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1.  Accumulation of BDCA1+ Dendritic Cells in Interstitial Fibrotic Lung Diseases and Th2-High Asthma 
PLoS ONE  2014;9(6):e99084.
Dendritic cells (DCs) significantly contribute to the pathology of several mouse lung disease models. However, little is known of the contribution of DCs to human lung diseases. In this study, we examined infiltration with BDCA1+ DCs of human lungs in patients with interstitial lung diseases or asthma. Using flow cytometry, we found that these DCs increased by 5∼6 fold in the lungs of patients with idiopathic pulmonary fibrosis or hypersensitivity pneumonitis, which are both characterized by extensive fibrosis in parenchyma. The same DC subset also significantly increased in the lung parenchyma of patients with chronic obstructive pulmonary disease, although the degree of increase was relatively modest. By employing immunofluorescence microscopy using FcεRI and MHCII as the specific markers for BDCA1+ DCs, we found that the numbers of BDCA1+ DCs also significantly increased in the airway epithelium of Th2 inflammation-associated asthma. These findings suggest a potential contribution of BDCA1+ DCs in human lung diseases associated with interstitial fibrosis or Th2 airway inflammation.
doi:10.1371/journal.pone.0099084
PMCID: PMC4051692  PMID: 24915147
2.  The Ratio of Angiopoietin-2 to Angiopoietin-1 as a Predictor of Mortality in Acute Lung Injury Patients 
Critical care medicine  2010;38(9):1845-1851.
Objective
To test the hypothesis that the concentration of angiopoietin-2 relative to angiopoietin-1 (Ang-2/Ang-1) may be a useful biologic marker of mortality in acute lung injury (ALI) patients. We also tested the association of Ang-2/Ang-1 with physiologic and biologic markers of activated endothelium.
Design
Prospective observational cohort study.
Setting
Intensive care units in a tertiary care university hospital and a university-affiliated city hospital.
Patients
Fifty-six mechanically ventilated patients with ALI.
Interventions
Baseline plasma samples and pulmonary dead space fraction measurements were collected within 48 hours of ALI diagnosis.
Measurements and Main Results
Plasma levels of Ang-1 and Ang-2 and of biomarkers of endothelial activation were measured by ELISA. Baseline Ang-2/Ang-1 was significantly higher in patients who died [median 58 (IQR 17–117) vs. 14 (IQR 6–35), p=0.01]. In a multivariable analysis stratified by dead space fraction, Ang-2/Ang-1 was an independent predictor of death with an adjusted odds ratio of 4.3 (95% CI 1.3–13.5, p=0.01) in those with an elevated pulmonary dead space fraction (p=0.03 for interaction between pulmonary dead space fraction and Ang-2/Ang-1). Moderate to weak correlation was found with biologic markers of endothelial activation.
Conclusions
The ratio of Ang-2/Ang-1 may be a prognostic biomarker of endothelial activation in ALI patients and, along with pulmonary dead space fraction, may be useful for risk stratification of ALI patients, particularly in identifying subgroups for future research and therapeutic trials.
doi:10.1097/CCM.0b013e3181eaa5bf
PMCID: PMC4009623  PMID: 20581666
acute lung injury; acute respiratory distress syndrome; angiopoietin; predictor; pulmonary dead space fraction; endothelial activation
4.  Noradrenergic neurons regulate monocyte trafficking and mortality during gram-negative peritonitis in mice1 
Effective host defense requires a robust, yet self-limited response to pathogens. A poorly calibrated response can lead to either bacterial dissemination due to insufficient inflammation or to organ injury due to excessive inflammation. Recent evidence suggests that the cholinergic anti-inflammatory reflex helps calibrate the immune response. However, the influence of peripheral noradrenergic neurons, which are primarily sympathetic neurons, in regulating immunity remains incompletely characterized. Using a model of 6-OHDA mediated noradrenergic nerve ablation, we show that elimination of noradrenergic neurons improves survival during K. pneumoniae peritonitis (67% vs. 23%, p<0.005) in mice. The survival benefit results from enhanced monocyte chemotactic protein (MCP-1) dependent monocyte recruitment and a subsequent decrease in bacterial loads. Splenectomy eliminated both the survival benefit of 6-OHDA and monocyte recruitment, suggesting that monocytes recruited to the peritoneum originate in the spleen. These results suggest that noradrenergic neurons regulate the immune response through two pathways. First, sympathetic nerve derived norepinephrine (NE) directly restrains MCP-1 production by peritoneal macrophages during infection. Second, NE derived from the vagally innervated splenic nerve regulates splenic monocyte egress. Removal of these two modulators of the immune response enhances antibacterial immunity and improves survival. These results may have implications for how states of catecholamine excess influence the host response to bacterial infections.
doi:10.4049/jimmunol.1300027
PMCID: PMC3973442  PMID: 23543756
Sepsis; neuro-immune interactions; sympathetic nervous system; spleen; monocytes; catecholamines; autonomic nervous system
5.  Risk Factors and Outcomes in Transfusion-associated Circulatory Overload 
The American journal of medicine  2013;126(4):357.e29-357.e38.
BACKGROUND
Transfusion-associated circulatory overload is characterized by new respiratory distress and hydrostatic pulmonary edema within 6 hours after blood transfusion, but its risk factors and outcomes are poorly characterized.
METHODS
Using a case control design, we enrolled 83 patients with severe transfusion-associated circulatory overload identified by active surveillance for hypoxemia and 163 transfused controls at the University of California, San Francisco (UCSF) and Mayo Clinic (Rochester, Minn) hospitals. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using multivariable logistic regression, and survival and length of stay were analyzed using proportional hazard models.
RESULTS
Transfusion-associated circulatory overload was associated with chronic renal failure (OR 27.0; 95% CI, 5.2–143), a past history of heart failure (OR 6.6; 95% CI, 2.1–21), hemorrhagic shock (OR 113; 95% CI, 14.1–903), number of blood products transfused (OR 1.11 per unit; 95% CI, 1.01–1.22), and fluid balance per hour (OR 9.4 per liter; 95% CI, 3.1–28). Patients with transfusion-associated circulatory overload had significantly increased in-hospital mortality (hazard ratio 3.20; 95% CI, 1.23–8.10) after controlling for Acute Physiology and Chronic Health Evaluation-II (APACHE-II) score, and longer hospital and intensive care unit lengths of stay.
CONCLUSIONS
The risk of transfusion-associated circulatory overload increases with the number of blood products administered and a positive fluid balance, and in patients with pre-existing heart failure and chronic renal failure. These data, if replicated, could be used to construct predictive algorithms for transfusion-associated circulatory overload, and subsequent modifications of transfusion practice might prevent morbidity and mortality associated with this complication.
doi:10.1016/j.amjmed.2012.08.019
PMCID: PMC3652681  PMID: 23357450
Blood transfusion; Morbidity; Mortality; Pulmonary edema; Risk factors
6.  Therapeutic Effects of Human Mesenchymal Stem Cells in Ex Vivo Human Lungs Injured with Live Bacteria 
Rationale: Mesenchymal stem cells secrete paracrine factors that can regulate lung permeability and decrease inflammation, making it a potentially attractive therapy for acute lung injury. However, concerns exist whether mesenchymal stem cells’ immunomodulatory properties may have detrimental effects if targeted toward infectious causes of lung injury.
Objectives: Therefore, we tested the effect of mesenchymal stem cells on lung fluid balance, acute inflammation, and bacterial clearance.
Methods: We developed an Escherichia coli pneumonia model in our ex vivo perfused human lung to test the therapeutic effects of mesenchymal stem cells on bacterial-induced acute lung injury.
Measurements and Main Results: Clinical-grade human mesenchymal stem cells restored alveolar fluid clearance to a normal level, decreased inflammation, and were associated with increased bacterial killing and reduced bacteremia, in part through increased alveolar macrophage phagocytosis and secretion of antimicrobial factors. Keratinocyte growth factor, a soluble factor secreted by mesenchymal stem cells, duplicated most of the antimicrobial effects. In subsequent in vitro studies, we discovered that human monocytes expressed the keratinocyte growth factor receptor, and that keratinocyte growth factor decreased apoptosis of human monocytes through AKT phosphorylation, an effect that increased bacterial clearance. Inhibition of keratinocyte growth factor by a neutralizing antibody reduced the antimicrobial effects of mesenchymal stem cells in the ex vivo perfused human lung and monocytes grown in vitro injured with E. coli bacteria.
Conclusions: In E. coli–injured human lungs, mesenchymal stem cells restored alveolar fluid clearance, reduced inflammation, and exerted antimicrobial activity, in part through keratinocyte growth factor secretion.
doi:10.1164/rccm.201206-0990OC
PMCID: PMC3678109  PMID: 23292883
acute lung injury; bacterial pneumonia; cell-based therapy; keratinocyte growth factor
7.  Plasma Angiopoietin-2 Predicts the Onset of Acute Lung Injury in Critically Ill Patients 
Rationale: Current clinical prediction scores for acute lung injury (ALI) have limited positive predictive value. No studies have evaluated predictive plasma biomarkers in a broad population of critically ill patients or as an adjunct to clinical prediction scores.
Objectives: To determine whether plasma angiopoietin-2 (Ang-2), von Willebrand factor (vWF), interleukin-8 (IL-8), and/or receptor for advanced glycation end products (sRAGE) predict ALI in critically ill patients.
Methods: Plasma samples were drawn from critically ill patients (n = 230) identified in the emergency department. Patients who had ALI at baseline or in the subsequent 6 hours were excluded, and the remaining patients were followed for development of ALI.
Measurements and Main Results: Nineteen patients developed ALI at least 6 hours after the sample draw. Higher levels of Ang-2 and IL-8 were significantly associated with increased development of ALI (P = 0.0008, 0.004, respectively). The association between Ang-2 and subsequent development of ALI was robust to adjustment for sepsis and vasopressor use. Ang-2 and the Lung Injury Prediction Score each independently discriminated well between those who developed ALI and those who did not (area under the receiver operating characteristic curve, 0.74 for each), and using the two together improved the area under the curve to 0.84 (vs. 0.74, P = 0.05). In contrast, plasma levels of sRAGE and vWF were not predictive of ALI.
Conclusions: Plasma biomarkers such as Ang-2 can improve clinical prediction scores and identify patients at high risk for ALI. In addition, the early rise of Ang-2 emphasizes the importance of endothelial injury in the early pathogenesis of ALI.
doi:10.1164/rccm.201208-1460OC
PMCID: PMC3678110  PMID: 23328529
acute respiratory distress syndrome; acute lung injury; receptor for advanced glycation end products; angiopoietin-2; Lung Injury Prediction Score
8.  Is there still a role for the lung injury score in the era of the Berlin definition ARDS? 
Background
The Lung Injury Score (LIS) remains a commonly utilized measure of lung injury severity though the additive value of LIS to predict ARDS outcomes over the recent Berlin definition of ARDS, which incorporates severity, is not known.
Methods
We tested the association of LIS (in which scores range from 0 to 4, with higher scores indicating more severe lung injury) and its four components calculated on the day of ARDS diagnosis with ARDS morbidity and mortality in a large, multi-ICU cohort of patients with Berlin-defined ARDS. Receiver Operator Characteristic (ROC) curves were generated to compare the predictive validity of LIS for mortality to Berlin stages of severity (mild, moderate and severe).
Results
In 550 ARDS patients, a one-point increase in LIS was associated with 58% increased odds of in-hospital death (95% CI 14 to 219%, P = 0.006), a 7% reduction in ventilator-free days (95% CI 2 to 13%, P = 0.01), and, among patients surviving hospitalization, a 25% increase in days of mechanical ventilation (95% CI 9 to 43%, P = 0.001) and a 16% increase (95% CI 2 to 31%, P = 0.02) in the number of ICU days. However, the mean LIS was only 0.2 points higher (95% CI 0.1 to 0.3) among those who died compared to those who lived. Berlin stages of severity were highly correlated with LIS (Spearman’s rho 0.72, P < 0.0001) and were also significantly associated with ARDS mortality and similar morbidity measures. The predictive validity of LIS for mortality was similar to Berlin stages of severity with an area under the curve of 0.58 compared to 0.60, respectively (P-value 0.49).
Conclusions
In a large, multi-ICU cohort of patients with ARDS, both LIS and the Berlin definition severity stages were associated with increased in-hospital morbidity and mortality. However, predictive validity of both scores was marginal, and there was no additive value of LIS over Berlin. Although neither LIS nor the Berlin definition were designed to prognosticate outcomes, these findings suggest that the role of LIS in characterizing lung injury severity in the era of the Berlin definition ARDS may be limited.
doi:10.1186/2110-5820-4-4
PMCID: PMC3931496  PMID: 24533450
Acute lung injury; Acute respiratory distress syndrome; Lung injury score; Berlin definition; Clinical outcomes; Critical illness
9.  Hyperoxic Acute Lung Injury 
Respiratory care  2013;58(1):123-141.
Prolonged breathing of very high FIO2 (FIO2 ≥ 0.9) uniformly causes severe hyperoxic acute lung injury (HALI) and, without a reduction of FIO2, is usually fatal. The severity of HALI is directly proportional to PO2 (particularly above 450 mm Hg, or an FIO2 of 0.6) and exposure duration. Hyperoxia produces extraordinary amounts of reactive O2 species that overwhelms natural antioxidant defenses and destroys cellular structures through several pathways. Genetic predisposition has been shown to play an important role in HALI among animals, and some genetics-based epidemiologic research suggests that this may be true for humans as well. Clinically, the risk of HALI likely occurs when FIO2exceeds 0.7, and may become problematic when FIO2 exceeds 0.8 for an extended period of time. Both high-stretch mechanical ventilation and hyperoxia potentiate lung injury and may promote pulmonary infection. During the 1960s, confusion regarding the incidence and relevance of HALI largely reflected such issues as the primitive control of FIO2, the absence of PEEP, and the fact that at the time both ALI and ventilator-induced lung injury were unknown. The advent of PEEP and precise control over FIO2, as well as lung-protective ventilation, and other adjunctive therapies for severe hypoxemia, has greatly reduced the risk of HALI for the vast majority of patients requiring mechanical ventilation in the 21st century. However, a subset of patients with very severe ARDS requiring hyperoxic therapy is at substantial risk for developing HALI, therefore justifying the use of such adjunctive therapies.
doi:10.4187/respcare.01963
PMCID: PMC3915523  PMID: 23271823
acute lung injury; acute respiratory distress syndrome; hyperoxia; oxygen toxicity; reactive oxygen species; ventilator-induced lung injury
10.  Activation of the Heat Shock Response Attenuates the IL-1β-mediated Inhibition of the Amiloride-Sensitive Alveolar Epithelial Ion Transport 
Shock (Augusta, Ga.)  2013;39(2):189-196.
Acute lung injury (ALI) is a clinical syndrome characterized by hypoxia which is caused by the breakdown of the alveolar capillary barrier. IL-1β a cytokine released within the airspace in ALI, down-regulates αENaC transcription and protein expression via p38 MAP kinase-dependent signaling. While induction of the heat shock response can restore alveolar fluid clearance compromised by IL-1β following the onset of severe hemorrhagic shock in rats, the mechanisms are not fully understood. In this study, we report that the induction of the heat shock response prevents IL-1β-dependent inhibition of αENaC mRNA expression and subsequent channel function. Heat shock results in IRAK1 detergent insolubility and a disruption of Hsp90 binding to IRAK1. Likewise, TAK1, another client protein of Hsp90 and signaling component of the IL-1β pathway is also detergent insoluble after heat shock. Twenty-four hours post-heat shock, both IRAK1 and TAK1 are again detergent soluble, which correlates with the IL-1β-dependent p38 activation. Remarkably, IL-1β-dependent p38 activation 24-hour post-heat shock did not result in an inhibition of αENaC mRNA expression and channel function. Further analysis demonstrates prolonged preservation of αENaC expression by the activation of the heat shock response that involves inducible Hsp70. Inhibition of Hsp70 at 24 hours post-heat shock results in p38-dependent IL-1β inhibition of αENaC mRNA expression while over-expression of Hsp70 attenuates the p38-dependent IL-1β inhibition of αENaC mRNA expression. These studies demonstrate new mechanisms by which the induction of the heat shock response protects the barrier function of the alveolar epithelium in acute lung injury.
doi:10.1097/SHK.0b013e31827e8ea3
PMCID: PMC3663580  PMID: 23324889
Lung; Stress Protein Response; αENaC; p38 MAP Kinase; IRAK-1; TAK-1
11.  Metabolomic Derangements Are Associated with Mortality in Critically Ill Adult Patients 
PLoS ONE  2014;9(1):e87538.
Objective
To identify metabolomic biomarkers predictive of Intensive Care Unit (ICU) mortality in adults.
Rationale
Comprehensive metabolomic profiling of plasma at ICU admission to identify biomarkers associated with mortality has recently become feasible.
Methods
We performed metabolomic profiling of plasma from 90 ICU subjects enrolled in the BWH Registry of Critical Illness (RoCI). We tested individual metabolites and a Bayesian Network of metabolites for association with 28-day mortality, using logistic regression in R, and the CGBayesNets Package in MATLAB. Both individual metabolites and the network were tested for replication in an independent cohort of 149 adults enrolled in the Community Acquired Pneumonia and Sepsis Outcome Diagnostics (CAPSOD) study.
Results
We tested variable metabolites for association with 28-day mortality. In RoCI, nearly one third of metabolites differed among ICU survivors versus those who died by day 28 (N = 57 metabolites, p<.05). Associations with 28-day mortality replicated for 31 of these metabolites (with p<.05) in the CAPSOD population. Replicating metabolites included lipids (N = 14), amino acids or amino acid breakdown products (N = 12), carbohydrates (N = 1), nucleotides (N = 3), and 1 peptide. Among 31 replicated metabolites, 25 were higher in subjects who progressed to die; all 6 metabolites that are lower in those who die are lipids. We used Bayesian modeling to form a metabolomic network of 7 metabolites associated with death (gamma-glutamylphenylalanine, gamma-glutamyltyrosine, 1-arachidonoylGPC(20:4), taurochenodeoxycholate, 3-(4-hydroxyphenyl) lactate, sucrose, kynurenine). This network achieved a 91% AUC predicting 28-day mortality in RoCI, and 74% of the AUC in CAPSOD (p<.001 in both populations).
Conclusion
Both individual metabolites and a metabolomic network were associated with 28-day mortality in two independent cohorts. Metabolomic profiling represents a valuable new approach for identifying novel biomarkers in critically ill patients.
doi:10.1371/journal.pone.0087538
PMCID: PMC3907548  PMID: 24498130
12.  Calcium flux and endothelial dysfunction during acute lung injury: a STIMulating target for therapy 
The Journal of Clinical Investigation  2013;123(3):1015-1018.
Bacterial pathogen-associated molecular pattern molecules (PAMPs) such as LPS activate the endothelium and can lead to lung injury, but the signaling pathways mediating endothelial injury remain incompletely understood. In a recent issue of the JCI, Gandhirajan et al. identify STIM1, an ER calcium sensor, as a key link between LPS-induced ROS, calcium oscillations, and endothelial cell (EC) dysfunction. In addition, they report that BTP2, an inhibitor of calcium channels, attenuates lung injury. This study identifies a novel endothelial signaling pathway that could be a future target for the treatment of lung injury.
doi:10.1172/JCI68093
PMCID: PMC3582152  PMID: 23434597
13.  Biomarkers of lung epithelial injury and inflammation distinguish severe sepsis patients with acute respiratory distress syndrome 
Critical Care  2013;17(5):R253.
Introduction
Despite recent modifications, the clinical definition of the acute respiratory distress syndrome (ARDS) remains non-specific, leading to under-diagnosis and under-treatment. This study was designed to test the hypothesis that a biomarker panel would be useful for biologic confirmation of the clinical diagnosis of ARDS in patients at risk of developing ARDS due to severe sepsis.
Methods
This was a retrospective case control study of 100 patients with severe sepsis and no evidence of ARDS compared to 100 patients with severe sepsis and evidence of ARDS on at least two of their first four ICU days. A panel that included 11 biomarkers of inflammation, fibroblast activation, proteolytic injury, endothelial injury, and lung epithelial injury was measured in plasma from the morning of ICU day two. A backward elimination model building strategy on 1,000 bootstrapped data was used to select the best performing biomarkers for further consideration in a logistic regression model for diagnosis of ARDS.
Results
Using the five best-performing biomarkers (surfactant protein-D (SP-D), receptor for advanced glycation end-products (RAGE), interleukin-8 (IL-8), club cell secretory protein (CC-16), and interleukin-6 (IL-6)) the area under the receiver operator characteristic curve (AUC) was 0.75 (95% CI: 0.7 to 0.84) for the diagnosis of ARDS. The AUC improved to 0.82 (95% CI: 0.77 to 0.90) for diagnosis of severe ARDS, defined as ARDS present on all four of the first four ICU days.
Conclusions
Abnormal levels of five plasma biomarkers including three biomarkers generated by lung epithelium (SP-D, RAGE, CC-16) provided excellent discrimination for diagnosis of ARDS in patients with severe sepsis. Altered levels of plasma biomarkers may be useful biologic confirmation of the diagnosis of ARDS in patients with sepsis, and also potentially for selecting patients for clinical trials that are designed to reduce lung epithelial injury.
doi:10.1186/cc13080
PMCID: PMC4056313  PMID: 24156650
14.  Age-, sex-, and race-based differences among patients enrolled versus not enrolled in acute lung injury clinical trials 
Critical care medicine  2010;38(6):1450-1457.
Objective
Little is known about the participation of racial/ethnic minorities, women, and the elderly into critical care clinical trials. We sought to characterize the representation of racial and ethnic minorities, women and older patients in clinical trials of patients with acute lung injury (ALI) and to determine the reasons for non-enrollment.
Design, Setting, an Patients
We performed a cross-sectional analysis of pooled screening logs from 44 academic hospitals participating in three multi-center, randomized, controlled trials conducted by the Acute Respiratory Distress Syndrome Network (ARDSnet) from 1996 to 2005.
Intervention
None
Measurements and Main Results
We calculated odds ratios (OR) of enrollment for age, sex, racial groups, and the OR for the presence of each exclusion criterion by age, sex, and race adjusted for demographics, ALI risk factor, study, and study center. 10.4% of 17,459 screened patients with ALI were enrolled. The median (range) enrollment by center was 15% (2–88%). Older patients of both sexes were less likely to be enrolled, but older women were more likely to be enrolled than older men. The adjusted OR (95% confidence interval [CI]) for enrollment among men ≥75 years of age was 0.59 (0.45–0.77) and for women ≥75 years of age was 0.45 (0.32–0.62), compared to men <35 years of age. There were no differences in the likelihood of enrollment among all racial/ethnic groups. Older patients and men were less likely to be enrolled because of medical comorbidity. Among all patients who were not enrolled, black patients and their families refused participation more often than white patients.
Conclusions
Older patients are less likely to be enrolled in ALI clinical trials. There is no evidence that women or racial/ethnic minorities are underrepresented in ALI clinical trials.
doi:10.1097/CCM.0b013e3181de451b
PMCID: PMC3799957  PMID: 20386308
Critical Illness; Ethics, Research; Healthcare Disparities; Research Methodology; Aged
15.  Correction: HMGB1 Accelerates Alveolar Epithelial Repair via an IL-1β- and αvβ6 Integrin-dependent Activation of TGF-β1 
PLoS ONE  2013;8(10):10.1371/annotation/88f820f2-18dd-4d3b-8989-68f170b26b04.
doi:10.1371/annotation/88f820f2-18dd-4d3b-8989-68f170b26b04
PMCID: PMC3806928  PMID: 24204477
16.  Protein Kinase C-α and Arginase I Mediate Pneumolysin-Induced Pulmonary Endothelial Hyperpermeability 
Antibiotics-induced release of the pore-forming virulence factor pneumolysin (PLY) in patients with pneumococcal pneumonia results in its presence days after lungs are sterile and is a major factor responsible for the induction of permeability edema. Here we sought to identify major mechanisms mediating PLY-induced endothelial dysfunction. We evaluated PLY-induced endothelial hyperpermeability in human lung microvascular endothelial cells (HL-MVECs) and human lung pulmonary artery endothelial cells in vitro and in mice instilled intratracheally with PLY. PLY increases permeability in endothelial monolayers by reducing stable and dynamic microtubule content and modulating VE-cadherin expression. These events, dependent upon an increased calcium influx, are preceded by protein kinase C (PKC)-α activation, perturbation of the RhoA/Rac1 balance, and an increase in myosin light chain phosphorylation. At later time points, PLY treatment increases the expression and activity of arginase in HL-MVECs. Arginase inhibition abrogates and suppresses PLY-induced endothelial barrier dysfunction by restoring NO generation. Consequently, a specific PKC-α inhibitor and the TNF-derived tonoplast intrinsic protein peptide, which blunts PLY-induced PKC-α activation, are able to prevent activation of arginase in HL-MVECs and to reduce PLY-induced endothelial hyperpermeability in mice. Arginase I (AI)+/−/arginase II (AII)−/− C57BL/6 mice, displaying a significantly reduced arginase I expression in the lungs, are significantly less sensitive to PLY-induced capillary leak than their wild-type or AI+/+/AII−/− counterparts, indicating an important role for arginase I in PLY-induced endothelial hyperpermeability. These results identify PKC-α and arginase I as potential upstream and downstream therapeutic targets in PLY-induced pulmonary endothelial dysfunction.
doi:10.1165/rcmb.2011-0332OC
PMCID: PMC3488628  PMID: 22582175
PKC; arginase; pneumococcus; pneumolysin; TNF
17.  Comparison of Chest Radiograph Scoring to Lung Weight as a Quantitative Index of Pulmonary Edema in Organ Donors 
Clinical transplantation  2012;26(5):665-671.
Quantification of the degree of pulmonary edema in organ donors is useful for assessing the clinical severity of pulmonary edema, determining response to therapy, and as an endpoint for therapeutic trials. Currently, there is no accurate non-invasive method for assessing the degree of pulmonary edema. We tested the performance of a four quadrant chest radiographic scoring system compared to quantification of pulmonary edema by excised lung weight in 84 donors whose lungs were not used for transplantation. Chest radiographs were taken 3.6 ± 3.0 hours prior to organ procurement and were scored by two of the authors. Lungs were excised without perfusion and individually weighed. The chest radiographic scoring system had good performance: correlation between total radiographic score and total lung weight of 0.61, p <0.001. Performance of the scoring system was improved when chest radiographs with atelectasis were excluded (r = 0.79, p < 0.001). The area under the receiver operator characteristic curve for detection of moderate pulmonary edema (total lung weight > 1000g) was 0.80. This chest radiographic scoring system may potentially be used to assess the clinical severity of pulmonary edema and may be useful as part of the evaluation of donors for suitability for lung transplantation.
doi:10.1111/j.1399-0012.2011.01591.x
PMCID: PMC3642873  PMID: 22324977
pulmonary edema; organ donor; lung transplantation; chest radiograph
18.  Comparison of thermodilution measured extravascular lung water with chest radiographic assessment of pulmonary oedema in patients with acute lung injury 
Background
Acute lung injury and the acute respiratory distress syndrome (ALI/ARDS) are characterized by pulmonary oedema, measured as extravascular lung water (EVLW). The chest radiograph (CXR) can potentially estimate the quantity of lung oedema while the transpulmonary thermodilution method measures the amount of EVLW. This study was designed to determine whether EVLW as estimated by a CXR score predicts EVLW measured by the thermodilution method and whether changes in EVLW by either approach predict mortality in ALI/ARDS.
Methods
Clinical data were collected within 48 hours of ALI/ARDS diagnosis and daily up to 14 days on 59 patients with ALI/ARDS. Two clinicians scored each CXR for the degree of pulmonary oedema, using a validated method. EVLW indexed to body weight was measured using the single indicator transpulmonary thermodilution technique.
Results
The CXR score had a modest, positive correlation with the EVLWI measurements (r = 0.35, p < 0.001). There was a 1.6 ml/kg increase in EVLWI per 10-point increase in the CXR score (p < 0.001, 95% confidence interval 0.92-2.35). The sensitivity of a high CXR score for predicting a high EVLWI was 93%; similarly the negative predictive value was high at 94%; the specificity (51%) and positive predictive value (50%) were lower. The CXR scores did not predict mortality but the EVLW thermodilution did predict mortality.
Conclusion
EVLW measured by CXR was modestly correlated with thermodilution measured EVLW. Unlike CXR findings, transpulmonary thermodilution EVLWI measurements over time predicted mortality in patients with ALI/ARDS.
doi:10.1186/2110-5820-3-25
PMCID: PMC3846630  PMID: 23937970
Extravascular lung water; Chest radiograph; Acute lung injury; Acute respiratory distress syndrome
19.  Informed Consent in Research to Improve the Number and Quality of Deceased-Donor Organs 
Critical care medicine  2011;39(2):280-283.
Improving the management of potential organ donors in the ICU could meet an important public health goal by increasing the number and quality of transplantable organs. However, randomized clinical trials (RCTs) are needed to quantify the extent to which specific interventions might enhance organ recovery and outcomes among transplant recipients. Among several barriers to conducting such studies are the absence of guidelines for obtaining informed consent for such studies, and the fact that deceased organ donors are not covered by extant federal regulations governing oversight of research with human subjects. This paper explores the underexamined ethical issues that arise in the context of donor management studies, and provides ethical guidelines and suggested regulatory oversight mechanisms to enable such studies to be conducted ethically. We conclude that both the respect that is traditionally accorded to the prior wishes of the dead and the possibility of post-mortem harm support a role for surrogate consent of donors in such RCTs. Furthermore, although recipients will often be considered human subjects under federal regulations, several ethical arguments support waiving requirements for recipient consent in donor management RCTs. Finally, we suggest that new regulatory mechanisms, perhaps linked to existing regional and national organ donation and transplantation infrastructures, must be established to protect patients in donor management studies while limiting unnecessary barriers to the conduct of this important research.
doi:10.1097/CCM.0b013e3181feeb04
PMCID: PMC3717371  PMID: 20975549
informed consent; organ donation; transplantation; research ethics
20.  Clinical Evidence of Early Acute Lung Injury Often Precedes the Diagnosis of ALI 
Background
Acute lung injury (ALI) has been primarily defined in patients who require positive pressure ventilation. As a result, the clinical characteristics of patients with early ALI (EALI) prior to the need for mechanical ventilation have not been well characterized. Early identification of patients with ALI and the impending need for positive pressure ventilation could define a study population for trials of novel therapies.
Methods
We analyzed clinical data from 93 patients at 12, 24, and 48 hours prior to the standard diagnosis of ALI. The time of ALI diagnosis was defined when patients were mechanically ventilated and met the 1994 American–European Consensus Conference diagnostic criteria for ALI.
Results
The majority of patients with ALI presented to the hospital more than 24 hours prior to developing ALI. Specifically, 73% presented more than 12 hours prior to diagnosis, and 57% presented more than 24 hours prior to diagnosis. Of patients hospitalized for at least 12 hours prior to ALI diagnosis, 94% had either bilateral infiltrates on chest radiograph, tachypnea, or an oxygen requirement greater than 2 L/min; 79% and 48% had 2 and 3 of these abnormalities, respectively.
Conclusion
The majority of hospitalized patients who are destined to develop ALI demonstrate tachypnea, increased oxygen requirements, and/or bilateral infiltrates on chest radiograph more than 12 hours prior to meeting criteria for diagnosis. Some patients with EALI may be identified prior to meeting diagnostic criteria during a potential therapeutic window.
doi:10.1177/0885066612450850
PMCID: PMC3482421  PMID: 22733725
early acute lung injury; acute respiratory distress syndrome; diagnosis
21.  Lung mast cell density defines a subpopulation of patients with idiopathic pulmonary fibrosis 
Histopathology  2012;61(1):98-106.
Aims
The relationship of mast cells to the pathogenesis of lung fibrosis remains undefined despite recognition of their presence in the lungs of patients with pulmonary fibrosis. This study was performed to characterize the relationship of mast cells to fibrotic lung diseases.
Methods and results
Lung tissues from patients with idiopathic pulmonary fibrosis (IPF), chronic hypersensitivity pneumonitis (HP), systemic sclerosis (SSc)-related interstitial lung disease (ILD) and normal individuals were subjected to chymase immunostaining and the mast cell density quantified. Eosinophils were quantified by immunostaining for eosinophil peroxidase. Changes in lung function were correlated with mast cell density. Lung tissue obtained from IPF patients had a higher density of chymase-immunoreactive mast cells than that from patients with HP, SSc-related ILD or normal lungs. IPF lung tissue had a higher density of eosinophils than normal lung. There was no correlation between mast cell density and eosinophil density in IPF lung. IPF patients with high mast cell density had a slower rate of decline in forced vital capacity (FVC) than IPF patients with low mast cell density.
Conclusions
Mast cell density in IPF lungs is higher than in other fibrotic lung diseases and normal lungs. Increased mast cell density in IPF may predict slower disease progression.
doi:10.1111/j.1365-2559.2012.04197.x
PMCID: PMC3371307  PMID: 22394225
chloroacetate esterase; eosinophil; hypersensitivity pneumonitis; idiopathic interstitial pneumonia; systemic sclerosis
22.  Clinical review: Early treatment of acute lung injury - paradigm shift toward prevention and treatment prior to respiratory failure 
Critical Care  2012;16(3):223.
Acute lung injury (ALI) remains a major cause of morbidity and mortality in critically ill patients. Despite improved understanding of the pathogenesis of ALI, supportive care with a lung protective strategy of mechanical ventilation remains the only treatment with a proven survival advantage. Most clinical trials in ALI have targeted mechanically ventilated patients. Past trials of pharmacologic agents may have failed to demonstrate efficacy in part due to the resultant delay in initiation of therapy until several days after the onset of lung injury. Improved early identification of at-risk patients provides new opportunities for risk factor modification to prevent the development of ALI and novel patient groups to target for early treatment of ALI before progression to the need for mechanical ventilation. This review will discuss current strategies that target prevention of ALI and some of the most promising pharmacologic agents for early treatment of ALI prior to the onset of respiratory failure that requires mechanical ventilation.
doi:10.1186/cc11144
PMCID: PMC3580596  PMID: 22713281
23.  Stem cells in sepsis and acute lung injury 
Critical care medicine  2010;38(12):2379-2385.
Objective
Sepsis and acute lung injury continue to be major causes of morbidity and mortality worldwide despite advances in our understanding of pathophysiology and the discovery of new management strategies. Recent investigations show that stem cells may be beneficial as prognostic biomarkers and novel therapeutic strategies in these syndromes. This article reviews the potential use of endogenous adult tissue-derived stem cells in sepsis and acute lung injury as prognostic markers and also as exogenous cell-based therapy.
Data Sources
A directed systematic search of the medical literature using PubMed and OVID, with particular emphasis on the time period after 2002, was done to evaluate topics related to 1) the epidemiology and pathophysiology of sepsis and acute lung injury; and 2) the definition, characterization, and potential use of stem cells in these diseases.
Data Synthesis and Findings
When available, preferential consideration was given to prospective nonrandomized clinical and preclinical studies.
Conclusions
Stem cells have shown significant promise in the field of critical care both for 1) prognostic value and 2) treatment strategies. Although several recent studies have identified the potential benefit of stem cells in sepsis and acute lung injury, further investigations are needed to more completely understand stem cells and their potential prognostic and therapeutic value.
doi:10.1097/CCM.0b013e3181f96f5f
PMCID: PMC3677751  PMID: 20838330
stem cells; sepsis; ARDS; biomarkers; cell-based therapy
24.  Mesenchymal stem cells enhance survival and bacterial clearance in murine Escherichia coli pneumonia 
Thorax  2012;67(6):533-539.
Rationale
Bacterial pneumonia is the most common infectious cause of death worldwide and treatment is increasingly hampered by antibiotic resistance. Mesenchymal stem cells (MSCs) have been demonstrated to provide protection against acute inflammatory lung injury; however, their potential therapeutic role in the setting of bacterial pneumonia has not been well studied.
Objective
This study focused on testing the therapeutic and mechanistic effects of MSCs in a mouse model of Gram-negative pneumonia.
Methods and results
Syngeneic MSCs from wild-type mice were isolated and administered via the intratracheal route to mice 4 h after the mice were infected with Escherichia coli. 3T3 fibroblasts and phosphate-buffered saline (PBS) were used as controls for all in vivo experiments. Survival, lung injury, bacterial counts and indices of inflammation were measured in each treatment group. Treatment with wild-type MSCs improved 48 h survival (MSC, 55%; 3T3, 8%; PBS, 0%; p<0.05 for MSC vs 3T3 and PBS groups) and lung injury compared with control mice. In addition, wild-type MSCs enhanced bacterial clearance from the alveolar space as early as 4 h after administration, an effect that was not observed with the other treatment groups. The antibacterial effect with MSCs was due, in part, to their upregulation of the antibacterial protein lipocalin 2.
Conclusions
Treatment with MSCs enhanced survival and bacterial clearance in a mouse model of Gram-negative pneumonia. The bacterial clearance effect was due, in part, to the upregulation of lipocalin 2 production by MSCs.
doi:10.1136/thoraxjnl-2011-201176
PMCID: PMC3358432  PMID: 22250097
25.  Plasma angiopoietin-2 in clinical acute lung injury: Prognostic and pathogenetic significance* 
Critical care medicine  2012;40(6):1731-1737.
Background
Angiopoietin-2 is a proinflammatory mediator of endothelial injury in animal models, and increased plasma angiopoietin-2 levels are associated with poor outcomes in patients with sepsis-associated acute lung injury. Whether angiopoietin-2 levels are modified by treatment strategies in patients with acute lung injury is unknown.
Objectives
To determine whether plasma angiopoietin-2 levels are associated with clinical outcomes and affected by fluid management strategy in a broad cohort of patients with acute lung injury.
Design, Setting, and Participants
Plasma levels of angiopoietin-2 and von Willebrand factor (a traditional marker of endothelial injury) were measured in 931 subjects with acute lung injury enrolled in a randomized trial of fluid liberal vs. fluid conservative management.
Measurements and Main Results
The presence of infection (sepsis or pneumonia) as the primary acute lung injury risk factor significantly modified the relationship between baseline angiopoietin-2 levels and mortality (p = .01 for interaction). In noninfection-related acute lung injury, higher baseline angiopoietin-2 levels were strongly associated with increased mortality (odds ratio, 2.43 per 1-log increase in angiopoietin-2; 95% confidence interval, 1.57–3.75; p < .001). In infection-related acute lung injury, baseline angiopoietin-2 levels were similarly elevated in survivors and nonsurvivors; however, patients whose plasma angiopoietin-2 levels increased from day 0 to day 3 had more than double the odds of death compared with patients whose angiopoietin-2 levels declined over the same period of time (odds ratio, 2.29; 95% confidence interval, 1.54–3.43; p < .001). Fluid-conservative therapy led to a 15% greater decline in angiopoietin-2 levels from day 0 to day 3 (95% confidence interval, 4.6–24.8%; p = .006) compared with fluid-liberal therapy in patients with infection-related acute lung injury. In contrast, plasma levels of von Willebrand factor were significantly associated with mortality in both infection-related and noninfection-related acute lung injury and were not affected by fluid therapy.
Conclusions
Unlike von Willebrand factor, plasma angiopoietin-2 has differential prognostic value for mortality depending on the presence or absence of infection as an acute lung injury risk factor. Fluid conservative therapy preferentially lowers plasma angiopoietin-2 levels over time and thus may be beneficial in part by decreasing endothelial inflammation.
doi:10.1097/CCM.0b013e3182451c87
PMCID: PMC3601049  PMID: 22610178
acute respiratory distress syndrome; angiopoietin-2; biomarkers; endothelial injury; pulmonary edema; von Willebrand factor

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