Daily Ards Research Analysis

OBJECTIVE: To investigate the role and underlying mechanism of Methyl-CpG binding domain protein 2 (MBD2) in the pathogenesis of acute respiratory distress syndrome (ARDS)-related pulmonary fibrosis. METHODS: Murine models for ARDS-related pulmonary fibrosis were established in wildtype or MBD2 knockout mice, expressions of MBD2 were determined with immunohistochemistry (IHC), immunofluorescence, and western blot. Epithelial-to-mesenchymal transition (EMT) was detected with determined with decreased expression of E-cadherin and increased expressions of N-cadherin, Vimentin, and α-smooth muscle actin (α-SMA). Transforming growth factor β (TGF-β) treated mouse lung epithelial-12 (MLE-12) cells and primary human type II alveolar epithelial cells were applied to establish in vitro model for EMT. Transcriptional sequencing with RNA-Seq and Chromatin immunoprecipitation (ChIP) assay were used to explore the potential targets of MBD2. Single cell sequencing data and Human pulmonary fibrosis samples were analyzed. RESULTS: Bleomycin (BLM) and lipopolysaccharide (LPS) induced EMT, pulmonary fibrosis, and increased expression of MBD2 in alveolar epithelial cells of mice, and MBD2 knockout significantly alleviated BLM- and LPS-induced pulmonary fibrosis and EMT. TGF-β induced EMT and elevated MBD2 expressions in alveolar epithelial cells, which was mitigated by MBD2 knockdown and aggravated by MBD2 overexpression. Frizzled 2 (FZD2) was found to be the potential target of MBD2. Single-cell sequencing analysis of ARDS patients suggested elevated expression of MBD2 in alveolar epithelial cells, and MBD2 expression was elevated in the lungs of patients with pulmonary fibrosis. CONCLUSION: Our results indicated that MBD2 could promote EMT and ARDS-related pulmonary fibrosis, potentially by modulating the expression of FZD2.

BACKGROUND: Bleeding is a common and sometimes fatal complication of venovenous extracorporeal membrane oxygenation (ECMO). Whether lowering the intensity of anticoagulation during venovenous ECMO is safe or effective is unknown. RESEARCH QUESTION: Is a large, multicenter randomized trial of low-intensity vs moderate-intensity anticoagulation during venovenous ECMO feasible? STUDY DESIGN AND METHODS: In a multicenter, parallel-group, randomized pilot trial conducted at 3 centers across the United States, we randomly assigned critically ill adults undergoing venovenous ECMO to low-intensity or moderate-intensity anticoagulation. Feasibility was assessed by enrollment rate and adherence to the assigned anticoagulation strategy. The primary efficacy outcome was major bleeding, and the primary safety outcome was thromboembolic events, both assessed between enrollment and 24 hours after decannulation. RESULTS: All of the 26 patients enrolled received the assigned intensity of anticoagulation. A major bleeding event occurred in 1 of 12 patients (8.3%) in the low-intensity anticoagulation group and in 4 of 14 patients (28.6%) in the moderate-intensity anticoagulation group (absolute risk difference, -20.2 percentage points; 95% CI, -48.6 to 8.1; P = .33). One patient experienced a thromboembolic event (8.3%) in the low-intensity anticoagulation group compared with none in the moderate-intensity group (difference, 8.3 percentage points; 95% CI, -7.3 to 24.0; P = .46). No patients died before discharge in the low-intensity anticoagulation group, compared with 2 patients (14.3%) in the moderate-intensity group, both of whom experienced major bleeding events. No patients died before discharge in the low-intensity anticoagulation group, compared with 2 patients (14.3%) in the moderate-intensity group, both of whom experienced major bleeding events. INTERPRETATION: Our results indicate that enrollment and separation between groups are feasible in a multicenter randomized trial of low-intensity vs moderate-intensity anticoagulation for critically ill adults receiving venovenous ECMO. A large, multicenter, randomized trial is needed and seems to be feasible. CLINICAL TRIAL REGISTRY: ClinicalTrials.gov; No.: N

BACKGROUND: Hemolysis is a common complication in critically ill patients with sepsis, acute respiratory distress syndrome (ARDS) or therapy with extracorporeal membrane oxygenation (ECMO). Heme degradation product bilirubin might accumulate in conditions of significant hemolysis. In patients with ARDS and therapy with veno-venous ECMO (vvECMO), the prognostic potential of elevated initial total bilirubin (tBili) was investigated. METHODS: Retrospective analysis of patients with ARDS and vvECMO-therapy (n = 327) admitted to a tertiary ARDS center. A tBili cut-off value was determined by binary recursive partitioning. Baseline characteristics were compared and relevant variables were included in a multivariate logistic regression model with backward variable selection. Primary endpoint was survival within 28 days analyzed with Kaplan-Meier-curves and cox regression. Secondary endpoints included failure free composites for organ dysfunction, renal replacement therapy (RRT), vasopressor therapy and ECMO within 28 days and were compared using competing risk regression analysis. RESULTS: A cut-off value of 3.6mg/dl divided the cohort for ICU mortality (tBili ≤ 3.6mg/dl: 46% (n = 273) vs. tBili > 3.6mg/dl: 78% (n = 54), p < 0.001). The group with tBili > 3.6mg/dl showed a higher 28-day mortality (HR 3.03 [95%CI 2.07-4.43], p < 0.001) and significantly lower chances of successful recovery from organ dysfunction (subdistribution hazard ratio (SHR) 0.29 [0.13-0.66], p < 0.001), RRT (SHR 0.34 [0.14-0.85], p = 0.02), and ECMO (SHR 0.46 [0.25-0.86], p = 0.015) compared to the group with tBili ≤ 3.6mg/dl. Recovery from vasopressor therapy did not differ between groups (SHR 0.63 [0.32-1.24], p = 0.18). CONCLUSION: Patients with ARDS, vvECMO-therapy and tBili > 3.6mg/dl had a higher mortality and lower chances for recovery from organ dysfunction, RRT, and ECMO within 28 days. The tBili-cut-off value may be useful to identify patients at risk for unfavorable outcomes.