permeability. Despite release of ATF3-dependent Nrf2 transcriptional inhibition, mice that lacked ATF3 expression in resident cells had increased Nrf2 protein degradation. Innovation: In our model, in the absence of ATF3 in parenchymal cells increased Nrf2 degradation is the result of increased Keap-1 expression and loss of DJ-1 (Parkinson disease [autosomal recessive, early onset] 7), previously not known to play a role in lung injury. Conclusion: Results suggest that ATF3 confers protection to lung injury by preventing inflammatory cell recruitment and barrier disruption in a cell-specific manner, opening novel opportunities for cell specific therapy for ALI/VILI. Antioxid. Redox Signal. 22, 651–668.
PMCID: PMC4346377  PMID: 25401197
4.  Injurious mechanical ventilation causes kidney apoptosis and dysfunction during sepsis but not after intra-tracheal acid instillation: an experimental study 
BMC Nephrology  2014;15:126.
Intratracheal aspiration and sepsis are leading causes of acute lung injury that frequently necessitate mechanical ventilation (MV), which may aggravate lung injury thereby potentially increasing the risk of acute kidney injury (AKI). We compared the effects of ventilation strategies and underlying conditions on the development of AKI.
Spraque Dawley rats were challenged by intratracheal acid instillation or 24 h of abdominal sepsis, followed by MV with a low tidal volume (LVT) and 5 cm H2O positive end-expiratory pressure (PEEP) or a high tidal volume (HVT) and no PEEP, which is known to cause more lung injury after acid instillation than in sepsis. Rats were ventilated for 4 hrs and kidney function and plasma mediator levels were measured. Kidney injury was assessed by microscopy; apoptosis was quantified by TUNEL staining.
During sepsis, but not after acid instillation, MV with HVT caused more renal apoptosis than MV with LVT. Increased plasma active plasminogen activator inhibitor-1 correlated to kidney apoptosis in the cortex and medulla. Increased apoptosis after HVT ventilation during sepsis was associated with a 40% decrease in creatinine clearance.
AKI is more likely to develop after MV induced lung injury during an indirect (as in sepsis) than after a direct (as after intra-tracheal instillation) insult to the lungs, since it induces kidney apoptosis during sepsis but not after acid instillation, opposite to the lung injury it caused. Our findings thus suggest using protective ventilatory strategies in human sepsis, even in the absence of overt lung injury, to protect the kidney.
PMCID: PMC4119441  PMID: 25073618
Acute kidney injury; Acute respiratory distress syndrome; Apoptosis; Mechanical ventilation; Sepsis
5.  Lung protection during non-invasive synchronized assist versus volume control in rabbits 
Critical Care  2014;18(1):R22.
Experimental work provides insight into potential lung protective strategies. The objective of this study was to evaluate markers of ventilator-induced lung injury after two different ventilation approaches: (1) a “conventional” lung-protective strategy (volume control (VC) with low tidal volume, positive end-expiratory pressure (PEEP) and paralysis), (2) a physiological approach with spontaneous breathing, permitting synchrony, variability and a liberated airway. For this, we used non-invasive Neurally Adjusted Ventilatory Assist (NIV-NAVA), with the hypothesis that liberation of upper airways and the ventilator’s integration with lung protective reflexes would be equally lung protective.
In this controlled and randomized in vivo laboratory study, 25 adult White New Zealand rabbits were studied, including five non-ventilated control animals. The twenty animals with aspiration-induced lung injury were randomized to ventilation with either VC (6 mL/kg, PEEP 5 cm H2O, and paralysis) or NIV-NAVA for six hours (PEEP = zero because of leaks). Markers of lung function, lung injury, vital signs and ventilator parameters were assessed.
At the end of six hours of ventilation (n = 20), there were no significant differences between VC and NIV-NAVA for vital signs, PaO2/FiO2 ratio, lung wet-to-dry ratio and broncho-alveolar Interleukin 8 (Il-8). Plasma IL-8 was higher in VC (P <0.05). Lung injury score was lower for NIV-NAVA (P = 0.03). Dynamic lung compliance recovered after six hours in NIV-NAVA but not in VC (P <0.05). During VC, peak pressures increased from 9.2 ± 2.4 cm H2O (hour 1) to 12.3 ± 12.3 cm H2O (hour 6) (P <0.05). During NIV-NAVA, the tracheal end-expiratory pressure was similar to the end-expiratory pressure during VC. Two animals regurgitated during NIV-NAVA, without clinical consequences, and survived the protocol.
In experimental acute lung injury, NIV-NAVA is as lung-protective as VC 6 ml/kg with PEEP.
Electronic supplementary material
The online version of this article (doi:10.1186/cc13706) contains supplementary material, which is available to authorized users.
PMCID: PMC4057206  PMID: 24456613
6.  Microarray Meta-Analysis Identifies Acute Lung Injury Biomarkers in Donor Lungs That Predict Development of Primary Graft Failure in Recipients 
PLoS ONE  2012;7(10):e45506.
To perform a meta-analysis of gene expression microarray data from animal studies of lung injury, and to identify an injury-specific gene expression signature capable of predicting the development of lung injury in humans.
We performed a microarray meta-analysis using 77 microarray chips across six platforms, two species and different animal lung injury models exposed to lung injury with or/and without mechanical ventilation. Individual gene chips were classified and grouped based on the strategy used to induce lung injury. Effect size (change in gene expression) was calculated between non-injurious and injurious conditions comparing two main strategies to pool chips: (1) one-hit and (2) two-hit lung injury models. A random effects model was used to integrate individual effect sizes calculated from each experiment. Classification models were built using the gene expression signatures generated by the meta-analysis to predict the development of lung injury in human lung transplant recipients.
Two injury-specific lists of differentially expressed genes generated from our meta-analysis of lung injury models were validated using external data sets and prospective data from animal models of ventilator-induced lung injury (VILI). Pathway analysis of gene sets revealed that both new and previously implicated VILI-related pathways are enriched with differentially regulated genes. Classification model based on gene expression signatures identified in animal models of lung injury predicted development of primary graft failure (PGF) in lung transplant recipients with larger than 80% accuracy based upon injury profiles from transplant donors. We also found that better classifier performance can be achieved by using meta-analysis to identify differentially-expressed genes than using single study-based differential analysis.
Taken together, our data suggests that microarray analysis of gene expression data allows for the detection of “injury" gene predictors that can classify lung injury samples and identify patients at risk for clinically relevant lung injury complications.
PMCID: PMC3470558  PMID: 23071521
7.  High tidal volume mechanical ventilation-induced lung injury in rats is greater after acid instillation than after sepsis-induced acute lung injury, but does not increase systemic inflammation: an experimental study 
BMC Anesthesiology  2011;11:26.
To examine whether acute lung injury from direct and indirect origins differ in susceptibility to ventilator-induced lung injury (VILI) and resultant systemic inflammatory responses.
Rats were challenged by acid instillation or 24 h of sepsis induced by cecal ligation and puncture, followed by mechanical ventilation (MV) with either a low tidal volume (Vt) of 6 mL/kg and 5 cm H2O positive end-expiratory pressure (PEEP; LVt acid, LVt sepsis) or with a high Vt of 15 mL/kg and no PEEP (HVt acid, HVt sepsis). Rats sacrificed immediately after acid instillation and non-ventilated septic animals served as controls. Hemodynamic and respiratory variables were monitored. After 4 h, lung wet to dry (W/D) weight ratios, histological lung injury and plasma mediator concentrations were measured.
Oxygenation and lung compliance decreased after acid instillation as compared to sepsis. Additionally, W/D weight ratios and histological lung injury scores increased after acid instillation as compared to sepsis. MV increased W/D weight ratio and lung injury score, however this effect was mainly attributable to HVt ventilation after acid instillation. Similarly, effects of HVt on oxygenation were only observed after acid instillation. HVt during sepsis did not further affect oxygenation, compliance, W/D weight ratio or lung injury score. Plasma interleukin-6 and tumour necrosis factor-α concentrations were increased after acid instillation as compared to sepsis, but plasma intercellular adhesion molecule-1 concentration increased during sepsis only. In contrast to lung injury parameters, no additional effects of HVt MV after acid instillation on plasma mediator concentrations were observed.
During MV more severe lung injury develops after acid instillation as compared to sepsis. HVt causes VILI after acid instillation, but not during sepsis. However, this differential effect was not observed in the systemic release of mediators.
PMCID: PMC3287130  PMID: 22204611
Ventilator-induced lung injury; acute lung injury; sepsis; cytokines; lung histology; mechanical ventilation.
8.  Activating Transcription Factor 3 Confers Protection against Ventilator-induced Lung Injury 
Rationale: Ventilator-induced lung injury (VILI) significantly contributes to mortality in patients with acute respiratory distress syndrome, the most severe form of acute lung injury. Understanding the molecular basis for response to cyclic stretch (CS) and its derangement during high-volume ventilation is of high priority.
Objectives: To identify specific molecular regulators involved in the development of VILI.
Methods: We undertook a comparative examination of cis-regulatory sequences involved in the coordinated expression of CS-responsive genes using microarray analysis. Analysis of stretched versus nonstretched cells identified significant enrichment for genes containing putative binding sites for the transcription factor activating transcription factor 3 (ATF3). To determine the role of ATF3 in vivo, we compared the response of ATF3 gene–deficient mice to wild-type mice in an in vivo model of VILI.
Measurements and Main Results: ATF3 protein expression and nuclear translocation is increased in the lung after mechanical ventilation in wild-type mice. ATF3-deficient mice have greater sensitivity to mechanical ventilation alone or in conjunction with inhaled endotoxin, as demonstrated by increased cell infiltration and proinflammatory cytokines in the lung and bronchoalveolar lavage, and increased pulmonary edema and indices of tissue injury. The expression of stretch-responsive genes containing putative ATF3 cis-regulatory regions was significantly altered in ATF3-deficient mice.
Conclusions: ATF3 deficiency confers increased sensitivity to mechanical ventilation alone or in combination with inhaled endotoxin. We propose ATF3 acts to counterbalance CS and high volume–induced inflammation, dampening its ability to cause injury and consequently protecting animals from injurious CS.
PMCID: PMC2937241  PMID: 20413626
mechanotransduction; transcriptional profiling; acute respiratory distress syndrome; bioinformatics; transgenic mice
9.  Plasma levels of surfactant protein D and KL-6 for evaluation of lung injury in critically ill mechanically ventilated patients 
Preventing ventilator-associated lung injury (VALI) has become pivotal in mechanical ventilation of patients with acute lung injury (ALI) or its more severe form, acute respiratory distress syndrome (ARDS). In the present study we investigated whether plasma levels of lung-specific biological markers can be used to evaluate lung injury in patients with ALI/ARDS and patients without lung injury at onset of mechanical ventilation.
Plasma levels of surfactant protein D (SP-D), Clara Cell protein (CC16), KL-6 and soluble receptor for advanced glycation end-products (sRAGE) were measured in plasma samples obtained from 36 patients - 16 patients who were intubated and mechanically ventilated because of ALI/ARDS and 20 patients without lung injury at the onset of mechanical ventilation and during conduct of the study. Patients were ventilated with either a lung-protective strategy using lower tidal volumes or a potentially injurious strategy using conventional tidal volumes. Levels of biological markers were measured retrospectively at baseline and after 2 days of mechanical ventilation.
Plasma levels of CC16 and KL-6 were higher in ALI/ARDS patients at baseline as compared to patients without lung injury. SP-D and sRAGE levels were not significantly different between these patients. In ALI/ARDS patients, SP-D and KL-6 levels increased over time, which was attenuated by lung-protective mechanical ventilation using lower tidal volumes (P = 0.02 for both biological markers). In these patients, with either ventilation strategy no changes over time were observed for plasma levels of CC16 and sRAGE. In patients without lung injury, no changes of plasma levels of any of the measured biological markers were observed.
Plasma levels of SP-D and KL-6 rise with potentially injurious ventilator settings, and thus may serve as biological markers of VALI in patients with ALI/ARDS.
PMCID: PMC2841652  PMID: 20158912
10.  Ischemia of the lung causes extensive long-term pulmonary injury: an experimental study 
Respiratory Research  2008;9(1):28.
Lung ischemia-reperfusion injury (LIRI) is suggested to be a major risk factor for development of primary acute graft failure (PAGF) following lung transplantation, although other factors have been found to interplay with LIRI. The question whether LIRI exclusively results in PAGF seems difficult to answer, which is partly due to the lack of a long-term experimental LIRI model, in which PAGF changes can be studied. In addition, the long-term effects of LIRI are unclear and a detailed description of the immunological changes over time after LIRI is missing. Therefore our purpose was to establish a long-term experimental model of LIRI, and to study the impact of LIRI on the development of PAGF, using a broad spectrum of LIRI parameters including leukocyte kinetics.
Male Sprague-Dawley rats (n = 135) were subjected to 120 minutes of left lung warm ischemia or were sham-operated. A third group served as healthy controls. Animals were sacrificed 1, 3, 7, 30 or 90 days after surgery. Blood gas values, lung compliance, surfactant conversion, capillary permeability, and the presence of MMP-2 and MMP-9 in broncho-alveolar-lavage fluid (BALf) were determined. Infiltration of granulocytes, macrophages and lymphocyte subsets (CD45RA+, CD5+CD4+, CD5+CD8+) was measured by flowcytometry in BALf, lung parenchyma, thoracic lymph nodes and spleen. Histological analysis was performed on HE sections.
LIRI resulted in hypoxemia, impaired left lung compliance, increased capillary permeability, surfactant conversion, and an increase in MMP-2 and MMP-9. In the BALf, most granulocytes were found on day 1 and CD5+CD4+ and CD5+CD8+-cells were elevated on day 3. Increased numbers of macrophages were found on days 1, 3, 7 and 90. Histology on day 1 showed diffuse alveolar damage, resulting in fibroproliferative changes up to 90 days after LIRI.
The short-, and long-term changes after LIRI in this model are similar to the changes found in both PAGF and ARDS after clinical lung transplantation. LIRI seems an independent risk factor for the development of PAGF and resulted in progressive deterioration of lung function and architecture, leading to extensive immunopathological and functional abnormalities up to 3 months after reperfusion.
PMCID: PMC2335107  PMID: 18366783
11.  Year in review 2005: Critical Care – Respirology: mechanical ventilation, infection, monitoring, and education 
Critical Care  2006;10(3):217.
We summarize all original research in the field of respiratory intensive care medicine published in 2005 in Critical Care. Twenty-seven articles were grouped into the following categories and subcategories to facilitate rapid overview: mechanical ventilation (physiology, spontaneous breathing during mechanical ventilation, high frequency oscillatory ventilation, side effects of mechanical ventilation, sedation, and prone positioning); infection (pneumonia and sepsis); monitoring (ventilatory monitoring, pulmonary artery catheter and pulse oxymeter); and education (training and health outcome).
PMCID: PMC1550947  PMID: 16817943
12.  The effect of open lung ventilation on right ventricular and left ventricular function in lung-lavaged pigs 
Critical Care  2006;10(3):R86.
Ventilation according to the open lung concept (OLC) consists of recruitment maneuvers, followed by low tidal volume and high positive end-expiratory pressure, aiming at minimizing atelectasis. The minimization of atelectasis reduces the right ventricular (RV) afterload, but the increased intrathoracic pressures used by OLC ventilation could increase the RV afterload. We hypothesize that when atelectasis is minimized by OLC ventilation, cardiac function is not affected despite the higher mean airway pressure.
After repeated lung lavage, each pig (n = 10) was conventionally ventilated and was ventilated according to OLC in a randomized cross-over setting. Conventional mechanical ventilation (CMV) consisted of volume-controlled ventilation with 5 cmH2O positive end-expiratory pressure and a tidal volume of 8–10 ml/kg. No recruitment maneuvers were performed. During OLC ventilation, recruitment maneuvers were applied until PaO2/FiO2 > 60 kPa. The peak inspiratory pressure was set to obtain a tidal volume of 6–8 ml/kg. The cardiac output (CO), the RV preload, the contractility and the afterload were measured with a volumetric pulmonary artery catheter. A high-resolution computed tomography scan measured the whole lung density and left ventricular (LV) volumes.
The RV end-systolic pressure–volume relationship, representing RV afterload, during steady-state OLC ventilation (2.7 ± 1.2 mmHg/ml) was not significantly different compared with CMV (3.6 ± 2.5 mmHg/ml). Pulmonary vascular resistance (OLC, 137 ± 49 dynes/s/cm5 versus CMV, 130 ± 34 dynes/s/cm5) was comparable between groups. OLC led to a significantly lower amount of atelectasis (13 ± 2% of the lung area) compared with CMV (52 ± 3% of the lung area). Atelectasis was not correlated with pulmonary vascular resistance or end-systolic pressure–volume relationship.
The LV contractility and afterload during OLC was not significantly different compared with CMV. Compared with baseline, the LV end-diastolic volume (66 ± 4 ml) decreased significantly during OLC (56 ± 5 ml) ventilation and not during CMV (61 ± 3 ml). Also, CO was significantly lower during OLC ventilation (OLC, 4.1 ± 0.3 l/minute versus CMV, 4.9 ± 0.3 l/minute).
In this experimental study, OLC resulted in significantly improved lung aeration. Despite the use of elevated airway pressures, no evidence was found for a negative effect of OLC on RV afterload or LV afterload, which might be associated with a loss of hypoxic pulmonary vasoconstriction due to alveolar recruitment. The reductions in the CO and in the mean pulmonary artery pressure were consequences of a reduced preload.
PMCID: PMC1550948  PMID: 16764730

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