Angiopoietin-1 is a Tie-2 receptor agonist that stabilizes vascular endothelium, promoting endothelial maturation and preventing capillary leak. Angiopoietin-2 is largely a competitive partial antagonist that is markedly elevated in humans and animal model

Background: Subphenotypes have been identified within heterogeneous diseases such as asthma and breast cancer, with important therapeutic implications. We assessed whether subphenotypes exist within acute respiratory distress syndrome (ARDS), another heterogeneous disorder. Methods: We used data from two ARDS randomised controlled trials (ARMA trial and ALVEOLI trial), sponsored by the National Heart, Lung, and Blood Institute. We applied latent class modelling to identify subphenotypes using clinical and biological data. We modelled data from both studies independently. We then tested the association of subphenotypes with clinical outcomes in both cohorts and with the response to positive end-expiratory pressure (PEEP) in the ALVEOLI cohort. Findings: We analysed data for 1022 patients: 473 in the ARMA cohort and 549 in the ALVEOLI cohort. Independent latent class models indicated that a two-class (ie, two subphenotype) model was the best fit for both cohorts. In both cohorts, we identified a hyperinflammatory subphenotype (phenotype 2) that was characterised by higher plasma concentrations of inflammatory biomarkers, a higher prevalence of vasopressor use, lower serum bicarbonate concentrations, and a higher prevalence of sepsis than phenotype 1. Participants in phenotype 2 had higher mortality and fewer ventilator-free days and organ failure-free days in both cohorts than did those in phenotype 1 (p<·007 for all). In the ALVEOLI cohort, the effects of ventilation strategy (high PEEP vs low PEEP) on mortality, ventilator-free days and organ failure-free days differed by phenotype (p=·049 for mortality, p=·018 for ventilator-free days, p=·003 for organ-failure-free days). Interpretation: We have identified two subphenotypes within ARDS, one of which is categorised by more severe inflammation, shock, and metabolic acidosis and by worse clinical outcomes. Response to treatment in a randomised trial of PEEP strategies differed on the basis of subphenotype. Identification of ARDS subphenotypes might be useful in selecting patients for future clinical trials. Funding: National Institutes of Health. © 2014 Elsevier Ltd.

Although recipients of donor lungs from smokers have worse clinical outcomes, the underlying mechanisms are unknown. We tested the association between donor smoking and the degree of pulmonary edema (as estimated by lung weight), the rate of alveolar fluid clearance (AFC; measured by airspace instillation of 5% albumin) and biomarkers of lung epithelial injury and inflammation (bronchoalveolar lavage [BAL] surfactant protein-D (SP-D) and IL-8) in ex vivo lungs recovered from 298 organ donors. The extent of pulmonary edema was higher in current smokers (n = 127) compared to nonsmokers (median 408 g, interquartile range [IQR] 364-500 vs. 385 g, IQR 340-460, p = 0.009). Oxygenation at study enrollment was worse in current smokers versus nonsmokers (median PaO2 /FiO2 214 mm Hg, IQR 126-323 vs. 266 mm Hg, IQR 154-370, p = 0.02). Current smokers with the highest exposure (≥20 pack years) had significantly lower rates of AFC, suggesting that the effects of cigarette smoke on alveolar epithelial fluid transport function may be dose related. BAL IL-8 was significantly higher in smokers while SP-D was lower. These findings indicate that chronic exposure to cigarette smoke has important effects on inflammation, gas exchange, lung epithelial function and lung fluid balance in the organ donor that could influence lung function in the lung transplant recipient.

OBJECTIVES:: Cigarette smoke exposure has recently been found to be associated with increased susceptibility to trauma-and transfusion-associated acute respiratory distress syndrome. We sought to determine 1) the incidence of cigarette smoke exposure in a diverse multicenter sample of acute respiratory distress syndrome patients and 2) whether cigarette smoke exposure is associated with severity of lung injury and mortality in acute respiratory distress syndrome. DESIGN:: Analysis of the Albuterol for the Treatment of Acute Lung Injury and Omega Acute Respiratory Distress Syndrome Network studies. SETTING:: Acute Respiratory Distress Syndrome Network hospitals. PATIENTS:: Three hundred eighty-one patients with acute respiratory distress syndrome. INTERVENTIONS:: None. MEASUREMENTS AND MAIN RESULTS:: 4-(Methylnitrosamino)-1-(3-pyridyl)-1- butanol, a validated tobacco-specific marker, was measured in urine samples from subjects enrolled in two National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome Network randomized controlled trials. Urine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol levels were consistent with active smoking in 36% of acute respiratory distress syndrome patients and with passive smoking in 41% of nonsmokers (vs 20% and 40% in general population, respectively). Patients with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol levels in the active smoking range were younger and had a higher incidence of alcohol misuse, fewer comorbidities, lower severity of illness, and less septic shock at enrollment compared with patients with undetectable 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol levels. Despite this lower severity of illness, the severity of lung injury did not significantly differ based on biomarker-determined smoking status. Cigarette smoke exposure was not significantly associated with death after adjusting for differences in age, alcohol use, comorbidities, and severity of illness. CONCLUSIONS:: In this first multicenter study of biomarker-determined cigarette smoke exposure in acute respiratory distress syndrome patients, we found that active cigarette smoke exposure was significantly more prevalent among acute respiratory distress syndrome patients compared to population averages. Despite their younger age, better overall health, and lower severity of illness, smokers by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol had similar severity of lung injury as patients with undetectable 4-(methylnitrosamino)-1-(3-pyridyl)-1- butanol. These findings suggest that active cigarette smoking may increase susceptibility to acute respiratory distress syndrome in younger, healthier patients. © 2014 by the Society of Critical Care Medicine and Lippincott Williams and Wilkins.

Although recipients of donor lungs from smokers have worse clinical outcomes, the underlying mechanisms are unknown. We tested the association between donor smoking and the degree of pulmonary edema (as estimated by lung weight), the rate of alveolar fluid clearance (AFC; measured by airspace instillation of 5% albumin) and biomarkers of lung epithelial injury and inflammation (bronchoalveolar lavage [BAL] surfactant protein-D (SP-D) and IL-8) in ex vivo lungs recovered from 298 organ donors. The extent of pulmonary edema was higher in current smokers (n=127) compared to nonsmokers (median 408g, interquartile range [IQR] 364-500 vs. 385g, IQR 340-460, p=0.009). Oxygenation at study enrollment was worse in current smokers versus nonsmokers (median PaO2/FiO2 214mm Hg, IQR 126-323 vs. 266mm Hg, IQR 154-370, p=0.02). Current smokers with the highest exposure (≥20 pack years) had significantly lower rates of AFC, suggesting that the effects of cigarette smoke on alveolar epithelial fluid transport function may be dose related. BAL IL-8 was significantly higher in smokers while SP-D was lower. These findings indicate that chronic exposure to cigarette smoke has important effects on inflammation, gas exchange, lung epithelial function and lung fluid balance in the organ donor that could influence lung function in the lung transplant recipient.

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

Objective: Thombomodulin (TM) is an activator of protein C and a biomarker for endothelial injury. We hypothesized that (1) elevated plasma levels would be associated with clinical outcomes and (2) polymorphisms in the TM gene would be associated with plasma levels.

© 2015 Orwoll et al.Introduction: The significance of endothelial injury in children with the acute respiratory distress syndrome (ARDS) has not been well studied. Plasma levels of soluble thrombomodulin (sTM), an endothelial surface protein involved in co