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    Oxygenation Saturation Index Predicts Clinical Outcomes in ARDS. DesPrez Katherine,McNeil J Brennan,Wang Chunxue,Bastarache Julie A,Shaver Ciara M,Ware Lorraine B Chest BACKGROUND:Traditional measures of ARDS severity such as Pao/Fio may not reliably predict clinical outcomes. The oxygenation index (OI [Fio × mean airway pressure × 100)/Pao]) may more accurately reflect ARDS severity but requires arterial blood gas measurement. We hypothesized that the oxygenation saturation index (OSI [Fio × mean airway pressure × 100)/oxygen saturation by pulse oximetry (Spo)]) is a reliable noninvasive surrogate for the OI that is associated with hospital mortality and ventilator-free days (VFDs) in patients with ARDS. METHODS:Critically ill patients enrolled in a prospective cohort study were eligible if they developed ARDS (Berlin criteria) during the first 4 ICU days and had mean airway pressure, Spo/Fio, and Pao/Fio values recorded on the first day of ARDS (N = 329). The highest mean airway pressure and lowest Spo/Fio and Pao/Fio values were used to calculate OI and OSI. The association between OI or OSI and hospital mortality or VFD was analyzed by using logistic regression and linear regression, respectively. The area under the receiver-operating characteristic curve (AUC) for mortality was compared among OI, OSI, Spo/Fio, Pao/Fio, and Acute Physiology and Chronic Health Evaluation II scores. RESULTS:OI and OSI were strongly correlated (rho = 0.862; P < .001). OSI was independently associated with hospital mortality (OR per 5-point increase in OSI, 1.228 [95% CI, 1.056-1.429]; P = .008). OI and OSI were each associated with a reduction in VFD (OI, P = .023; OSI, P = .005). The AUC for mortality prediction was greatest for Acute Physiology and Chronic Health Evaluation II scores (AUC, 0.695; P < .005) and OSI (AUC, 0.602; P = .007). The AUC for OSI was substantially better in patients aged < 40 years (AUC, 0.779; P < .001). CONCLUSIONS:In patients with ARDS, the OSI was correlated with the OI. The OSI on the day of ARDS diagnosis was significantly associated with increased mortality and fewer VFDs. The findings suggest that OSI is a reliable surrogate for OI that can noninvasively provide prognostic information and assessment of ARDS severity. 10.1016/j.chest.2017.08.002
    A prospective international observational prevalence study on prone positioning of ARDS patients: the APRONET (ARDS Prone Position Network) study. Guérin C,Beuret P,Constantin J M,Bellani G,Garcia-Olivares P,Roca O,Meertens J H,Maia P Azevedo,Becher T,Peterson J,Larsson A,Gurjar M,Hajjej Z,Kovari F,Assiri A H,Mainas E,Hasan M S,Morocho-Tutillo D R,Baboi L,Chrétien J M,François G,Ayzac L,Chen L,Brochard L,Mercat A, Intensive care medicine INTRODUCTION:While prone positioning (PP) has been shown to improve patient survival in moderate to severe acute respiratory distress syndrome (ARDS) patients, the rate of application of PP in clinical practice still appears low. AIM:This study aimed to determine the prevalence of use of PP in ARDS patients (primary endpoint), the physiological effects of PP, and the reasons for not using it (secondary endpoints). METHODS:The APRONET study was a prospective international 1-day prevalence study performed four times in April, July, and October 2016 and January 2017. On each study day, investigators in each ICU had to screen every patient. For patients with ARDS, use of PP, gas exchange, ventilator settings and plateau pressure (Pplat) were recorded before and at the end of the PP session. Complications of PP and reasons for not using PP were also documented. Values are presented as median (1st-3rd quartiles). RESULTS:Over the study period, 6723 patients were screened in 141 ICUs from 20 countries (77% of the ICUs were European), of whom 735 had ARDS and were analyzed. Overall 101 ARDS patients had at least one session of PP (13.7%), with no differences among the 4 study days. The rate of PP use was 5.9% (11/187), 10.3% (41/399) and 32.9% (49/149) in mild, moderate and severe ARDS, respectively (P = 0.0001). The duration of the first PP session was 18 (16-23) hours. Measured with the patient in the supine position before and at the end of the first PP session, PaO/FO increased from 101 (76-136) to 171 (118-220) mmHg (P = 0.0001) driving pressure decreased from 14 [11-17] to 13 [10-16] cmHO (P = 0.001), and Pplat decreased from 26 [23-29] to 25 [23-28] cmHO (P = 0.04). The most prevalent reason for not using PP (64.3%) was that hypoxemia was not considered sufficiently severe. Complications were reported in 12 patients (11.9%) in whom PP was used (pressure sores in five, hypoxemia in two, endotracheal tube-related in two ocular in two, and a transient increase in intracranial pressure in one). CONCLUSIONS:In conclusion, this prospective international prevalence study found that PP was used in 32.9% of patients with severe ARDS, and was associated with low complication rates, significant increase in oxygenation and a significant decrease in driving pressure. 10.1007/s00134-017-4996-5
    The emergence of pathogenic TNF/iNOS producing dendritic cells (Tip-DCs) in a malaria model of acute respiratory distress syndrome (ARDS) is dependent on CCR4. Galvão-Filho Bruno,de Castro Júlia Teixeira,Figueiredo Maria Marta,Rosmaninho Claudio Gonçalves,Antonelli Lis Ribeiro do Valle,Gazzinelli Ricardo Tostes Mucosal immunology Malaria-associated acute respiratory distress syndrome (MA-ARDS) and acute lung injury (ALI) are complications that cause lung damage and often leads to death. The MA-ARDS/ALI is associated with a Type 1 inflammatory response mediated by T lymphocytes and IFN-γ. Here, we used the Plasmodium berghei NK65 (PbN)-induced MA-ALI/ARDS model that resembles human disease and confirmed that lung CD4 and CD8 T cells predominantly expressed Tbet and IFN-γ. Surprisingly, we found that development of MA-ALI/ARDS was dependent on functional CCR4, known to mediate the recruitment of Th2 lymphocytes and regulatory T cells. However, in this Type 1 inflammation-ARDS model, CCR4 was not involved in the recruitment of T lymphocytes, but was required for the emergence of TNF-α/iNOS producing dendritic cells (Tip-DCs) in the lungs. In contrast, recruitment of Tip-DCs and development of MA-ALI/ARDS were not altered in CCR2 mice. Importantly, we showed that NOS2 mice are resistant to PbN-induced lung damage, indicating that reactive nitrogen species produced by Tip-DCs play an essential role in inducing MA-ARDS/ALI. Lastly, our experiments suggest that production of IFN-γ primarily by CD8 T cells is required for inducing Tip-DCs differentiation in the lungs and the development of MA-ALI/ARDS model. 10.1038/s41385-018-0093-5
    Rapidly Improving ARDS in Therapeutic Randomized Controlled Trials. Schenck Edward J,Oromendia Clara,Torres Lisa K,Berlin David A,Choi Augustine M K,Siempos Ilias I Chest BACKGROUND:Observational studies suggest that some patients meeting criteria for ARDS no longer fulfill the oxygenation criterion early in the course of their illness. This subphenotype of rapidly improving ARDS has not been well characterized. We attempted to assess the prevalence, characteristics, and outcomes of rapidly improving ARDS and to identify which variables are useful to predict it. METHODS:A secondary analysis was performed of patient level data from six ARDS Network randomized controlled trials. We defined rapidly improving ARDS, contrasted with ARDS > 1 day, as extubation or a Pao to Fio ratio (Pao:Fio) > 300 on the first study day following enrollment. RESULTS:The prevalence of rapidly improving ARDS was 10.5% (458 of 4,361 patients) and increased over time. Of the 1,909 patients enrolled in the three most recently published trials, 197 (10.3%) were extubated on the first study day, and 265 (13.9%) in total had rapidly improving ARDS. Patients with rapidly improving ARDS had lower baseline severity of illness and lower 60-day mortality (10.2% vs 26.3%; P < .0001) than ARDS > 1 day. Pao:Fio at screening, change in Pao:Fio from screening to enrollment, use of vasopressor agents, Fio at enrollment, and serum bilirubin levels were useful predictive variables. CONCLUSIONS:Rapidly improving ARDS, mostly defined by early extubation, is an increasingly prevalent and distinct subphenotype, associated with better outcomes than ARDS > 1 day. Enrollment of patients with rapidly improving ARDS may negatively affect the prognostic enrichment and contribute to the failure of therapeutic trials. 10.1016/j.chest.2018.09.031
    Nucleated red blood cells as predictors of mortality in patients with acute respiratory distress syndrome (ARDS): an observational study. Menk Mario,Giebelhäuser Lena,Vorderwülbecke Gerald,Gassner Martina,Graw Jan A,Weiss Björn,Zimmermann Mathias,Wernecke Klaus-D,Weber-Carstens Steffen Annals of intensive care BACKGROUND:Nucleated red blood cells (NRBCs) in critically ill patients are associated with increased mortality and poor outcome. The aim of the present study was to evaluate the predictive value of NRBCs in patients with acute respiratory distress syndrome (ARDS). METHODS:This observational study was conducted at an ARDS referral center and included patients from 2007 to 2014. Daily NRBC counts were assessed and the predictive validity of NRBCs on mortality was statistically evaluated. A cutoff for prediction of mortality based on NRBCs was evaluated using ROC analysis and specified according to Youden's method. Multivariate nonparametric analysis for longitudinal data was applied to prove for differences between groups over the whole time course. Independent predictors of mortality were identified with multiple logistic and Cox' regression analyses. Kaplan-Meier estimations visualized the survival; the corresponding curves were tested for differences with the log-rank test. RESULTS:A total of 404 critically ill ARDS patients were analyzed. NRBCs were found in 75.5% of the patients, which was associated with longer length of ICU stay [22 (11; 39) vs. 14 (7; 26) days; p < 0.05] and higher mortality rates (50.8 vs. 27.3%; p < 0.001). Logistic regression analysis with mortality as response showed NRBC positivity per se to be an independent risk factor for mortality in ARDS with a doubled risk for ICU death (OR 2.03; 95% CI 1.16-3.55; p < 0.05). Also, NRBC value at ICU admission was found to be an independent risk factor for mortality (OR 3.25; 95% CI 1.09-9.73, p = 0.035). A cutoff level of 220 NRBC/µl was associated with a more than tripled risk of ICU death (OR 3.2; 95% CI 1.93-5.35; p < 0.0001). ARDS patients below this threshold level had a significant survival advantage (median survival 85 days vs. 29 days; log rank p < 0.001). Presence of a severe ARDS was identified as independent risk factor for the occurrence of NRBCs > 220/µl (OR 1.81; 95% CI 1.1-2.97; p < 0.05). CONCLUSIONS:NRBCs may predict mortality in ARDS with high prognostic power. The presence of NRBCs in the blood might be regarded as a marker of disease severity indicating a higher risk of ICU death. 10.1186/s13613-018-0387-5
    Management of Acute Respiratory Distress Syndrome and Refractory Hypoxemia. A Multicenter Observational Study. Duan Erick H,Adhikari Neill K J,D'Aragon Frederick,Cook Deborah J,Mehta Sangeeta,Alhazzani Waleed,Goligher Ewan,Charbonney Emmanuel,Arabi Yaseen M,Karachi Tim,Turgeon Alexis F,Hand Lori,Zhou Qi,Austin Peggy,Friedrich Jan,Lamontagne Francois,Lauzier François,Patel Rakesh,Muscedere John,Hall Richard,Aslanian Pierre,Piraino Thomas,Albert Martin,Bagshaw Sean M,Jacka Mike,Wood Gordon,Henderson William,Dorscheid Delbert,Ferguson Niall D,Meade Maureen O, Annals of the American Thoracic Society RATIONALE:Clinicians' current practice patterns in the management of acute respiratory distress syndrome (ARDS) and refractory hypoxemia are not well described. OBJECTIVES:To describe mechanical ventilation strategies and treatment adjuncts for adults with ARDS, including refractory hypoxemia. METHODS:This was a prospective cohort study (March 2014-February 2015) of mechanically ventilated adults with moderate-to-severe ARDS requiring an Fi of 0.50 or greater in 24 intensive care units. RESULTS:We enrolled 664 patients: 222 (33%) with moderate and 442 (67%) with severe ARDS. On Study Day 1, mean Vt was 7.5 (SD = 2.1) ml/kg predicted body weight (n = 625); 80% (n = 501) received Vt greater than 6 ml/kg. Mean positive end-expiratory pressure (PEEP) was 10.5 (3.7) cm HO (n = 653); 568 patients (87%) received PEEP less than 15 cm HO. Treatment adjuncts were common (n = 440, 66%): neuromuscular blockers (n = 276, 42%), pulmonary vasodilators (n = 118, 18%), prone positioning (n = 67, 10%), extracorporeal life support (n = 29, 4%), and high-frequency oscillatory ventilation (n = 29, 4%). Refractory hypoxemia, defined as Pa less than 60 mm Hg on Fi of 1.0, occurred in 138 (21%) patients. At onset of refractory hypoxemia, mean Vt was 7.1 (SD = 2.0) ml/kg (n = 124); 95 patients (77%) received Vt greater than 6 ml/kg. Mean PEEP was 12.1 (SD = 4.4) cm HO (n = 133); 99 patients (74%) received PEEP less than 15 cm HO. Among patients with refractory hypoxemia, 91% received treatment adjuncts (126/138), with increased use of neuromuscular blockers (n = 87, 63%), pulmonary vasodilators (n = 57, 41%), and prone positioning (n = 32, 23%). CONCLUSIONS:Patients with moderate-to-severe ARDS receive treatment adjuncts frequently, especially with refractory hypoxemia. Paradoxically, therapies with less evidence supporting their use (e.g., pulmonary vasodilators) were over-used, whereas those with more evidence (e.g., prone positioning, neuromuscular blockade) were under-used. Patients received higher Vts and lower PEEP than would be suggested by the evidence. 10.1513/AnnalsATS.201612-1042OC
    Effects of neuromuscular blockers on transpulmonary pressures in moderate to severe acute respiratory distress syndrome. Guervilly Christophe,Bisbal Magali,Forel Jean Marie,Mechati Malika,Lehingue Samuel,Bourenne Jeremy,Perrin Gilles,Rambaud Romain,Adda Melanie,Hraiech Sami,Marchi Elisa,Roch Antoine,Gainnier Marc,Papazian Laurent Intensive care medicine PURPOSE:To investigate whether neuromuscular blocking agents (NMBA) exert beneficial effects in acute respiratory distress syndrome (ARDS) by reason of their action on respiratory mechanics, particularly transpulmonary pressures (P ). METHODS:A prospective randomised controlled study in patients with moderate to severe ARDS within 48 h of the onset of ARDS. All patients were monitored by means of an oesophageal catheter and followed up for 48 h. Moderate ARDS patients were randomised into two groups according to whether they were given a 48-h continuous infusion of cisatracurium besylate or not (control group). Severe ARDS patients did not undergo randomisation and all received cisatracurium besylate per protocol. The changes during the 48-h study period in oxygenation and in respiratory mechanics, including inspiratory and expiratory P and driving pressure, were assessed and compared. Delta P (∆P ) was defined as inspiratory P minus expiratory P . RESULTS:Thirty patients were included, 24 with moderate ARDS and 6 with severe ARDS. NMBA infusion was associated with an improvement in oxygenation in both moderate and severe ARDS, accompanied by a decrease in both plateau pressure and total positive end-expiratory pressure. The mean inspiratory and expiratory P were higher in the moderate ARDS group receiving NMBA than in the control group. In contrast, there was no change in either driving pressure or ∆P related to NMBA administration. CONCLUSIONS:NMBA could exert beneficial effects in patients with moderate ARDS, at least in part, by limiting expiratory efforts. 10.1007/s00134-016-4653-4
    External validation of a biomarker and clinical prediction model for hospital mortality in acute respiratory distress syndrome. Zhao Zhiguo,Wickersham Nancy,Kangelaris Kirsten N,May Addison K,Bernard Gordon R,Matthay Michael A,Calfee Carolyn S,Koyama Tatsuki,Ware Lorraine B Intensive care medicine PURPOSE:Mortality prediction in ARDS is important for prognostication and risk stratification. However, no prediction models have been independently validated. A combination of two biomarkers with age and APACHE III was superior in predicting mortality in the NHLBI ARDSNet ALVEOLI trial. We validated this prediction tool in two clinical trials and an observational cohort. METHODS:The validation cohorts included 849 patients from the NHLBI ARDSNet Fluid and Catheter Treatment Trial (FACTT), 144 patients from a clinical trial of sivelestat for ARDS (STRIVE), and 545 ARDS patients from the VALID observational cohort study. To evaluate the performance of the prediction model, the area under the receiver operating characteristic curve (AUC), model discrimination, and calibration were assessed, and recalibration methods were applied. RESULTS:The biomarker/clinical prediction model performed well in all cohorts. Performance was better in the clinical trials with an AUC of 0.74 (95% CI 0.70-0.79) in FACTT, compared to 0.72 (95% CI 0.67-0.77) in VALID, a more heterogeneous observational cohort. The AUC was 0.73 (95% CI 0.70-0.76) when FACTT and VALID were combined. CONCLUSION:We validated a mortality prediction model for ARDS that includes age, APACHE III, surfactant protein D, and interleukin-8 in a variety of clinical settings. Although the model performance as measured by AUC was lower than in the original model derivation cohort, the biomarker/clinical model still performed well and may be useful for risk assessment for clinical trial enrollment, an issue of increasing importance as ARDS mortality declines, and better methods are needed for selection of the most severely ill patients for inclusion. 10.1007/s00134-017-4854-5
    Pulmonary Mechanics and Mortality in Mechanically Ventilated Patients Without Acute Respiratory Distress Syndrome: A Cohort Study. Fuller Brian M,Page David,Stephens Robert J,Roberts Brian W,Drewry Anne M,Ablordeppey Enyo,Mohr Nicholas M,Kollef Marin H Shock (Augusta, Ga.) BACKGROUND:Driving pressure has been proposed as a major determinant of outcome in patients with acute respiratory distress syndrome (ARDS), but there is little data examining the association between pulmonary mechanics, including driving pressure, and outcomes in mechanically ventilated patients without ARDS. METHODS:Secondary analysis from 1,705 mechanically ventilated patients enrolled in a clinical study that examined outcomes associated with the use of early lung-protective mechanical ventilation. The primary outcome was mortality and the secondary outcome was the incidence of ARDS. Multivariable models were constructed to: define the association between pulmonary mechanics (driving pressure, plateau pressure, and compliance) and mortality; and evaluate if driving pressure contributed information beyond that provided by other pulmonary mechanics. RESULTS:The mortality rate for the entire cohort was 26.0%. Compared with survivors, non-survivors had significantly higher driving pressure [15.9 (5.4) vs. 14.9 (4.4), P = 0.005] and plateau pressure [21.4 (5.7) vs. 20.4 (4.6), P = 0.001]. Driving pressure was independently associated with mortality [adjusted OR, 1.04 (1.01-1.07)]. Models related to plateau pressure also revealed an independent association with mortality, with similar effect size and interval estimates as driving pressure. There were 152 patients who progressed to ARDS (8.9%). Along with driving pressure and plateau pressure, mechanical power [adjusted OR, 1.03 (1.00-1.06)] was also independently associated with ARDS development. CONCLUSIONS:In mechanically ventilated patients, driving pressure and plateau pressure are risk factors for mortality and ARDS, and provide similar information. Mechanical power is also a risk factor for ARDS. 10.1097/SHK.0000000000000977
    Acute respiratory distress syndrome in mechanically ventilated patients with community-acquired pneumonia. Cilloniz Catia,Ferrer Miquel,Liapikou Adamanthia,Garcia-Vidal Carolina,Gabarrus Albert,Ceccato Adrian,Puig de La Bellacasa Jorge,Blasi Francesco,Torres Antoni The European respiratory journal Our aim was to assess the incidence, characteristics, aetiology, risk factors and mortality of acute respiratory distress syndrome (ARDS) in intensive care unit (ICU) patients with community-acquired pneumonia (CAP) using the Berlin definition.We prospectively enrolled consecutive mechanically ventilated adult ICU patients with CAP over 20 years, and compared them with mechanically ventilated patients without ARDS. The main outcome was 30-day mortality.Among 5334 patients hospitalised with CAP, 930 (17%) were admitted to the ICU and 432 required mechanical ventilation; 125 (29%) cases met the Berlin ARDS criteria. ARDS was present in 2% of hospitalised patients and 13% of ICU patients. Based on the baseline arterial oxygen tension/inspiratory oxygen fraction ratio, 60 (48%), 49 (40%) and 15 (12%) patients had mild, moderate and severe ARDS, respectively. was the most frequent pathogen, with no significant differences in aetiology between groups. Higher organ system dysfunction and previous antibiotic use were independent risk factors for ARDS in the multivariate analysis, while previous inhaled corticosteroids were independently associated with a lower risk. The 30-day mortality was similar between patients with and without ARDS (25% 30%, p=0.25), confirmed by propensity-adjusted multivariate analysis.ARDS occurs as a complication of CAP in 29% of mechanically ventilated patients, but is not related to the aetiology or mortality. 10.1183/13993003.02215-2017
    Monitoring of vascular endothelial growth factor and its soluble receptor levels in early trauma. Guo Jianying,Yan Wenwen,Yang Yong,Wang Zhiyong,Tian Fengjun The journal of trauma and acute care surgery BACKGROUND:This clinical observation study aimed to investigate the relationship between the serum levels of vascular endothelial growth factor (VEGF) and its soluble receptors with the severity and the occurrence of late acute respiratory distress syndrome (ARDS) in early trauma. METHODS:Sixty patients with multiple injuries were divided into three groups according to the Injury Severity Score (ISS) and the serum levels of VEGF, soluble VEGF receptor 1 (sVEGFR1), and sVEGFR2, were measured. Ten healthy people were recruited as controls. The incidence of late ARDS was also monitored, and its relationship to the above measures analyzed. RESULTS:VEGF was not associated with ISS (p > 0.05); sVEGFR1 was positively associated with ISS (r = 0.459, p < 0.0001); however, sVEGFR2 was negatively associated with ISS (r = 0.510, p < 0.0001). The serum VEGF levels between the ARDS group and the non-ARDS group showed no significant difference (p > 0.05). sVEGFR1 in the ARDS group was significantly higher than that in the non-ARDS group (p < 0.0001), and sVEGFR2 in the ARDS group was significantly lower than that in the non-ARDS group (p < 0.0001). CONCLUSION:In conclusion, the increasing of sVEGFR1 and the decreasing of sVEGFR2 in early trauma might be closely related to the occurrence of late ARDS. LEVEL OF EVIDENCE:Prognostic study, level III. 10.1097/TA.0000000000001373
    Plasma Neutrophil Elastase and Elafin as Prognostic Biomarker for Acute Respiratory Distress Syndrome: A Multicenter Survival and Longitudinal Prospective Observation Study. Wang Tiehua,Zhu Zhaozhong,Liu Zhuang,Yi Liang,Yang Zhixu,Bian Weishuai,Chen Wei,Wang Shupeng,Li Gang,Li Ang,Martin Greg S,Zhu Xi Shock (Augusta, Ga.) BACKGROUND:Neutrophil elastase (HNE) is a destructive enzyme and plays crucial roles in the pathophysiology of acute respiratory distress syndrome (ARDS). Endogenous proteinase inhibitors elafin (PI3) is important to protect against lung tissue destruction. We proposed to examine whether HNE and PI3 serve as prognostic biomarkers for ARDS. METHODS:This study is a survival and longitudinal analysis of plasma profiles of HNE and PI3 in ARDS patients from a multicenter prospective observational cohort in Beijing, China. Plasma samples were collected on day-1, day-3, and day-7 of study enrollment. RESULTS:HNE levels were higher in ARDS non-survivors than survivors, whereas PI3 showed opposite direction for all three measurements (P < 0.01 for all). Patients with HNE level above median and PI3 level below median values had the lowest survival probability and died the fastest. There was a significant longitudinal effect of HNE levels and PI3 level on mortality. Receiver-operating characteristic analysis demonstrated combination of HNE and PI3 had the discrimination ability for 28-day mortality (area under the receiver-operating characteristic curve [AUC]: 0.76), better than the combination of Berlin categories and APACHE II (AUC: 0.63). The addition of HNE and PI3 to Berlin categories and APACHE II has significantly improved the prognostic discrimination ability (AUC: 0.81, P < 0.0001). CONCLUSIONS:Imbalance between HNE and PI3 levels in ARDS patients was associated with ARDS mortality. By combining these biomarkers with Berlin categories and APACHE II, prognostic power of ARDS was greatly improved. Circulation levels of HNE and PI3 may have the potential to predict ARDS mortality and better inform clinicians about ARDS mortality risk. 10.1097/SHK.0000000000000845
    Extracellular histones are clinically relevant mediators in the pathogenesis of acute respiratory distress syndrome. Lv Xin,Wen Tao,Song Jiong,Xie Dong,Wu Liang,Jiang Xuemei,Jiang Ping,Wen Zongmei Respiratory research BACKGROUND:Extracellular histones were recently identified as an inflammatory mediator involved in the pathogenesis of various organ injuries. This study aimed to examine extracellular histone levels and their clinical implications in acute respiratory distress syndrome (ARDS) patients and to explore histone-mediated effects through ex-vivo investigations. METHODS:Extracellular histones, cytokine profiles and clinical data from 96 ARDS patients and 30 healthy volunteers were obtained. Human bronchial epithelial cells (BEAS-2B), human pulmonary artery endothelial cells (HPAEC), and human monocytic U937 cells were exposed to bronchoalveolar lavage fluid (BALF) collected from ARDS patients, and cellular damage and cytokine production were assessed. Furthermore, the effect of histone-targeted interventions by heparin or anti-histone antibody was evaluated. RESULTS:Plasma and BALF extracellular histone levels were much higher in ARDS patients than in healthy controls. There was a significant association between extracellular histones and ARDS severity and mortality. In addition, extracellular histones correlated with an evident systemic inflammation detected in ARDS patients. Ex-vivo analysis further showed that ARDS patient's BALF remarkably induced epithelial and endothelial cell damage and stimulated cytokine production in the supernatant of U937 cells. The adverse effects on these cells could be abrogated by heparin or anti-histone antibody. CONCLUSIONS:Extracellular histones in ARDS patients are excessively increased and may contribute to disease aggravation by inducing cellular damage and promoting systemic inflammation. Targeting extracellular histones may provide a promising approach for treating ARDS. 10.1186/s12931-017-0651-5
    Severity scoring of lung oedema on the chest radiograph is associated with clinical outcomes in ARDS. Warren Melissa A,Zhao Zhiguou,Koyama Tatsuki,Bastarache Julie A,Shaver Ciara M,Semler Matthew W,Rice Todd W,Matthay Michael A,Calfee Carolyn S,Ware Lorraine B Thorax BACKGROUND:There is no accurate, non-invasive measurement to estimate the degree of pulmonary oedema in acute respiratory distress syndrome (ARDS). We developed the Radiographic Assessment of Lung Oedema (RALE) score to evaluate the extent and density of alveolar opacities on chest radiographs. After first comparing the RALE score to gravimetric assessment of pulmonary oedema in organ donors, we then evaluated the RALE score in patients with ARDS for its relationship to oxygenation and clinical outcomes. METHODS:We compared radiographs with excised lung weights from 72 organ donors (derivation cohort) and radiographs with clinical data from 174 patients with ARDS in the ARDSNet Fluid and Catheter Treatment Trial (validation cohort). To calculate RALE, each radiographic quadrant was scored for extent of consolidation (0-4) and density of opacification (1-3). The product of the consolidation and density scores for each of the four quadrants was summed (maximum score=48). RESULTS:Agreement between two independent reviewers for RALE score was excellent (intraclass correlation coefficient=0.93, 95% CI 0.91 to 0.95). In donors, pre-procurement RALE score correlated with height-adjusted total lung weight (ρ=0.59, p<0.001). In patients with ARDS, higher RALE scores were independently associated with lower PaO/fractional inspired oxygen and worse survival. Conservative fluid management significantly decreased RALE score over 3 days compared with liberal fluid management. CONCLUSIONS:The RALE score can be used to assess both the extent of pulmonary oedema and the severity of ARDS, by utilising information that is already obtained routinely, safely and inexpensively in every patient with ARDS. This novel non-invasive measure should be useful for assessing ARDS severity and monitoring response to therapy. 10.1136/thoraxjnl-2017-211280
    The diagnostic accuracy for ARDS of global versus regional lung ultrasound scores - a post hoc analysis of an observational study in invasively ventilated ICU patients. Pisani Luigi,Vercesi Veronica,van Tongeren Patricia S I,Lagrand Wim K,Leopold Stije J,Huson Mischa A M,Henwood Patricia C,Walden Andrew,Smit Marry R,Riviello Elisabeth D,Pelosi Paolo,Dondorp Arjen M,Schultz Marcus J, Intensive care medicine experimental BACKGROUND:Semi-quantification of lung aeration by ultrasound helps to assess presence and extent of pulmonary pathologies, including the acute respiratory distress syndrome (ARDS). It is uncertain which lung regions add most to the diagnostic accuracy for ARDS of the frequently used global lung ultrasound (LUS) score. We aimed to compare the diagnostic accuracy of the global versus those of regional LUS scores in invasively ventilated intensive care unit patients. METHODS:This was a post-hoc analysis of a single-center observational study in the mixed medical-surgical intensive care unit of a university-affiliated hospital in the Netherlands. Consecutive patients, aged ≥ 18 years, and are expected to receive invasive ventilation for > 24 h underwent a LUS examination within the first 2 days of ventilation. The Berlin Definition was used to diagnose ARDS, and to classify ARDS severity. From the 12-region LUS examinations, the global score (minimum 0 to maximum 36) and 3 regional scores (the 'anterior,' 'lateral,' and 'posterior' score, minimum 0 to maximum 12) were computed. The area under the receiver operating characteristic (AUROC) curve was calculated and the best cutoff for ARDS discrimination was determined for all scores. RESULTS:The study enrolled 152 patients; 35 patients had ARDS. The global score was higher in patients with ARDS compared to patients without ARDS (median 19 [15-23] vs. 5 [3-9]; P < 0.001). The posterior score was the main contributor to the global score, and was the only score that increased significantly with ARDS severity. However, the posterior score performed worse than the global score in diagnosing ARDS, and it had a positive predictive value of only 50 (41-59)% when using the optimal cutoff. The combined anterolateral score performed as good as the global score (AUROC of 0.91 [0.85-0.97] vs. 0.91 [0.86-0.95]). CONCLUSIONS:While the posterior score increases with ARDS severity, its diagnostic accuracy for ARDS is hampered due to an unfavorable signal-to-noise ratio. An 8-region 'anterolateral' score performs as well as the global score and may prove useful to exclude ARDS in invasively ventilated ICU patients. 10.1186/s40635-019-0241-6
    Receptor for advanced glycation end-products and ARDS prediction: a multicentre observational study. Jabaudon Matthieu,Berthelin Pauline,Pranal Thibaut,Roszyk Laurence,Godet Thomas,Faure Jean-Sébastien,Chabanne Russell,Eisenmann Nathanael,Lautrette Alexandre,Belville Corinne,Blondonnet Raiko,Cayot Sophie,Gillart Thierry,Pascal Julien,Skrzypczak Yvan,Souweine Bertrand,Blanchon Loic,Sapin Vincent,Pereira Bruno,Constantin Jean-Michel Scientific reports Acute respiratory distress syndrome (ARDS) prediction remains challenging despite available clinical scores. To assess soluble receptor for advanced glycation end-products (sRAGE), a marker of lung epithelial injury, as a predictor of ARDS in a high-risk population, adult patients with at least one ARDS risk factor upon admission to participating intensive care units (ICUs) were enrolled in a multicentre, prospective study between June 2014 and January 2015. Plasma sRAGE and endogenous secretory RAGE (esRAGE) were measured at baseline (ICU admission) and 24 hours later (day one). Four AGER candidate single nucleotide polymorphisms (SNPs) were also assayed because of previous reports of functionality (rs1800625, rs1800624, rs3134940, and rs2070600). The primary outcome was ARDS development within seven days. Of 500 patients enrolled, 464 patients were analysed, and 59 developed ARDS by day seven. Higher baseline and day one plasma sRAGE, but not esRAGE, were independently associated with increased ARDS risk. AGER SNP rs2070600 (Ser/Ser) was associated with increased ARDS risk and higher plasma sRAGE in this cohort, although confirmatory studies are needed to assess the role of AGER SNPs in ARDS prediction. These findings suggest that among at-risk ICU patients, higher plasma sRAGE may identify those who are more likely to develop ARDS. 10.1038/s41598-018-20994-x
    Edaravone attenuates lipopolysaccharide-induced acute respiratory distress syndrome associated early pulmonary fibrosis via amelioration of oxidative stress and transforming growth factor-β1/Smad3 signaling. Wang Xida,Lai Rongde,Su Xiangfen,Chen Guibin,Liang Zijing Biochemical and biophysical research communications Pulmonary fibrosis is responsible for the both short-term and long-term outcomes in patients with acute respiratory distress syndrome (ARDS). There is still no effective cure to improve prognosis. The purpose of this study was to investigate whether edaravone, a free radical scavenger, have anti-fibrosis effects in the rat model of ARDS associated early pulmonary fibrosis by lipopolysaccharide (LPS) administration. Rats were subjected to intravenous injection of LPS, and edaravone was given intraperitoneally after LPS administration daily for 7 consecutive days. LPS treatment rapidly increased lung histopathology abnormalities, coefficient of lung, hydroxyproline and collagen I levels, stimulated myofibroblast differentiation and induced expression of TGF-β1 and activation of TGF-β1/Smad3 signaling as early as day 7 after LPS injection. Moreover, LPS intoxication significantly increased the contents of malondialdehyde (MDA), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), whereas it dramatically decreased superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) activities from day 1 after LPS treatment. On the contrary, edaravone treatment ameliorated LPS-induced myofibroblast differentiation and pulmonary fibrosis, simultaneously, and attenuated LPS-stimulated oxidative stress and activation of TGF-β1/Smad3 signaling. Collectively, edaravone may attenuate ARDS associated early pulmonary fibrosis through amelioration of oxidative stress and TGF-β1/Smad3 signaling pathway. Edaravone may be a promising drug candidate for the treatment of ARDS-related pulmonary fibrosis in early period. 10.1016/j.bbrc.2017.10.165
    Acute Respiratory Distress Syndrome: Advances in Diagnosis and Treatment. Fan Eddy,Brodie Daniel,Slutsky Arthur S JAMA Importance:Acute respiratory distress syndrome (ARDS) is a life-threatening form of respiratory failure that affects approximately 200 000 patients each year in the United States, resulting in nearly 75 000 deaths annually. Globally, ARDS accounts for 10% of intensive care unit admissions, representing more than 3 million patients with ARDS annually. Objective:To review advances in diagnosis and treatment of ARDS over the last 5 years. Evidence Review:We searched MEDLINE, EMBASE, and the Cochrane Database of Systematic Reviews from 2012 to 2017 focusing on randomized clinical trials, meta-analyses, systematic reviews, and clinical practice guidelines. Articles were identified for full text review with manual review of bibliographies generating additional references. Findings:After screening 1662 citations, 31 articles detailing major advances in the diagnosis or treatment of ARDS were selected. The Berlin definition proposed 3 categories of ARDS based on the severity of hypoxemia: mild (200 mm Hg<Pao2/Fio2≤300 mm Hg), moderate (100 mm Hg<Pao2/Fio2≤200 mm Hg), and severe (Pao2/Fio2 ≤100 mm Hg), along with explicit criteria related to timing of the syndrome's onset, origin of edema, and the chest radiograph findings. The Berlin definition has significantly greater predictive validity for mortality than the prior American-European Consensus Conference definition. Clinician interpretation of the origin of edema and chest radiograph criteria may be less reliable in making a diagnosis of ARDS. The cornerstone of management remains mechanical ventilation, with a goal to minimize ventilator-induced lung injury (VILI). Aspirin was not effective in preventing ARDS in patients at high-risk for the syndrome. Adjunctive interventions to further minimize VILI, such as prone positioning in patients with a Pao2/Fio2 ratio less than 150 mm Hg, were associated with a significant mortality benefit whereas others (eg, extracorporeal carbon dioxide removal) remain experimental. Pharmacologic therapies such as β2 agonists, statins, and keratinocyte growth factor, which targeted pathophysiologic alterations in ARDS, were not beneficial and demonstrated possible harm. Recent guidelines on mechanical ventilation in ARDS provide evidence-based recommendations related to 6 interventions, including low tidal volume and inspiratory pressure ventilation, prone positioning, high-frequency oscillatory ventilation, higher vs lower positive end-expiratory pressure, lung recruitment maneuvers, and extracorporeal membrane oxygenation. Conclusions and Relevance:The Berlin definition of acute respiratory distress syndrome addressed limitations of the American-European Consensus Conference definition, but poor reliability of some criteria may contribute to underrecognition by clinicians. No pharmacologic treatments aimed at the underlying pathology have been shown to be effective, and management remains supportive with lung-protective mechanical ventilation. Guidelines on mechanical ventilation in patients with acute respiratory distress syndrome can assist clinicians in delivering evidence-based interventions that may lead to improved outcomes. 10.1001/jama.2017.21907
    The preventive effect of antiplatelet therapy in acute respiratory distress syndrome: a meta-analysis. Wang Yingqin,Zhong Ming,Wang Zhichao,Song Jieqiong,Wu Wei,Zhu Duming Critical care (London, England) BACKGROUND:Acute respiratory distress syndrome (ARDS) is a life-threatening condition with high mortality that imposes a serious medical burden. Antiplatelet therapy is a potential strategy for preventing ARDS in patients with a high risk of developing this condition. A meta-analysis was performed to investigate whether antiplatelet therapy could reduce the incidence of newly developed ARDS and its associated mortality in high-risk patients. METHODS:The Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, Embase, Medline, and the Web of Science were searched for published studies from inception to 26 October 2017. We included randomized clinical trials, cohort studies and case-control studies investigating antiplatelet therapy in adult patients presenting to the hospital or ICU with a high risk for ARDS. Baseline patient characteristics, interventions, controls and outcomes were extracted. Our primary outcome was the incidence of newly developed ARDS in high-risk patients. Secondary outcomes were hospital and ICU mortality. A random-effects or fixed-effects model was used for quantitative synthesis. RESULTS:We identified nine eligible studies including 7660 high-risk patients who received antiplatelet therapy. Based on seven observational studies, antiplatelet therapy was associated with a decreased incidence of ARDS (odds ratio (OR) 0.68, 95% confidence interval (CI) 0.52-0.88; I = 68.4%, p = 0.004). In two randomized studies, no significant difference was found in newly developed ARDS between the antiplatelet groups and placebo groups (OR 1.32, 95% CI 0.72-2.42; I = 0.0%, p = 0.329). Antiplatelet therapy did not reduce hospital mortality in randomized studies (OR 1.15, 95% CI 0.58-2.27; I = 0.0%; p = 0.440) or observational studies (OR 0.80, 95% CI 0.62-1.03; I = 31.9%, p = 0.221). CONCLUSIONS:Antiplatelet therapy did not significantly decrease hospital mortality in high-risk patients. However, whether antiplatelet therapy is associated with a decreased incidence of ARDS in patients at a high risk of developing the condition remains unclear. 10.1186/s13054-018-1988-y
    Moderate and Severe Acute Respiratory Distress Syndrome: Hemodynamic and Cardiac Effects of an Open Lung Strategy With Recruitment Maneuver Analyzed Using Echocardiography. Mercado Pablo,Maizel Julien,Kontar Loay,Nalos Marek,Huang Stephen,Orde Sam,McLean Anthony,Slama Michel Critical care medicine OBJECTIVES:Open lung ventilation with a recruitment maneuver could be beneficial for acute respiratory distress syndrome patients. However, the increased airway pressures resulting from the recruitment maneuver may induce cardiac dysfunction, limiting the benefit of this maneuver. We analyzed the effect of a recruitment maneuver and decremental positive end-expiratory pressure titration on cardiac function. SETTINGS:Medical ICU Amiens, France. PATIENTS:Twenty patients with moderate to severe acute respiratory distress syndrome INTERVENTIONS:: Patients underwent a stepwise recruitment maneuver with respiratory evaluation and echocardiography assessment of cardiac function including longitudinal strain at baseline, peak positive end-expiratory pressure of recruitment maneuver (positive end-expiratory pressure 40 cm H2O), and at "optimal" positive end-expiratory pressure. The patients were divided into two groups based on change on the PaO2/FIO2 ratio (nonresponders < 50%; responders ≥ 50%). MEASUREMENTS AND MAIN RESULTS:At peak positive end-expiratory pressure during the recruitment maneuver, the arterial pressure, cardiac output, left ventricular size decreased and right ventricular size increased. The left ventricular ejection fraction decreased from 60% ± 13% to 48% ± 18% (p = 0.05). Both left and right ventricular global longitudinal strain were impaired (-15.8% ± 4.5% to -11% ± 4.7% and -19% ± 5% to -14% ± 6% [p = 0.05] respectively). Fifty percent of patients were nonresponders and demonstrated a lower hemodynamic tolerance to the recruitment maneuver than responders. Optimal positive end-expiratory pressure was 14 ± 5 cm H2O (vs 11 ± 4 cm H2O at baseline), and PaO2/FIO2 ratio increased from 111 ± 25 to 197 ± 89 mm Hg (p < 0.0001). All hemodynamic variables returned to their baseline value after the recruitment maneuver despite a higher positive end-expiratory pressure. CONCLUSIONS:An open lung strategy with a stepwise recruitment maneuver permitted a higher positive end-expiratory pressure and improved oxygenation without any cardiac impairment. The recruitment maneuver was associated with mild and transient, cardiac dysfunction, with nonresponders demonstrating poorer tolerance. 10.1097/CCM.0000000000003287
    Prehospital aspirin use is associated with reduced risk of acute respiratory distress syndrome in critically ill patients: a propensity-adjusted analysis. Chen Wei,Janz David R,Bastarache Julie A,May Addison K,O'Neal Hollis R,Bernard Gordon R,Ware Lorraine B Critical care medicine OBJECTIVES:Platelet activation plays an active role in the pathogenesis of acute respiratory distress syndrome. In our prior study of 575 patients at high risk for acute respiratory distress syndrome, concurrent statin and aspirin use was associated with reduced acute respiratory distress syndrome. However, the largest study (n = 3,855) to date found no significant benefit of prehospital aspirin in a lower-risk population when adjusted for the propensity for aspirin use. We aimed to determine whether prehospital aspirin use is associated with decreased acute respiratory distress syndrome in patients at high risk for acute respiratory distress syndrome after adjusting for the propensity to receive aspirin. DESIGN:Secondary analysis of patients enrolled prospectively in the Validating Acute Lung Injury Markers for Diagnosis study. PATIENTS:A total of 1,149 critically ill patients (≥40 years old) admitted to the medical or surgical ICUs of an academic tertiary care hospital including 575 previously reported patients as well as additional patients who were enrolled after completion of the prior statin and aspirin study. INTERVENTION:None. MEASUREMENTS AND RESULTS:Of 1,149 patients, 368 (32%) developed acute respiratory distress syndrome during the first 4 ICU days and 287 (25%) patients had prehospital aspirin use. Patients with prehospital aspirin had significantly lower prevalence of acute respiratory distress syndrome (27% vs 34%; p=0.034). In a multivariable, propensity-adjusted analysis including age, gender, race, sepsis, and Acute Physiology and Chronic Health Evaluation score II, prehospital aspirin use was associated with a decreased risk of acute respiratory distress syndrome (odds ratio, 0.66; 95% CI, 0.46-0.94) in the entire cohort and in a subgroup of 725 patients with sepsis (odds ratio, 0.60; 95% CI, 0.41-0.90). CONCLUSIONS:In this selected cohort of critically ill patients, prehospital aspirin use was independently associated with a decreased risk of acute respiratory distress syndrome even after adjusting for the propensity of prehospital aspirin use. These findings support the need for prospective clinical trials to determine whether aspirin may be beneficial for the prevention of clinical acute respiratory distress syndrome. 10.1097/CCM.0000000000000789
    Acute Respiratory Distress Syndrome Neutrophils Have a Distinct Phenotype and Are Resistant to Phosphoinositide 3-Kinase Inhibition. Juss Jatinder K,House David,Amour Augustin,Begg Malcolm,Herre Jurgen,Storisteanu Daniel M L,Hoenderdos Kim,Bradley Glyn,Lennon Mark,Summers Charlotte,Hessel Edith M,Condliffe Alison,Chilvers Edwin R American journal of respiratory and critical care medicine RATIONALE:Acute respiratory distress syndrome is refractory to pharmacological intervention. Inappropriate activation of alveolar neutrophils is believed to underpin this disease's complex pathophysiology, yet these cells have been little studied. OBJECTIVES:To examine the functional and transcriptional profiles of patient blood and alveolar neutrophils compared with healthy volunteer cells, and to define their sensitivity to phosphoinositide 3-kinase inhibition. METHODS:Twenty-three ventilated patients underwent bronchoalveolar lavage. Alveolar and blood neutrophil apoptosis, phagocytosis, and adhesion molecules were quantified by flow cytometry, and oxidase responses were quantified by chemiluminescence. Cytokine and transcriptional profiling were used in multiplex and GeneChip arrays. MEASUREMENTS AND MAIN RESULTS:Patient blood and alveolar neutrophils were distinct from healthy circulating cells, with increased CD11b and reduced CD62L expression, delayed constitutive apoptosis, and primed oxidase responses. Incubating control cells with disease bronchoalveolar lavage recapitulated the aberrant functional phenotype, and this could be reversed by phosphoinositide 3-kinase inhibitors. In contrast, the prosurvival phenotype of patient cells was resistant to phosphoinositide 3-kinase inhibition. RNA transcriptomic analysis revealed modified immune, cytoskeletal, and cell death pathways in patient cells, aligning closely to sepsis and burns datasets but not to phosphoinositide 3-kinase signatures. CONCLUSIONS:Acute respiratory distress syndrome blood and alveolar neutrophils display a distinct primed prosurvival profile and transcriptional signature. The enhanced respiratory burst was phosphoinositide 3-kinase-dependent but delayed apoptosis and the altered transcriptional profile were not. These unexpected findings cast doubt over the utility of phosphoinositide 3-kinase inhibition in acute respiratory distress syndrome and highlight the importance of evaluating novel therapeutic strategies in patient-derived cells. 10.1164/rccm.201509-1818OC
    MMI-0100 ameliorates lung inflammation in a mouse model of acute respiratory distress syndrome by reducing endothelial expression of ICAM-1. He Binchan,Geng Shen,Zhou Wei,Rui Yuwen,Mu Xianmin,Zhang Chen,You Qiang,Su Xin Drug design, development and therapy Purpose:ICAM-1 plays a critical role in the development of acute respiratory distress syndrome (ARDS). MK2 regulates the expression of ICAM-1 in human pulmonary microvascular endothelial cells. To explore whether the inhibition of MK2 activation has the same effect in experimental animals, MMI-0100, a peptide-mediated inhibitor of MK2, was used to verify whether MMI-0100 can ameliorate lung inflammation in a mouse model of ARDS by reducing endothelial expression of ICAM-1. Methods:In this study, C57BL/6 mice were randomly divided into three groups: a control group, an lipopolysaccharides (LPS) group, and an LPS plus MMI-0100 group. Mice were killed 24 hours after the administration of LPS and MMI-0100. The mouse lung tissue histopathology, wet/dry weight ratio (W/D), and the neutrophil count were used to measure the severity of lung inflammation in mice. The pulmonary microvascular endothelial cells (PMVECs) of the mice were isolated. The mRNA expression of ICAM-1 in mouse PMVECs was determined using RT-PCR, and the protein expression of MK2 and ICAM-1 in mouse PMVECs was analyzed using Western blotting and immunohistochemistry. Results:We found that the level of phosphorylated MK2 in the LPS plus MMI-0100 group was reduced. Compared with the LPS group, the LPS plus MMI-0100 group of mice showed less severe inflammation, including a lower W/D and neutrophil count. The mRNA and protein expression of ICAM-1 in the LPS group was significantly higher than in the control group in mouse PMVECs, and the ICAM-1 level was reduced after the administration of MMI-0100. Conclusion:These data indicate that MMI-0100 ameliorates lung inflammation in a mouse model of ARDS by reducing endothelial expression of ICAM-1. 10.2147/DDDT.S188095
    Embelia ribes ameliorates lipopolysaccharide-induced acute respiratory distress syndrome. Shirole R L,Shirole N L,Saraf M N Journal of ethnopharmacology ETHNOPHARMACOLOGICAL RELEVANCE:Embelia ribes Burm. f. (Fam. Myrsinaceae) locally known as Vidanga have been used for treating tumors, ascites, bronchitis, jaundice, diseases of the heart and brain in traditional Indian medicine. However, no scientific studies providing new insights in its pharmacological properties with respect to acute respiratory distress syndrome have been investigated. AIM:The present investigation aimed to elucidate the effectiveness of Embelin isolated from Embelia ribes seeds on attenuation of LPS-induced acute respiratory distress syndrome in murine models. METHODS:Embelin (5, 10 and 20 mg/kg/day, i.p.) and Roflumilast (1 mg/kg/day, p.o.) were administered for four days and prior to LPS in rats (i.t.). Four hour after LPS challenge animals were anesthesized and bronchoalveolar lavage was done with ice-cold phosphate buffer. Assessment of BAL fluid was done for albumin, total protein, total cell and neutrophil count, TNF-α levels, nitrosoative stress. Superior lobe of right lung was used for histopathologic evaluation. Inferior lobe of right lung was used to obtain lung edema. Left lung was used for myeloperoxidase estimation. Arterial blood was collected immediately and analyzed for pH, pO2 and pCO2 were estimated. RESULTS:Pretreatment with embelin (5, 10 and 20 mg/kg, i.p.) decreased lung edema, mononucleated cellular infiltration, nitrate/nitrite, total protein, albumin concentrations, TNF-α in the bronchoalveolar lavage fluid and myeloperoxidase activity in lung homogenate. Embelin markedly prevented pO2 down-regulation and pCO2 augmentation. Additionally, it attenuated lung histopathological changes in acute respiratory distress syndrome model. CONCLUSION:The study demonstrates the effectiveness of Embelia ribes Burm. f. (Fam. Myrsinaceae) seeds in acute respiratory distress syndrome possibly related to its anti-inflammatory and protective effect against LPS induced airway inflammation by reducing nitrosative stress, reducing physiological parameters of blood gas change, TNF-α and mononucleated cellular infiltration indicating it as a potential therapeutic agent for acute respiratory distress syndrome. 10.1016/j.jep.2015.03.009
    Interleukin-17A Is Associated With Alveolar Inflammation and Poor Outcomes in Acute Respiratory Distress Syndrome. Mikacenic Carmen,Hansen Elizabeth E,Radella Frank,Gharib Sina A,Stapleton Renee D,Wurfel Mark M Critical care medicine OBJECTIVE:Interleukin-17A is a proinflammatory cytokine known to play a role in host defense and pathologic inflammation in murine models of lung injury. The relationship between interleukin-17A and inflammation in human lung injury is unknown. Our primary objective was to determine whether interleukin-17A levels are associated with alveolar measures of inflammation and injury in patients with acute respiratory distress syndrome. Our secondary objective was to test whether interleukin-17A levels are associated with acute respiratory distress syndrome-related outcomes. DESIGN:Observational study. SETTING:Six North American medical centers. PATIENTS:We studied two groups of patients with acute respiratory distress syndrome: 1) patients previously enrolled in a placebo-controlled clinical trial of omega-3 fatty acids performed at five North American medical centers (n = 86, acute respiratory distress syndrome 1), and 2) patients with systemic inflammatory response syndrome admitted to an ICU who developed acute respiratory distress syndrome (n = 140, acute respiratory distress syndrome 2). In acute respiratory distress syndrome 1, we used paired serum and bronchoalveolar lavage fluid samples obtained within 48 hours of acute respiratory distress syndrome onset, whereas in acute respiratory distress syndrome 2, we used plasma obtained within the first 24 hours of ICU admission. INTERVENTIONS:None. MEASUREMENTS AND MAIN RESULTS:We measured circulating interleukin-17A in acute respiratory distress syndrome 1 and acute respiratory distress syndrome 2. We also measured interleukin-17A, neutrophil counts, and total protein in bronchoalveolar lavage fluid from acute respiratory distress syndrome 1. We found that bronchoalveolar lavage interleukin-17A was strongly associated with higher bronchoalveolar lavage percent neutrophils (p < 0.001) and bronchoalveolar lavage total protein (p < 0.01) in acute respiratory distress syndrome1. In both acute respiratory distress syndrome 1 and acute respiratory distress syndrome 2, elevated interleukin-17A was associated with higher Sequential Organ Failure Assessment scores (p < 0.05). CONCLUSIONS:Elevated circulating and alveolar levels of interleukin-17A are associated with increased percentage of alveolar neutrophils, alveolar permeability, and organ dysfunction in acute respiratory distress syndrome. 10.1097/CCM.0000000000001409
    New Insights into the Immune Molecular Regulation of the Pathogenesis of Acute Respiratory Distress Syndrome. Yang Chin-Yao,Chen Chien-Sheng,Yiang Giou-Teng,Cheng Yeung-Leung,Yong Su-Boon,Wu Meng-Yu,Li Chia-Jung International journal of molecular sciences Acute respiratory distress syndrome is an inflammatory disease characterized by dysfunction of pulmonary epithelial and capillary endothelial cells, infiltration of alveolar macrophages and neutrophils, cell apoptosis, necroptosis, NETosis, and fibrosis. Inflammatory responses have key effects on every phase of acute respiratory distress syndrome. The severe inflammatory cascades impaired the regulation of vascular endothelial barrier and vascular permeability. Therefore, understanding the relationship between the molecular regulation of immune cells and the pulmonary microenvironment is critical for disease management. This article reviews the current clinical and basic research on the pathogenesis of acute respiratory distress syndrome, including information on the microenvironment, vascular endothelial barrier and immune mechanisms, to offer a strong foundation for developing therapeutic interventions. 10.3390/ijms19020588
    Macrophage Polarization Favors Epithelial Repair During Acute Respiratory Distress Syndrome. Garnier Marc,Gibelin Aude,Mailleux Arnaud A,Leçon Véronique,Hurtado-Nedelec Margarita,Laschet Jamila,Trebbia Grégoire,Neuville Mathilde,Tanaka Sébastien,Crestani Bruno,Dehoux Monique,Quesnel Christophe Critical care medicine OBJECTIVES:Alveolar macrophage polarization and role on alveolar repair during human acute respiratory distress syndrome remain unclear. This study aimed to determine during human acute respiratory distress syndrome: the alveolar macrophage polarization, the effect of alveolar environment on macrophage polarization, and the role of polarized macrophages on epithelial repair. DESIGN:Experimental ex vivo and in vitro investigations. SETTING:Four ICUs in three teaching hospitals. PATIENTS:Thirty-three patients with early moderate-to-severe acute respiratory distress syndrome were enrolled for assessment of the polarization of alveolar macrophages. INTERVENTIONS:Polarization of acute respiratory distress syndrome macrophages was studied by flow cytometry and quantitative polymerase chain reaction. Modulation of macrophage polarization was studied in vitro using phenotypic and functional readouts. Macrophage effect on repair was studied using alveolar epithelial cells in wound healing models. MEASUREMENTS AND MAIN RESULTS:Ex vivo, alveolar macrophages from early acute respiratory distress syndrome patients exhibited anti-inflammatory characteristics with high CD163 expression and interleukin-10 production. Accordingly, early acute respiratory distress syndrome-bronchoalveolar lavage fluid drives an acute respiratory distress syndrome-specific anti-inflammatory macrophage polarization in vitro, close to that induced by recombinant interleukin-10. Culture supernatants from macrophages polarized in vitro with acute respiratory distress syndrome-bronchoalveolar lavage fluid or interleukin-10 and ex vivo acute respiratory distress syndrome alveolar macrophages specifically promoted lung epithelial repair. Inhibition of the hepatocyte growth factor pathway in epithelial cells and hepatocyte growth factor production in macrophages both reversed this effect. Finally, hepatocyte growth factor and soluble form of CD163 concentrations expressed relatively to macrophage count were higher in bronchoalveolar lavage fluid from acute respiratory distress syndrome survivors. CONCLUSIONS:Early acute respiratory distress syndrome alveolar environment drives an anti-inflammatory macrophage polarization favoring epithelial repair through activation of the hepatocyte growth factor pathway. These results suggest that macrophage polarization may be an important step for epithelial repair and acute respiratory distress syndrome recovery. 10.1097/CCM.0000000000003150
    Vascular endothelial growth factor increased the permeability of respiratory barrier in acute respiratory distress syndrome model in mice. Zhang Zhao,Wu Zhouyang,Xu Younian,Lu Dongshi,Zhang Shihai Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie BACKGROUND:Acute respiratory distress syndrome is associated with a mortality of 45%. The authors investigated the possible mechanisms and effect of vascular endothelial growth factor on alveolar epithelial barrier permeability in acute respiratory distress syndrome mice model. METHODS:Eighty Male BALB/c mice were randomly assigned to four group: PBS group, LPS group, sFlt group, or LPS + sFlt group. The levels of vascular endothelial growth factor and total protein in bronchoalveolar lavage fluid were compared, together with lung injury score and the histopathology of alveolar epithelial barrier. The expressions of vascular endothelial growth factor and tight junction proteins mRNA in lung tissue were also studied. RESULTS:Lipopolysaccharide (LPS) inhaling was accompanied with increasing lung vascular endothelial growth factor (VEGF) expression. Anti-VEGF with soluble fms-like tyrosine kinase-1 (sFlt-1) attenuated the lung injury effectively. CONCLUSIONS:Our data indicate that anti-vascular endothelial growth factor with soluble fms-like tyrosine kinase-1 could maintain the normal structure and function of respiratory membrane in acute respiratory distress syndrome mice model and might be a suitable therapeutic tool for the treatment of acute respiratory distress syndrome. 10.1016/j.biopha.2018.11.132
    Beyond Low Tidal Volume Ventilation: Treatment Adjuncts for Severe Respiratory Failure in Acute Respiratory Distress Syndrome. Fielding-Singh Vikram,Matthay Michael A,Calfee Carolyn S Critical care medicine OBJECTIVES:Despite decades of research, the acute respiratory distress syndrome remains associated with significant morbidity and mortality. This Concise Definitive Review provides a practical and evidence-based summary of treatments in addition to low tidal volume ventilation and their role in the management of severe respiratory failure in acute respiratory distress syndrome. DATA SOURCES:We searched the PubMed database for clinical trials, observational studies, and review articles describing treatment adjuncts in acute respiratory distress syndrome patients, including high positive end-expiratory pressure strategies, recruitment maneuvers, high-frequency oscillatory ventilation, neuromuscular blockade, prone positioning, inhaled pulmonary vasodilators, extracorporeal membrane oxygenation, glucocorticoids, and renal replacement therapy. STUDY SELECTION AND DATA EXTRACTION:Results were reviewed by the primary author in depth. Disputed findings and conclusions were then reviewed with the other authors until consensus was achieved. DATA SYNTHESIS:Severe respiratory failure in acute respiratory distress syndrome may present with refractory hypoxemia, severe respiratory acidosis, or elevated plateau airway pressures despite lung-protective ventilation according to acute respiratory distress syndrome Network protocol. For severe hypoxemia, first-line treatment adjuncts include high positive end-expiratory pressure strategies, recruitment maneuvers, neuromuscular blockade, and prone positioning. For refractory acidosis, we recommend initial modest liberalization of tidal volumes, followed by neuromuscular blockade and prone positioning. For elevated plateau airway pressures, we suggest first decreasing tidal volumes, followed by neuromuscular blockade, modification of positive end-expiratory pressure, and prone positioning. Therapies such as inhaled pulmonary vasodilators, glucocorticoids, and renal replacement therapy have significantly less evidence in favor of their use and should be considered second line. Extracorporeal membrane oxygenation may be life-saving in selected patients with severe acute respiratory distress syndrome but should be used only when other alternatives have been applied. CONCLUSIONS:Severe respiratory failure in acute respiratory distress syndrome often necessitates the use of treatment adjuncts. Evidence-based application of these therapies in acute respiratory distress syndrome remains a significant challenge. However, a rational stepwise approach with frequent monitoring for improvement or harm can be achieved. 10.1097/CCM.0000000000003406
    A study on the protective effects of CpG oligodeoxynucleotide-induced mucosal immunity against lung injury in a mouse acute respiratory distress syndrome model. Wang Guan,Liu Zong-Jian,Liu Xuan,Liu Feng-Ge,Li Yan,Weng Yi-Bing,Zhou Jian-Xin Journal of cellular physiology This study aims to determine the feasibility of using oligodeoxynucleotides with unmethylated cytosine-guanine dinucleotide sequences (CpG ODN) as an immunity protection strategy for a mouse model of acute respiratory distress syndrome (ARDS). This is a prospective laboratory animal investigation. Twenty-week-old BALB/c mice in Animal research laboratory were randomized into groups. An ARDS model was induced in mice using lipopolysaccharides (LPSs). CpG ODN was intranasally and transrectally immunized before or after the 3rd and 7th days of establishing the ARDS model. Mice were euthanized on Day 7 after the second immunization. Then, retroorbital bleeding was carried out and the chest was rapidly opened to collect the trachea and tissues from both lungs for testing. CpG ODN significantly improved the pathologic impairment in mice lung, especially after the intranasal administration of 50 μg. This resulted in the least severe lung tissue injury. Furthermore, interleukin-6 (IL-6) and IL-8 concentrations were lower, which was second to mice treated with the rectal administration of 20 µg CpG ODN. In contrast, the nasal and rectal administration of CpG ODN in BALB/c mice before LPS immunization did not appear to exhibit any significant protective effects. The intranasal administration of CpG ODN may be a potential treatment approach to ARDS. More studies are needed to further determine the protective mechanism of CpG ODN. 10.1002/jcp.28613
    Resveratrol decreases CD45 CD206 subtype macrophages in LPS-induced murine acute lung injury by SOCS3 signalling pathway. Hu Lu,Chen Zhihong,Li Liyang,Jiang Zhilong,Zhu Lei Journal of cellular and molecular medicine Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) are life-threatening condition in critically ill patients. Resveratrol (Res), a natural polyphenol, has therapeutic effect in animal model with ALI; however, whether Res attenuates ALI through modulation of macrophage phenotypes in the animal model remains unknown. We in this study treated LPS-induced murine ALI with 30 mg/kg Res and observed significantly reduced severity of ALI in the Res-treated mice 48 hours after Res treatment. Neutrophil infiltrates were significantly reduced, accompanied with lower infiltration of CD45 Siglec F phenotype macrophages, but higher population of CD45 Siglec F and CD45 CD206 alternatively activated macrophages (M2 cells) in the Res-treated mice with ALI. In addition, the expression of IL-1beta and CXCL15 cytokines was suppressed in the treated mice. However, Res treatment in mice with myeloid cell-restricted SOCS3 deficiency did not significantly attenuate ALI severity and failed to increase population of both CD45 Siglec F and CD45 CD206 M2 subtype macrophages in the murine ALI. Further studies in wild-type macrophages revealed that Res treatment effectively reduced the expression of IL-6 and CXCL15, and increased the expression of arginase-1, SIRT1 and SOCS3. However, macrophages' lack of SOCS3 expression were resistant to the Res-induced suppression of IL-6 and CXCL15 in vitro. Thus, we conclude that Res suppressed CD45 Siglec F and CD45 CD206 M1 subtype macrophages through SOCS3 signalling in the LPS-induced murine ALI. 10.1111/jcmm.14680
    Regulation of Lung Epithelial Sodium Channels by Cytokines and Chemokines. Wynne Brandi M,Zou Li,Linck Valerie,Hoover Robert S,Ma He-Ping,Eaton Douglas C Frontiers in immunology Acute lung injury leading to acute respiratory distress (ARDS) is a global health concern. ARDS patients have significant pulmonary inflammation leading to flooding of the pulmonary alveoli. This prevents normal gas exchange with consequent hypoxemia and causes mortality. A thin fluid layer in the alveoli is normal. The maintenance of this thin layer results from fluid movement out of the pulmonary capillaries into the alveolar interstitium driven by vascular hydrostatic pressure and then through alveolar tight junctions. This is then balanced by fluid reabsorption from the alveolar space mediated by transepithelial salt and water transport through alveolar cells. Reabsorption is a two-step process: first, sodium enters sodium-permeable channels in the apical membranes of alveolar type 1 and 2 cells followed by active extrusion of sodium into the interstitium by the basolateral Na, K-ATPase. Anions follow the cationic charge gradient and water follows the salt-induced osmotic gradient. The proximate cause of alveolar flooding is the result of a failure to reabsorb sufficient salt and water or a failure of the tight junctions to prevent excessive movement of fluid from the interstitium to alveolar lumen. Cytokine- and chemokine-induced inflammation can have a particularly profound effect on lung sodium transport since they can alter both ion channel and barrier function. Cytokines and chemokines affect alveolar amiloride-sensitive epithelial sodium channels (ENaCs), which play a crucial role in sodium transport and fluid reabsorption in the lung. This review discusses the regulation of ENaC local and systemic cytokines during inflammatory disease and the effect on lung fluid balance. 10.3389/fimmu.2017.00766
    Andrographolide sulfonate ameliorates lipopolysaccharide-induced acute lung injury in mice by down-regulating MAPK and NF-κB pathways. Peng Shuang,Hang Nan,Liu Wen,Guo Wenjie,Jiang Chunhong,Yang Xiaoling,Xu Qiang,Sun Yang Acta pharmaceutica Sinica. B Acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) is a severe, life-threatening medical condition characterized by widespread inflammation in the lungs, and is a significant source of morbidity and mortality in the patient population. New therapies for the treatment of ALI are desperately needed. In the present study, we examined the effect of andrographolide sulfonate, a water-soluble form of andrographolide (trade name: Xi-Yan-Ping Injection), on lipopolysaccharide (LPS)-induced ALI and inflammation. Andrographolide sulfonate was administered by intraperitoneal injection to mice with LPS-induced ALI. LPS-induced airway inflammatory cell recruitment and lung histological alterations were significantly ameliorated by andrographolide sulfonate. Protein levels of pro-inflammatory cytokines in bronchoalveolar lavage fluid (BALF) and serum were reduced by andrographolide sulfonate administration. mRNA levels of pro-inflammatory cytokines in lung tissue were also suppressed. Moreover, andrographolide sulfonate markedly suppressed the activation of mitogen-activated protein kinase (MAPK) as well as p65 subunit of nuclear factor-κB (NF-κB). In summary, these results suggest that andrographolide sulfonate ameliorated LPS-induced ALI in mice by inhibiting NF-κB and MAPK-mediated inflammatory responses. Our study shows that water-soluble andrographolide sulfonate may represent a new therapeutic approach for treating inflammatory lung disorders. 10.1016/j.apsb.2016.02.002
    Apigenin C-glycosides of Microcos paniculata protects lipopolysaccharide induced apoptosis and inflammation in acute lung injury through TLR4 signaling pathway. Li Kunping,He Zhuoru,Wang Xinqiuyue,Pineda Miguel,Chen Runbao,Liu Haiqi,Ma Kaiting,Shen Huanjia,Wu Chunhui,Huang Ningtin,Pan Tianling,Liu Yun,Guo Jiao Free radical biology & medicine Acute lung injury (ALI) and its more severe form acute respiratory distress syndrome (ARDS) are life-threatening conditions with high morbility and mortality, underscoring the urgent need for novel treatments. Leaves of the medicinal herb Microcos paniculata have been traditionally used for treating upper airway infections, by virtue of its content of flavonoids such as apigenin C-glycosides (ACGs). C-glycosides have been shown to exert strong anti-inflammatory properties, although their mechanism of action remains unknown. Herein, hypothesizing that ACGs from M. paniculata inhibit progression of ALI, we used the experimental model of lipopolysaccharide (LPS)-induced ALI in BALB/c mice to evaluate the therapeutic potential of purified ACGs. Our results showed that M. paniculata ACGs inhibited lung inflammation in animals undergoing ALI. The protective effects of ACGs were assessed by determination of cytokine levels and in situ analysis of lung inflammation. ACGs reduced the pulmonary edema and microvascular permeability, demonstrating a dose-dependent down-regulation of LPS-induced TNF-α, IL-6 and IL-1β expression in lung tissue and bronchoalveolar lavage fluid, along with reduced apoptosis. Moreover, metabolic profiling of mice serum and subsequent Ingenuity Pathway Analysis suggested that ACGs activated protective protein networks and pathways involving inflammatory regulators and apoptosis-related factors, such as JNK, ERK1/2 and caspase-3/7, suggesting that ACGs-dependent effects were related to MAPKs and mitochondrial apoptosis pathways. These results were further supported by evaluation of protein expression, showing that ACGs blocked LPS-activated phosphorylation of p38, ERK1/2 and JNK on the MAPKs signaling, and significantly upregulated the expression of Bcl-2 whilst down-regulated Bax and cleaved caspase-3. Remarkably, ACGs inhibited the LPS-dependent TLR4 and TRPC6 upregulation observed during ALI. Our study shows for the first time that ACGs inhibit acute inflammation and apoptosis by suppressing activation of TLR4/TRPC6 signaling pathway in a murine model of ALI. Our findings provide new evidence for better understanding the anti-inflammatory effects of ACGs. In this regard, ACGs could be exploited in the development of novel therapeutics for ALI and ARDS. 10.1016/j.freeradbiomed.2018.06.009
    Poldip2 deficiency protects against lung edema and vascular inflammation in a model of acute respiratory distress syndrome. Forrester Steven J,Xu Qian,Kikuchi Daniel S,Okwan-Duodu Derick,Campos Ana Carolina,Faidley Elizabeth A,Zhang Guogang,Lassègue Bernard,Sadikot Ruxana T,Griendling Kathy K,Hernandes Marina S Clinical science (London, England : 1979) Acute respiratory distress syndrome (ARDS) in a deadly disease that can be brought on by endotoxins such as lipopolysaccharide (LPS). ARDS is characterized by vascular permeability, a severe inflammatory response, lung leukocyte infiltration, and resultant lung edema. Polymerase δ-interacting protein 2 (Poldip2) is a novel regulator of blood-brain barrier permeability; however, its role in regulating lung permeability and vascular inflammation is unknown. Here, the role of Poldip2 in regulating vascular permeability and inflammation in a mouse model of ARDS was assessed. Heterozygous deletion of Poldip2 was found to reduce LPS-induced mortality within 20 h, lung inflammatory signaling, and leukocyte infiltration. Moreover, reduced Poldip2-suppressed LP-induced vascular cell adhesion molecule (VCAM)-1 induction, leukocyte recruitment, and mitochondrial reactive oxygen species (ROS) production These data indicate that Poldip2 is an important regulator of the debilitating consequences of ARDS, potentially through the regulation of mitochondrial ROS-induced inflammatory signaling. Consequently, inhibition of Poldip2 may be a viable option for therapeutic discovery moving forward. 10.1042/CS20180944
    Neutrophils in the initiation and resolution of acute pulmonary inflammation: understanding biological function and therapeutic potential. Potey Philippe Md,Rossi Adriano G,Lucas Christopher D,Dorward David A The Journal of pathology Acute respiratory distress syndrome (ARDS) is the often fatal sequelae of a broad range of precipitating conditions. Despite decades of intensive research and clinical trials there remain no therapies in routine clinical practice that target the dysregulated and overwhelming inflammatory response that characterises ARDS. Neutrophils play a central role in the initiation, propagation and resolution of this complex inflammatory environment by migrating into the lung and executing a variety of pro-inflammatory functions. These include degranulation with liberation of bactericidal proteins, release of cytokines and reactive oxygen species as well as production of neutrophil extracellular traps. Although these functions are advantageous in clearing bacterial infection, the consequence of associated tissue damage, the contribution to worsening acute inflammation and prolonged neutrophil lifespan at sites of inflammation are deleterious. In this review, the importance of the neutrophil will be considered, together with discussion of recent advances in understanding neutrophil function and the factors that influence them throughout the phases of inflammation in ARDS. From a better understanding of neutrophils in this context, potential therapeutic targets are identified and discussed. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. 10.1002/path.5221
    Nimbolide protects against endotoxin-induced acute respiratory distress syndrome by inhibiting TNF-α mediated NF-κB and HDAC-3 nuclear translocation. Pooladanda Venkatesh,Thatikonda Sowjanya,Bale Swarna,Pattnaik Bijay,Sigalapalli Dilep Kumar,Bathini Nagendra Babu,Singh Shashi Bala,Godugu Chandraiah Cell death & disease Acute respiratory distress syndrome (ARDS) is characterized by an excessive acute inflammatory response in lung parenchyma, which ultimately leads to refractory hypoxemia. One of the earliest abnormalities seen in lung injury is the elevated levels of inflammatory cytokines, among them, the soluble tumor necrosis factor (TNF-α) has a key role, which exerts cytotoxicity in epithelial and endothelial cells thus exacerbates edema. The bacterial lipopolysaccharide (LPS) was used both in vitro (RAW 264.7, THP-1, MLE-12, A549, and BEAS-2B) and in vivo (C57BL/6 mice), as it activates a plethora of overlapping inflammatory signaling pathways involved in ARDS. Nimbolide is a chemical constituent of Azadirachta indica, which contains multiple biological properties, while its role in ARDS is elusive. Herein, we have investigated the protective effects of nimbolide in abrogating the complications associated with ARDS. We showed that nimbolide markedly suppressed the nitrosative-oxidative stress, inflammatory cytokines, and chemokines expression by suppressing iNOS, myeloperoxidase, and nitrotyrosine expression. Moreover, nimbolide mitigated the migration of neutrophils and mast cells whilst normalizing the LPS-induced hypothermia. Also, nimbolide modulated the expression of epigenetic regulators with multiple HDAC inhibitory activity by suppressing the nuclear translocation of NF-κB and HDAC-3. We extended our studies using molecular docking studies, which demonstrated a strong interaction between nimbolide and TNF-α. Additionally, we showed that treatment with nimbolide increased GSH, Nrf-2, SOD-1, and HO-1 protein expression; concomitantly abrogated the LPS-triggered TNF-α, p38 MAPK, mTOR, and GSK-3β protein expression. Collectively, these results indicate that TNF-α-regulated NF-κB and HDAC-3 crosstalk was ameliorated by nimbolide with promising anti-nitrosative, antioxidant, and anti-inflammatory properties in LPS-induced ARDS. 10.1038/s41419-018-1247-9
    Enhancement of glycolysis by inhibition of oxygen-sensing prolyl hydroxylases protects alveolar epithelial cells from acute lung injury. Tojo Kentaro,Tamada Nao,Nagamine Yusuke,Yazawa Takuya,Ota Shuhei,Goto Takahisa FASEB journal : official publication of the Federation of American Societies for Experimental Biology Cellular bioenergetic failure caused by mitochondrial dysfunction is a key process of alveolar epithelial injury during acute respiratory distress syndrome (ARDS). Prolyl hydroxylases (PHDs) act as cellular oxygen sensors, and their inhibition activates hypoxia-inducible factor (HIF), resulting in enhanced cellular glycolytic activity, which could compensate for impaired mitochondrial function and protect alveolar epithelial cells from ARDS. Here, we evaluated the effects of pharmacological PHD inhibition with dimethyloxalylglycine (DMOG) on alveolar epithelial cell injury using in vitro and in vivo ARDS models. We established an in vitro model of alveolar epithelial injury mimicking ARDS by adding isolated neutrophils and LPS to cultured MLE12 alveolar epithelial cells. DMOG treatment protected MLE12 cells from neutrophil-LPS-induced ATP decline and cell death. Knockdown of HIF-1α or inhibition of glycolysis abolished the protective effect of DMOG, suggesting that it was exerted by HIF-1-dependent enhancement of glycolysis. Additionally, intratracheal DMOG administration to mice protected the alveolar epithelial barrier and improved arterial oxygenation, preventing ATP decline during LPS-induced lung injury. In summary, enhancement of glycolysis by PHD inhibition is a potential therapeutic approach for ARDS, protecting alveolar epithelial cells from bioenergetic failure and cell death.-Tojo, K., Tamada, N., Nagamine, Y., Yazawa, T., Ota, S., Goto, T. Enhancement of glycolysis by inhibition of oxygen-sensing prolyl hydroxylases protects alveolar epithelial cells from acute lung injury. 10.1096/fj.201700888R
    Omentin protects against LPS-induced ARDS through suppressing pulmonary inflammation and promoting endothelial barrier via an Akt/eNOS-dependent mechanism. Qi Di,Tang Xumao,He Jing,Wang Daoxin,Zhao Yan,Deng Wang,Deng Xinyu,Zhou Guoqi,Xia Jing,Zhong Xi,Pu Shenglan Cell death & disease Acute respiratory distress syndrome (ARDS) is characterized by increased pulmonary inflammation and endothelial barrier permeability. Omentin has been shown to benefit obesity-related systemic vascular diseases; however, its effects on ARDS are unknown. In the present study, the level of circulating omentin in patients with ARDS was assessed to appraise its clinical significance in ARDS. Mice were subjected to systemic administration of adenoviral vector expressing omentin (Ad-omentin) and one-shot treatment of recombinant human omentin (rh-omentin) to examine omentin's effects on lipopolysaccharide (LPS)-induced ARDS. Pulmonary endothelial cells (ECs) were treated with rh-omentin to further investigate its underlying mechanism. We found that a decreased level of circulating omentin negatively correlated with white blood cells and procalcitonin in patients with ARDS. Ad-omentin protected against LPS-induced ARDS by alleviating the pulmonary inflammatory response and endothelial barrier injury in mice, accompanied by Akt/eNOS pathway activation. Treatment of pulmonary ECs with rh-omentin attenuated inflammatory response and restored adherens junctions (AJs), and cytoskeleton organization promoted endothelial barrier after LPS insult. Moreover, the omentin-mediated enhancement of EC survival and differentiation was blocked by the Akt/eNOS pathway inactivation. Therapeutic rh-omentin treatment also effectively protected against LPS-induced ARDS via the Akt/eNOS pathway. Collectively, these data indicated that omentin protects against LPS-induced ARDS by suppressing inflammation and promoting the pulmonary endothelial barrier, at least partially, through an Akt/eNOS-dependent mechanism. Therapeutic strategies aiming to restore omentin levels may be valuable for the prevention or treatment of ARDS. 10.1038/cddis.2016.265
    Platelet-derived TLT-1 is a prognostic indicator in ALI/ARDS and prevents tissue damage in the lungs in a mouse model. Morales-Ortíz Jessica,Deal Victoria,Reyes Fiorella,Maldonado-Martínez Gerónimo,Ledesma Nahomy,Staback Franklin,Croft Cheyanne,Pacheco Amanda,Ortiz-Zuazaga Humberto,Yost C Christian,Rowley Jesse W,Madera Bismark,John Alex St,Chen Junmei,Lopez Jose,Rondina Matthew T,Hunter Robert,Gibson Angelia,Washington A Valance Blood Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) affect >200 000 individuals yearly with a 40% mortality rate. Although platelets are implicated in the progression of ALI/ARDS, their exact role remains undefined. Triggering receptor expressed in myeloid cells (TREM)-like transcript 1 (TLT-1) is found on platelets, binds fibrinogen, and mediates clot formation. We hypothesized that platelets use TLT-1 to manage the progression of ALI/ARDS. Here we retrospectively measure plasma levels of soluble TLT-1 (sTLT-1) from the ARDS Network clinical trial and show that patients whose sTLT-1 levels were >1200 pg/mL had nearly twice the mortality risk as those with <1200 pg/mL ( < .001). After correcting for confounding factors such as creatinine levels, Acute Physiology And Chronic Health Evaluation III scores, age, platelet counts, and ventilation volume, sTLT-1 remains significant, suggesting that sTLT-1 is an independent prognostic factor ( < .0001). These data point to a role for TLT-1 during the progression of ALI/ARDS. We use a murine lipopolysaccharide-induced ALI model and demonstrate increased alveolar bleeding, aberrant neutrophil transmigration and accumulation associated with decreased fibrinogen deposition, and increased pulmonary tissue damage in the absence of TLT-1. The loss of TLT-1 resulted in an increased proportion of platelet-neutrophil conjugates (43.73 ± 24.75% vs 8.92 ± 2.4% in wild-type mice), which correlated with increased neutrophil death. Infusion of sTLT-1 restores normal fibrinogen deposition and reduces pulmonary hemorrhage by 40% ( ≤ .001) and tissue damage by 25% ( ≤ .001) in vivo. Our findings suggest that TLT-1 uses fibrinogen to govern the transition between inflammation and hemostasis and facilitate controlled leukocyte transmigration during the progression of ARDS. 10.1182/blood-2018-03-841593
    Personalised mechanical ventilation tailored to lung morphology versus low positive end-expiratory pressure for patients with acute respiratory distress syndrome in France (the LIVE study): a multicentre, single-blind, randomised controlled trial. Constantin Jean-Michel,Jabaudon Matthieu,Lefrant Jean-Yves,Jaber Samir,Quenot Jean-Pierre,Langeron Olivier,Ferrandière Martine,Grelon Fabien,Seguin Philippe,Ichai Carole,Veber Benoit,Souweine Bertrand,Uberti Thomas,Lasocki Sigismond,Legay François,Leone Marc,Eisenmann Nathanael,Dahyot-Fizelier Claire,Dupont Hervé,Asehnoune Karim,Sossou Achille,Chanques Gérald,Muller Laurent,Bazin Jean-Etienne,Monsel Antoine,Borao Lucile,Garcier Jean-Marc,Rouby Jean-Jacques,Pereira Bruno,Futier Emmanuel, The Lancet. Respiratory medicine BACKGROUND:The effect of personalised mechanical ventilation on clinical outcomes in patients with acute respiratory distress syndrome (ARDS) remains uncertain and needs to be evaluated. We aimed to test whether a mechanical ventilation strategy that was personalised to individual patients' lung morphology would improve the survival of patients with ARDS when compared with standard of care. METHODS:We designed a multicentre, single-blind, stratified, parallel-group, randomised controlled trial enrolling patients with moderate-to-severe ARDS in 20 university or non-university intensive care units in France. Patients older than 18 years with early ARDS for less than 12 h were randomly assigned (1:1) to either the control group or the personalised group using a minimisation algorithm and stratified according to the study site, lung morphology, and duration of mechanical ventilation. Only the patients were masked to allocation. In the control group, patients received a tidal volume of 6 mL/kg per predicted bodyweight and positive end-expiratory pressure (PEEP) was selected according to a low PEEP and fraction of inspired oxygen table, and early prone position was encouraged. In the personalised group, the treatment approach was based on lung morphology; patients with focal ARDS received a tidal volume of 8 mL/kg, low PEEP, and prone position. Patients with non-focal ARDS received a tidal volume of 6 mL/kg, along with recruitment manoeuvres and high PEEP. The primary outcome was 90-day mortality as established by intention-to-treat analysis. This study is registered online with ClinicalTrials.gov, NCT02149589. FINDINGS:From June 12, 2014, to Feb 2, 2017, 420 patients were randomly assigned to treatment. 11 patients were excluded in the personalised group and nine patients were excluded in the control group; 196 patients in the personalised group and 204 in the control group were included in the analysis. In a multivariate analysis, there was no difference in 90-day mortality between the group treated with personalised ventilation and the control group in the intention-to-treat analysis (hazard ratio [HR] 1·01; 95% CI 0·61-1·66; p=0·98). However, misclassification of patients as having focal or non-focal ARDS by the investigators was observed in 85 (21%) of 400 patients. We found a significant interaction between misclassification and randomised group allocation with respect to the primary outcome (p<0·001). In the subgroup analysis, the 90-day mortality of the misclassified patients was higher in the personalised group (26 [65%] of 40 patients) than in the control group (18 [32%] of 57 patients; HR 2·8; 95% CI 1·5-5·1; p=0·012. INTERPRETATION:Personalisation of mechanical ventilation did not decrease mortality in patients with ARDS, possibly because of the misclassification of 21% of patients. A ventilator strategy misaligned with lung morphology substantially increases mortality. Whether improvement in ARDS phenotyping can decrease mortality should be assessed in a future clinical trial. FUNDING:French Ministry of Health (Programme Hospitalier de Recherche Clinique InterRégional 2013). 10.1016/S2213-2600(19)30138-9
    Impaired efferocytosis and neutrophil extracellular trap clearance by macrophages in ARDS. Grégoire Murielle,Uhel Fabrice,Lesouhaitier Mathieu,Gacouin Arnaud,Guirriec Marion,Mourcin Frederic,Dumontet Erwan,Chalin Arnaud,Samson Michel,Berthelot Laure-Line,Tissot Adrien,Kerjouan Mallorie,Jouneau Stéphane,Le Tulzo Yves,Tarte Karin,Zmijewski Jaroslaw W,Tadié Jean-Marc The European respiratory journal Exaggerated release of neutrophil extracellular traps (NETs) along with decreased NET clearance and inability to remove apoptotic cells (efferocytosis) may contribute to sustained inflammation in acute respiratory distress syndrome (ARDS). Recent studies in experimental models of ARDS have revealed the crosstalk between AMP-activated protein kinase (AMPK) and high-mobility group box 1 (HMGB1), which may contribute to effectiveness of efferocytosis, thereby reducing inflammation and ARDS severity.We investigated neutrophil and NET clearance by macrophages from control and ARDS patients and examined how bronchoalveolar lavage (BAL) fluid from control and ARDS patients could affect NET formation and efferocytosis. Metformin (an AMPK activator) and neutralising antibody against HMGB1 were applied to improve efferocytosis and NET clearance.Neutrophils from ARDS patients showed significantly reduced apoptosis. Conversely, NET formation was significantly enhanced in ARDS patients. Exposure of neutrophils to ARDS BAL fluid promoted NET production, while control BAL fluid had no effect. Macrophage engulfment of NETs and apoptotic neutrophils was diminished in ARDS patients. Notably, activation of AMPK in macrophages or neutralisation of HMGB1 in BAL fluid improved efferocytosis and NET clearance.In conclusion, restoration of AMPK activity with metformin or specific neutralisation of HMGB1 in BAL fluid represent promising therapeutic strategies to decrease sustained lung inflammation during ARDS. 10.1183/13993003.02590-2017
    Immunonutrition for acute respiratory distress syndrome (ARDS) in adults. Dushianthan Ahilanandan,Cusack Rebecca,Burgess Victoria A,Grocott Michael Pw,Calder Philip C The Cochrane database of systematic reviews BACKGROUND:Acute respiratory distress syndrome (ARDS) is an overwhelming systemic inflammatory process associated with significant morbidity and mortality. Pharmacotherapies that moderate inflammation in ARDS are lacking. Several trials have evaluated the effects of pharmaconutrients, given as part of a feeding formula or as a nutritional supplement, on clinical outcomes in critical illness and ARDS. OBJECTIVES:To systematically review and critically appraise available evidence on the effects of immunonutrition compared to standard non-immunonutrition formula feeding on mechanically ventilated adults (aged 18 years or older) with acute respiratory distress syndrome (ARDS). SEARCH METHODS:We searched MEDLINE, Embase, CENTRAL, conference proceedings, and trial registries for appropriate studies up to 25 April 2018. We checked the references from published studies and reviews on this topic for potentially eligible studies. SELECTION CRITERIA:We included all randomized controlled trials (RCTs) and quasi-randomized controlled trials comparing immunonutrition versus a control or placebo nutritional formula in adults (aged 18 years or older) with ARDS, as defined by the Berlin definition of ARDS or, for older studies, by the American-European Consensus Criteria for both ARDS and acute lung injury. DATA COLLECTION AND ANALYSIS:Two review authors independently assessed the quality of studies and extracted data from the included trials. We sought additional information from study authors. We performed statistical analysis according to Cochrane methodological standards. Our primary outcome was all-cause mortality. Secondary outcomes included intensive care unit (ICU) length of stay, ventilator days, indices of oxygenation, cardiac adverse events, gastrointestinal adverse events, and total number of adverse events. We used GRADE to assess the quality of evidence for each outcome. MAIN RESULTS:We identified 10 randomized controlled trials with 1015 participants. All studies compared an enteral formula or additional supplemental omega-3 fatty acids (i.e. eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA)), gamma-linolenic acid (GLA), and antioxidants. We assessed some of the included studies as having high risk of bias due to methodological shortcomings. Studies were heterogenous in nature and varied in several ways, including type and duration of interventions given, calorific targets, and reported outcomes. All studies reported mortality. For the primary outcome, study authors reported no differences in all-cause mortality (longest period reported) with the use of an immunonutrition enteral formula or additional supplements of omega-3 fatty acids and antioxidants (risk ratio (RR) 0.79, 95% confidence interval (CI) 0.59 to 1.07; participants = 1015; studies = 10; low-quality evidence).For secondary outcomes, we are uncertain whether immunonutrition with omega-3 fatty acids and antioxidants reduces ICU length of stay (mean difference (MD) -3.09 days. 95% CI -5.19 to -0.99; participants = 639; studies = 8; very low-quality evidence) and ventilator days (MD -2.24 days, 95% CI -3.77 to -0.71; participants = 581; studies = 7; very low-quality evidence). We are also uncertain whether omega-3 fatty acids and antioxidants improve oxygenation, defined as ratio of partial pressure of arterial oxygen (PaO₂) to fraction of inspired oxygen (FiO₂), at day 4 (MD 39 mmHg, 95% CI 10.75 to 67.02; participants = 676; studies = 8), or whether they increase adverse events such as cardiac events (RR 0.87, 95% CI 0.09 to 8.46; participants = 339; studies = 3; very low-quality evidence), gastrointestinal events (RR 1.11, 95% CI 0.71 to 1.75; participants = 427; studies = 4; very low-quality evidence), or total adverse events (RR 0.91, 95% CI 0.67 to 1.23; participants = 517; studies = 5; very low-quality evidence). AUTHORS' CONCLUSIONS:This meta-analysis of 10 studies of varying quality examined effects of omega-3 fatty acids and/or antioxidants in adults with ARDS. This intervention may produce little or no difference in all-cause mortality between groups. We are uncertain whether immunonutrition with omega-3 fatty acids and antioxidants improves the duration of ventilator days and ICU length of stay or oxygenation at day 4 due to the very low quality of evidence. Adverse events associated with immunonutrition are also uncertain, as confidence intervals include the potential for increased cardiac, gastrointestinal, and total adverse events. 10.1002/14651858.CD012041.pub2