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1.  Year in review 2012: Critical Care - respirology 
Critical Care  2013;17(6):249.
Acute respiratory failure is a dominant feature of critical illness. In this review, we discuss 17 studies published last year in Critical Care. The discussion focuses on articles on several topics: respiratory monitoring, acute respiratory distress syndrome, noninvasive ventilation, airway management, secretion management and weaning.
doi:10.1186/cc13129
PMCID: PMC4056602  PMID: 24267541
2.  Early activation of pro-fibrotic WNT5A in sepsis-induced acute lung injury 
Critical Care  2014;18(5):568.
Introduction
The 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.
Methods
We 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.
Results
Protein 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.
Conclusions
Our 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.
Electronic supplementary material
The online version of this article (doi:10.1186/s13054-014-0568-z) contains supplementary material, which is available to authorized users.
doi:10.1186/s13054-014-0568-z
PMCID: PMC4220065  PMID: 25331176
3.  Year in review 2013: Critical Care - respirology 
Critical Care  2014;18(5):577.
This review documents important progress made in 2013 in the field of critical care respirology, in particular with regard to acute respiratory failure and acute respiratory distress syndrome. Twenty-five original articles published in the respirology and critical care sections of Critical Care are discussed in the following categories: pre-clinical studies, protective lung ventilation – how low can we go, non-invasive ventilation for respiratory failure, diagnosis and prognosis in acute respiratory distress syndrome and respiratory failure, and promising interventions for acute respiratory distress syndrome.
doi:10.1186/s13054-014-0577-y
PMCID: PMC4331417  PMID: 25673260
5.  Monocyte interaction accelerates HCl-induced lung epithelial remodeling 
BMC Pulmonary Medicine  2014;14:135.
Background
Acute respiratory distress syndrome (ARDS) is characterized by overwhelming inflammatory responses and lung remodeling. We hypothesized that leukocyte infiltration during the inflammatory response modulates epithelial remodeling through a mechanism of epithelial-mesenchymal transition (EMT).
Methods
Human lung epithelial cells were treated for 30 min with hydrochloric acid (HCl). Human monocytes were then cocultured with the epithelial cells for up to 48 h, in the presence or absence of blocking peptides against lymphocyte function-associated antigen-1 (LFA-1), or tyrphostin A9, a specific inhibitor for platelet-derived growth factor (PDGF) receptor tyrosine kinase.
Results
Exposure of lung epithelial cells to HCl resulted in increased expression of intercellular adhesion molecule-1 (ICAM-1) and production of interleukin (IL)-8 at 24 h. The expression of the epithelial markers E-cadherin decreased while the mesenchymal markers vimentin and α-smooth muscle actin (α-SMA) increased at 24 h and remained high at 48 h. The addition of monocytes augmented the profiles of lower expression of epithelial markers and higher mesenchymal markers accompanied by increased collagen deposition. This EMT profile was associated with an enhanced production of IL-8 and PDGF. Treatment of the lung epithelial cells with the LAF-1 blocking peptides CD11a237–246 or/and CD18112–122 suppressed monocyte adhesion, production of IL-8, PDGF and hydroxyproline as well as EMT markers. Treatment with tyrphostin A9 prevented the EMT profile shift induced by HCl stimulation.
Conclusions
The interaction between epithelial cells and monocytes enhanced epithelial remodelling after initial injury through EMT signalling that is associated with the release of soluble mediators, including IL-8 and PDGF.
doi:10.1186/1471-2466-14-135
PMCID: PMC4141266  PMID: 25108547
ARDS; PDGF; Chemokine; EMT
6.  Circadian rhythms: From basic mechanisms to the intensive care unit 
Critical care medicine  2012;40(1):246-253.
Objective
Circadian rhythms are intrinsic timekeeping mechanisms that allow for adaptation to cyclic environmental changes. Increasing evidence suggests that circadian rhythms may influence progression of a variety of diseases as well as effectiveness and toxicity of drugs commonly used in the intensive care unit. In this perspective, we provide a brief review of the molecular mechanisms of circadian rhythms and its relevance to critical care.
Data Sources, Study Selection, Data Extraction, and Data Synthesis
Articles related to circadian rhythms and organ systems in normal and disease conditions were searched through the PubMed library with the goal of providing a concise review.
Conclusions
Critically ill patients may be highly vulnerable to disruption of circadian rhythms as a result of the severity of their underlying diseases as well as the intensive care unit environment where noise and frequent therapeutic/diagnostic interventions take place. Further basic and clinical research addressing the importance of circadian rhythms in the context of critical care is warranted to develop a better understanding of the complex pathophysiology of critically ill patients as well as to identify novel therapeutic approaches for these patients.
doi:10.1097/CCM.0b013e31822f0abe
PMCID: PMC3977926  PMID: 21926587 CAMSID: cams2913
clock gene; diurnal variation; inflammation
7.  Protective effects of adenosine A2A receptor agonist in ventilator-induced lung injury in rats 
Critical care medicine  2009;37(7):2235-2241.
Objectives
Mechanical ventilation is associated with overwhelming inflammatory responses that are associated with ventilator- induced lung injury (VILI) in patients with acute respiratory distress syndrome. The activation of adenosine A2A receptors has been reported to attenuate inflammatory cascades.
Hypothesis
The administration of A2A receptors agonist ameliorates VILI.
Methods
Rats were subjected to hemorrhagic shock and resuscitation as a first hit to induce systemic inflammation. The animals randomly received the selective A2A receptor agonist CGS-21680 or a vehicle control in a blinded fashion at the onset of resuscitation phase. They were then randomized to receive mechanical ventilation as a second hit with a high tidal volume of 20 mL/kg and zero positive end-expiratory pressure, or a low tidal volume of 6 mL/kg with positive end-expiratory pressure of 5 cm H2O.
Results
The administration of CGS-21680 attenuated lung injury as evidenced by a decrease in respiratory elastance, lung edema, lung injury scores, neutrophil recruitment in the lung, and production of inflammatory cytokines, compared with the vehicle treated animals.
Conclusions
The selective A2A receptor agonist may have a place as a novel therapeutic approach in reducing VILI.
doi:10.1097/CCM.0b013e3181a55273
PMCID: PMC3951985  PMID: 19487932 CAMSID: cams2915
acute respiratory distress syndrome; inflammation; neutrophils
8.  Lung protection during non-invasive synchronized assist versus volume control in rabbits 
Critical Care  2014;18(1):R22.
Introduction
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.
Methods
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.
Results
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.
Conclusions
In experimental acute lung injury, NIV-NAVA is as lung-protective as VC 6 ml/kg with PEEP.
doi:10.1186/cc13706
PMCID: PMC4057206  PMID: 24456613
9.  CXCL10-CXCR3 Enhances the Development of Neutrophil-mediated Fulminant Lung Injury of Viral and Nonviral Origin 
Rationale: Patients who developed acute respiratory distress syndrome (ARDS) after infection with severe respiratory viruses (e.g., severe acute respiratory syndrome–coronavirus, H5N1 avian influenza virus), exhibited unusually high levels of CXCL10, which belongs to the non-ELR (glutamic-leucine-arginine) CXC chemokine superfamily. CXCL10 may not be a bystander to the severe virus infection but may directly contribute to the pathogenesis of neutrophil-mediated, excessive pulmonary inflammation.
Objectives: We investigated the contribution of CXCL10 and its receptor CXCR3 axis to the pathogenesis of ARDS with nonviral and viral origins.
Methods: We induced nonviral ARDS by acid aspiration and viral ARDS by intratracheal influenza virus infection in wild-type mice and mice deficient in CXCL10, CXCR3, IFNAR1 (IFN-α/β receptor 1), or TIR domain-containing adaptor inducing IFN-β (TRIF).
Measurements and Main Results: We found that the mice lacking CXCL10 or CXCR3 demonstrated improved severity and survival of nonviral and viral ARDS, whereas mice that lack IFNAR1 did not control the severity of ARDS in vivo. The increased levels of CXCL10 in lungs with ARDS originate to a large extent from infiltrated pulmonary neutrophils, which express a unique CXCR3 receptor via TRIF. CXCL10-CXCR3 acts in an autocrine fashion on the oxidative burst and chemotaxis in the inflamed neutrophils, leading to fulminant pulmonary inflammation.
Conclusions: CXCL10-CXCR3 signaling appears to be a critical factor for the exacerbation of the pathology of ARDS. Thus, the CXCL10-CXCR3 axis could represent a prime therapeutic target in the treatment of the acute phase of ARDS of nonviral and viral origins.
doi:10.1164/rccm.201203-0508OC
PMCID: PMC3927876  PMID: 23144331
CXCL10; CXCR3; ARDS
10.  Intensive Care Unit-Acquired Bacteremia in Mechanically Ventilated Patients: Clinical Features and Outcomes 
PLoS ONE  2013;8(12):e83298.
Intensive care unit (ICU)-acquired bacteremia (IAB) is associated with high medical expenditure and mortality. Mechanically ventilated patients represent one third of all patients admitted to ICU, but the clinical features and outcomes in mechanically ventilated patients who develop IAB remain unknown. We conducted a 3-year retrospective observational cohort study, and 1,453 patients who received mechanical ventilation on ICU admission were enrolled. Among patients enrolled, 126 patients who had developed IAB ≧48 hours after ICU admission were identified. The study patients were divided into IAB and no IAB groups, and clinical characteristics of IAB based on specific bacterial species were further analyzed. The multivariate Cox regression analysis showed that ventilator support for chronic obstructive pulmonary disease and congestive heart failure, and patients admitted from nursing home were the independent risk factors for developing IAB. Patients with IAB were significantly associated with longer length of ICU stay, prolonged ventilator use, lower rate of successful weaning, and higher rate of ventilator dependence and ICU mortality as compared to those without IAB. IAB was the independent risk factor for ICU mortality (HR, 1.510, 95% CI 1.054–1.123; p = 0.010). The clinical characteristics of IAB related to specific bacterial species included IAB due to Pseudomonas aeruginosa being likely polymicrobial, lung source and prior antibiotic use; Escherichia coli developing earlier and from urinary tract source; methicillin-resistant Staphylococcus aureus related to central venous catheter and multiple sets of positive hemoculture; and Elizabethkingia meningoseptica significantly associated with delayed/inappropriate antibiotic treatment. In summary, IAB was significantly associated with poor patient outcomes in mechanically ventilated ICU patients. The clinical features related to IAB and clinical characteristics of IAB based on specific bacterial species identified in our study may be utilized to refine the management of IAB.
doi:10.1371/journal.pone.0083298
PMCID: PMC3871544  PMID: 24376683
11.  Year in review 2011: Critical Care - respirology 
Critical Care  2012;16(6):243.
Management of acute respiratory failure is an important component of intensive care. In this review, we analyze 21 original research articles published last year in Critical Care in the field of respiratory and critical care medicine. The articles are summarized according to the following topic categories: acute respiratory distress syndrome, mechanical ventilation, adjunctive therapies, and pneumonia.
doi:10.1186/cc11422
PMCID: PMC3672547
12.  An automated and standardized neural index to quantify patient-ventilator interaction 
Critical Care  2013;17(5):R239.
Introduction
The aim of this study was to validate an automated, objective and standardized algorithm for quantifying and displaying patient-ventilator interaction.
Methods
Using a new method to detect patient-ventilator synchrony, the present study re-analyzed previously acquired and published data from 24 mechanically ventilated adult patients (Colombo et al., Crit Care Med. 2011 Nov;39(11):2452–7). Patient-ventilator interactions were evaluated by comparing ventilator pressure and diaphragm electrical activity (EAdi) waveforms, recorded during pressure support ventilation. The EAdi and ventilator pressure waveforms were analyzed for their timings (manually and automatically determined), and the error between the two waveforms was quantified. A new index of patient-ventilator interaction (NeuroSync index), which is standardized and automated, was validated and compared to manual analysis and previously published indices of asynchrony.
Results
The comparison of manual and automated detection methods produced high test-retest and inter-rater reliability (Intraclass correlation coefficient = 0.95). The NeuroSync index increased the sensitivity of detecting dyssynchronies, compared to previously published indices, which were found to only detect asynchronies.
Conclusion
The present study introduces an automated method and the NeuroSync index to determine patient-ventilator interaction with a more sensitive analysis method than those previously described. A dashboard-style of graphical display allows a rapid overview of patient-ventilator interaction and breathing pattern at the bedside.
doi:10.1186/cc13063
PMCID: PMC4056567  PMID: 24131701
13.  Acute respiratory distress syndrome: new definition, current and future therapeutic options 
Journal of Thoracic Disease  2013;5(3):326-334.
Since acute respiratory distress syndrome (ARDS) was first described in 1967 there has been large number of studies addressing its pathogenesis and therapies. Despite this intense research activity, there are very few effective therapies for ARDS other than the use of lung protection strategies. This lack of therapeutic modalities is not only related to the complex pathogenesis of this syndrome but also the insensitive and nonspecific diagnostic criteria to diagnose ARDS. This review article will summarize the key features of the new definition of ARDS, and provide a brief overview of innovative therapeutic options that are being assessed in the management of ARDS.
doi:10.3978/j.issn.2072-1439.2013.04.05
PMCID: PMC3698298  PMID: 23825769
Acute respiratory distress syndrome (ARDS); pathogenesis; therapeutic options
14.  Novel approaches to minimize ventilator-induced lung injury 
BMC Medicine  2013;11:85.
Despite over 40 years of research, there is no specific lung-directed therapy for the acute respiratory distress syndrome (ARDS). Although much has evolved in our understanding of its pathogenesis and factors affecting patient outcome, supportive care with mechanical ventilation remains the cornerstone of treatment. Perhaps the most important advance in ARDS research has been the recognition that mechanical ventilation, although necessary to preserve life, can itself aggravate or cause lung damage through a variety of mechanisms collectively referred to as ventilator-induced lung injury (VILI). This improved understanding of ARDS and VILI has been important in designing lung-protective ventilatory strategies aimed at attenuating VILI and improving outcomes. Considerable effort has been made to enhance our mechanistic understanding of VILI and to develop new ventilatory strategies and therapeutic interventions to prevent and ameliorate VILI with the goal of improving outcomes in patients with ARDS. In this review, we will review the pathophysiology of VILI, discuss a number of novel physiological approaches for minimizing VILI, therapies to counteract biotrauma, and highlight a number of experimental studies to support these concepts.
doi:10.1186/1741-7015-11-85
PMCID: PMC3621434  PMID: 23536968
Acute lung injury; Acute respiratory distress syndrome; Critical illness; Cytokines; Extracorporeal membrane oxygenation; Heat shock response; Mechanical ventilation; Ventilatory support
15.  Lower tidal volume strategy (≈3 ml/kg) combined with extracorporeal CO2 removal versus ‘conventional’ protective ventilation (6 ml/kg) in severe ARDS 
Intensive Care Medicine  2013;39(5):847-856.
Background
Acute respiratory distress syndrome is characterized by damage to the lung caused by various insults, including ventilation itself, and tidal hyperinflation can lead to ventilator induced lung injury (VILI). We investigated the effects of a low tidal volume (VT) strategy (VT ≈ 3 ml/kg/predicted body weight [PBW]) using pumpless extracorporeal lung assist in established ARDS.
Methods
Seventy-nine patients were enrolled after a ‘stabilization period’ (24 h with optimized therapy and high PEEP). They were randomly assigned to receive a low VT ventilation (≈3 ml/kg) combined with extracorporeal CO2 elimination, or to a ARDSNet strategy (≈6 ml/kg) without the extracorporeal device. The primary outcome was the 28-days and 60-days ventilator-free days (VFD). Secondary outcome parameters were respiratory mechanics, gas exchange, analgesic/sedation use, complications and hospital mortality.
Results
Ventilation with very low VT’s was easy to implement with extracorporeal CO2-removal. VFD’s within 60 days were not different between the study group (33.2 ± 20) and the control group (29.2 ± 21, p = 0.469), but in more hypoxemic patients (PaO2/FIO2 ≤150) a post hoc analysis demonstrated significant improved VFD-60 in study patients (40.9 ± 12.8) compared to control (28.2 ± 16.4, p = 0.033). The mortality rate was low (16.5 %) and did not differ between groups.
Conclusions
The use of very low VT combined with extracorporeal CO2 removal has the potential to further reduce VILI compared with a ‘normal’ lung protective management. Whether this strategy will improve survival in ARDS patients remains to be determined (Clinical trials NCT 00538928).
Electronic supplementary material
The online version of this article (doi:10.1007/s00134-012-2787-6) contains supplementary material, which is available to authorized users.
doi:10.1007/s00134-012-2787-6
PMCID: PMC3625408  PMID: 23306584
Lung protective ventilation; Pumpless extracorporeal lung support; Carbon dioxide removal; Acute respiratory distress syndrome; Ultraprotective ventilation
16.  Year in review 2010: Critical Care - respirology 
Critical Care  2011;15(6):240.
In this review, 21 original papers published last year in the respirology and critical care sections of Critical Care are classified and analyzed in the following categories: mechanical ventilation, lung recruitment maneuvers, and weaning; the role of positive end-expiratory pressure in acute lung injury models; animal models of ventilator-induced lung injury; diaphragmatic dysfunction; the role of mechanical ventilation in heart-lung interaction; and miscellanea.
doi:10.1186/cc10541
PMCID: PMC3388674  PMID: 22146748
17.  Characterization of Neural Breathing Pattern in Spontaneously Breathing Preterm Infants 
Pediatric research  2011;70(6):607-613.
The aim was to characterize the neural breathing pattern in non-intubated preterm infants. The diaphragm electrical activity (EAdi) and heart rate were simultaneously measured repeatedly for 1 hour over several days using a modified feeding tube equipped with miniaturized sensors. The EAdi waveform was quantified for phasic and tonic activity, neural timings, and prevalence of recurring patterns, including central apnea. Ten infants with mean age 7 days (range 3–13) were studied. Their birth weight was 1512 g (1158–1800g), and gestational age (GA) at birth 31 weeks (28–36). Neural inspiratory and expiratory times were 278 ms (195–450 ms) and 867 ms (668–1436 ms), and correlated with GA (p<0.001). Tonic EAdi represented 29.5% of phasic EAdi (16–40%), and was related to GA (r=0.61, p<0.001). For the group, 68% of the time was regular phasic breathing (without tonic activity), and 29% of the time with elevated tonic activity. Central apneas >5s occurred on average 10 times per hour (2–29). Heart rate reductions were correlated to central apnea duration. In conclusion, esophageal recordings of the EAdi waveform demonstrate that neural breathing pattern is variable, with regards to timing, amplitude and pattern with a distinct amount of tonic diaphragm activity.
doi:10.1203/PDR.0b013e318232100e
PMCID: PMC3210880  PMID: 21857389
19.  Anti-Inflammatory Activity of a Novel Family of Aryl Ureas Compounds in an Endotoxin-Induced Airway Epithelial Cell Injury Model 
PLoS ONE  2012;7(11):e48468.
Background
Despite our increased understanding of the mechanisms involved in acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS), there is no specific pharmacological treatment of proven benefit. We used a novel screening methodology to examine potential anti-inflammatory effects of a small structure-focused library of synthetic carbamate and urea derivatives in a well established cell model of lipopolysaccharide (LPS)-induced ALI/ARDS.
Methodology/Principal Findings
After a pilot study to develop an in vitro LPS-induced airway epithelial cell injury model, a library of synthetic carbamate and urea derivates was screened against representative panels of human solid tumor cell lines and bacterial and fungal strains. Molecules that were non-cytotoxic and were inactive in terms of antiproliferative and antimicrobial activities were selected to study the effects on LPS-induced inflammatory response in an in vitro cell culture model using A549 human alveolar and BEAS-2B human bronchial cells. These cells were exposed for 18 h to LPS obtained from Escherichia coli, either alone or in combination with the test compounds. The LPS antagonists rhein and emodin were used as reference compounds. The most active compound (CKT0103) was selected as the lead compound and the impact of CKT0103 on pro-inflammatory IL-6 and IL-8 cytokine levels, expression of toll-like receptor-4 (TLR4) and nuclear factor kappa B inhibitor alpha (IκBα) was measured. CKT0103 significantly inhibited the synthesis and release of IL-6 and IL-8 induced by LPS. This suppression was associated with inhibition of TLR4 up-regulation and IκBα down-regulation. Immunocytochemical staining for TLR4 and IκBα supported these findings.
Conclusions/Significance
Using a novel screening methodology, we identified a compound – CKT0103 – with potent anti-inflammatory effects. These findings suggest that CKT0103 is a potential target for the treatment of the acute phase of sepsis and sepsis-induced ALI/ARDS.
doi:10.1371/journal.pone.0048468
PMCID: PMC3493555  PMID: 23144889
20.  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.
Objectives
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1371/journal.pone.0045506
PMCID: PMC3470558  PMID: 23071521
21.  Neuroventilatory efficiency and extubation readiness in critically ill patients 
Critical Care  2012;16(4):R143.
Introduction
Based on the hypothesis that failure of weaning from mechanical ventilation is caused by respiratory demand exceeding the capacity of the respiratory muscles, we evaluated whether extubation failure could be characterized by increased respiratory drive and impaired efficiency to generate inspiratory pressure and ventilation.
Methods
Airway pressure, flow, volume, breathing frequency, and diaphragm electrical activity were measured in a heterogeneous group of patients deemed ready for a spontaneous breathing trial. Efficiency to convert neuromuscular activity into inspiratory pressure was calculated as the ratio of negative airway pressure and diaphragm electrical activity during an inspiratory occlusion. Efficiency to convert neuromuscular activity into volume was calculated as the ratio of the tidal volume to diaphragm electrical activity. All variables were obtained during a 30-minute spontaneous breathing trial on continuous positive airway pressure (CPAP) of 5 cm H2O and compared between patients for whom extubation succeeded with those for whom either the spontaneous breathing trial failed or for those who passed, but then the extubation failed.
Results
Of 52 patients enrolled in the study, 35 (67.3%) were successfully extubated, and 17 (32.7%) were not. Patients for whom it failed had higher diaphragm electrical activity (48%; P < 0.001) and a lower efficiency to convert neuromuscular activity into inspiratory pressure and tidal volume (40% (P < 0.001) and 53% (P < 0.001)), respectively. Neuroventilatory efficiency demonstrated the greatest predictability for weaning success.
Conclusions
This study shows that a mixed group of critically ill patients for whom weaning fails have increased neural respiratory drive and impaired ability to convert neuromuscular activity into tidal ventilation, in part because of diaphragm weakness.
Trial Registration
Clinicaltrials.gov identifier NCT01065428. ©2012 Liu et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
doi:10.1186/cc11451
PMCID: PMC3580730  PMID: 22849707
22.  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.
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1186/1471-2253-11-26
PMCID: PMC3287130  PMID: 22204611
Ventilator-induced lung injury; acute lung injury; sepsis; cytokines; lung histology; mechanical ventilation.
23.  Activation of the Wnt/β-Catenin Signaling Pathway by Mechanical Ventilation Is Associated with Ventilator-Induced Pulmonary Fibrosis in Healthy Lungs 
PLoS ONE  2011;6(9):e23914.
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 (n = 6/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.
doi:10.1371/journal.pone.0023914
PMCID: PMC3174135  PMID: 21935365
24.  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.
doi:10.1164/rccm.200906-0925OC
PMCID: PMC2937241  PMID: 20413626
mechanotransduction; transcriptional profiling; acute respiratory distress syndrome; bioinformatics; transgenic mice
25.  Neurally Adjusted Ventilatory Assist and Pressure Support Ventilation in Small Species and the Impact of Instrumental Dead Space 
Neonatology  2009;97(3):279-285.
Background
Neurally adjusted ventilatory assist (NAVA) is a pneumatically-independent mode of mechanical ventilation controlled by diaphragm electrical activity (EAdi), and has not yet been implemented in very small species.
Objectives
The aims of the study were to evaluate the feasibility of applying NAVA in very small species and to compare this to pressure support ventilation (PSV) in terms of ventilatory efficiency and breathing pattern, and evaluate the impact of instrumental dead space on breathing pattern during both modes.
Methods
Nine healthy rats (mean weight 385 ± 4 g) were studied while breathing on PSV or NAVA, at baseline or with added dead space.
Results
A clear difference in breathing pattern between NAVA and PSV was observed during both baseline and dead space, where PSV – despite similar EAdi and tidal volume as during NAVA – caused shortened inspiratory time (p < 0.05) and increased the respiratory rate (p < 0.05). A higher minute ventilation (p < 0.05) in order to reach the same arterial CO2 was observed. Ineffective inspiratory efforts occurred only during PSV and decreased with the dead space.
Conclusion
This study demonstrates, in a small group of animals, that NAVA can deliver assist in very small species with a higher efficiency than PSV in terms of eliminating CO2 for a given minute ventilation.
doi:10.1159/000255167
PMCID: PMC3701441  PMID: 19887857
Neurally adjusted ventilatory assist; Pressure support ventilation; Diaphragm electrical activity; Instrumental dead space

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