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5.  Obesity: Changing Asthma in the 21st Century 
doi:10.1164/rccm.201206-1092ED
PMCID: PMC3443799  PMID: 22942341
6.  Focusing on the Flood 
doi:10.1164/rccm.201104-0623ED
PMCID: PMC3114056  PMID: 21596828
8.  Evaluating the NET Influence of Inflammation on Pneumonia Biology 
doi:10.1164/rccm.201209-1702ED
PMCID: PMC3530208  PMID: 23155213
15.  Waiting in Anticipation 
doi:10.1164/rccm.201209-1666ED
PMCID: PMC3530217  PMID: 23118082
17.  Interferon-λ1 and Viral Wheeze in Asthma: A Gothic Duality? 
doi:10.1164/rccm.201112-2195ED
PMCID: PMC3297104  PMID: 22383563
18.  The Pros and Cons of Airway Lining Fluid Composition Analysis 
doi:10.1164/rccm.201111-2010ED
PMCID: PMC3297111  PMID: 22298360
19.  Straining to Make Mechanical Ventilation Safe and Simple 
doi:10.1164/rccm.201102-0195ED
PMCID: PMC3114057  PMID: 21596829
20.  Just a Spoonful of Technology Makes the Protocol Go Down 
doi:10.1164/rccm.200607-933ED
PMCID: PMC2648053  PMID: 17021356
21.  Cluster Analysis and Clinical Asthma Phenotypes 
Rationale
Heterogeneity in asthma expression is multidimensional, including variability in clinical, physiologic, and pathologic parameters. Classification requires consideration of these disparate domains in a unified model.
Objectives
To explore the application of a multivariate mathematical technique, k-means cluster analysis, for identifying distinct phenotypic groups.
Methods
We performed k-means cluster analysis in three independent asthma populations. Clusters of a population managed in primary care (n = 184) with predominantly mild to moderate disease, were compared with a refractory asthma population managed in secondary care (n = 187). We then compared differences in asthma outcomes (exacerbation frequency and change in corticosteroid dose at 12 mo) between clusters in a third population of 68 subjects with predominantly refractory asthma, clustered at entry into a randomized trial comparing a strategy of minimizing eosinophilic inflammation (inflammation-guided strategy) with standard care.
Measurements and Main Results
Two clusters (early-onset atopic and obese, noneosinophilic) were common to both asthma populations. Two clusters characterized by marked discordance between symptom expression and eosinophilic airway inflammation (early-onset symptom predominant and late-onset inflammation predominant) were specific to refractory asthma. Inflammation-guided management was superior for both discordant subgroups leading to a reduction in exacerbation frequency in the inflammation-predominant cluster (3.53 [SD, 1.18] vs. 0.38 [SD, 0.13] exacerbation/patient/yr, P = 0.002) and a dose reduction of inhaled corticosteroid in the symptom-predominant cluster (mean difference, 1,829 μg beclomethasone equivalent/d [95% confidence interval, 307–3,349 μg]; P = 0.02).
Conclusions
Cluster analysis offers a novel multidimensional approach for identifying asthma phenotypes that exhibit differences in clinical response to treatment algorithms.
doi:10.1164/rccm.200711-1754OC
PMCID: PMC3992366  PMID: 18480428
taxonomy; corticosteroid response; multivariate classification
22.  Superoxide Dismutase Expression Attenuates Cigarette Smoke– or Elastase-generated Emphysema in Mice 
Rationale
Oxidants are believed to play a major role in the development of emphysema.
Objectives
This study aimed to determine if the expression of human copper–zinc superoxide dismutase (CuZnSOD) within the lungs of mice protects against the development of emphysema.
Methods
Transgenic CuZnSOD and littermate mice were exposed to cigarette smoke (6 h/d, 5 d/wk, for 1 yr) and compared with nonexposed mice. A second group was treated with intratracheal elastase to induce emphysema.
Measurements
Lung inflammation was measured by cell counts and myeloperoxidase levels. Oxidative damage was assessed by immunofluorescence for 3-nitrotyrosine and 8-hydroxydeoxyguanosine and lipid peroxidation levels. The development of emphysema was determined by measuring the mean linear intercept (Lm).
Main Results
Smoke exposure caused a fourfold increase in neutrophilic inflammation and doubled lung myeloperoxidase activity. This inflammatory response did not occur in the smoke-exposed CuZnSOD mice. Similarly, CuZnSOD expression prevented the 58% increase in lung lipid peroxidation products that occurred after smoke exposure. Most important, CuZnSOD prevented the onset of emphysema in both the smoke-induced model (Lm, 68 exposed control vs. 58 exposed transgenic; p < 0.04) and elastase-generated model (Lm, 80 exposed control vs. 63 exposed transgenic; p < 0.03). These results demonstrate for the first time that antioxidants can prevent smoke-induced inflammation and can counteract the proteolytic cascade that leads to emphysema formation in two separate animal models of the disease.
Conclusions
These findings indicate that strategies aimed at enhancing or supplementing lung antioxidants could be effective for the prevention and treatment of this disease.
doi:10.1164/rccm.200506-850OC
PMCID: PMC3982860  PMID: 16387805
emphysema; inflammation; oxidants
23.  Statin Use and Risk of Delirium in the Critically Ill 
Rationale
Delirium is common in intensive care unit (ICU) patients and is a predictor of worse outcomes and neuroinflammation is a possible mechanism. The antiinflammatory actions of statins may reduce delirium.
Objectives
To determine whether critically ill patients receiving statin therapy had a reduced risk of delirium than those not on statins.
Methods
A prospective cohort analysis of data from consecutive ICU patients admitted to a UK mixed medical and surgical critical care unit between August 2011 and February 2012; the Confusion Assessment Method for ICU was used to determine the days each patient was assessed as being free of delirium during ICU admission.
Measurements and Main Results
Delirium-free days, daily administration of statins, and serum C-reactive protein (CRP) were recorded. Four hundred and seventy consecutive critical care patients were followed, of whom 151 patients received statins. Using random-effects multivariable logistic regression, statin administration the previous evening was associated with the patient being assessed as free of delirium (odds ratio, 2.28; confidence interval, 1.01–5.13; P < 0.05) and with lower CRP (β = −0.52; P < 0.01) the following day. When the association between statin and being assessed as free of delirium was controlled for CRP, the effect size became nonsignificant (odds ratio, 1.56; confidence interval, 0.64–3.79; P = 0.32).
Conclusions
Ongoing statin therapy is associated with a lower daily risk of delirium in critically ill patients. An ongoing clinical trial, informed by this study, is investigating if statins are a potential therapy for delirium in the critically ill.
doi:10.1164/rccm.201306-1150OC
PMCID: PMC3974585  PMID: 24417431
delirium; statin; inflammation; C-reactive protein; critical care
24.  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
25.  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

Results 1-25 (1065)