Yongbo Huang

Sepsis and ARDS: The Dark Side of Histones

Despite advances in management over the last several decades, sepsis and acute respiratory distress syndrome (ARDS) still remain major clinical challenges and the leading causes of death for patients in intensive care units (ICUs) due to insufficient understanding of the pathophysiological mechanisms of these diseases. However, recent studies have shown that histones, also known as chromatin-basic structure proteins, could be released into the extracellular space during severe stress and physical challenges to the body (e.g., sepsis and ARDS). Due to their cytotoxic and proinflammatory effects, extracellular histones can lead to excessive and overwhelming cell damage and death, thus contributing to the pathogenesis of both sepsis and ARDS. In addition, antihistone-based treatments (e.g., neutralizing antibodies, activated protein C, and heparin) have shown protective effects and have significantly improved the outcomes of mice suffering from sepsis and ARDS. Here, we review researches related to the pathological role of histone in context of sepsis and ARDS and evaluate the potential value of histones as biomarkers and therapeutic targets of these diseases.

Proteomic Analysis of Lung Tissue in a Rat Acute Lung Injury Model: Identification of PRDX1 as a Promoter of Inflammation

Acute respiratory distress syndrome (ARDS) remains a high morbidity and mortality disease entity in critically ill patients, despite decades of numerous investigations into its pathogenesis. To obtain global protein expression changes in acute lung injury (ALI) lung tissues, we employed a high-throughput proteomics method to identify key components which may be involved in the pathogenesis of ALI. In the present study, we analyzed lung tissue proteomes of Pseudomonas aeruginosa-induced ALI rats and identified eighteen proteins whose expression levels changed more than twofold as compared to normal controls. In particular, we found that PRDX1 expression in culture medium was elevated by a lipopolysaccharide (LPS) challenge in airway epithelial cells in vitro. Furthermore, overexpression of PRDX1 increased the expression of proinflammatory cytokines interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor-α (TNF-α), whereas knockdown of PRDX1 led to downregulated expression of cytokines induced by LPS. In conclusion, our findings provide a global alteration in the proteome of lung tissues in the ALI rat model and indicate that PRDX1 may play a critical role in the pathogenesis of ARDS by promoting inflammation and represent a novel strategy for the development of new therapies against ALI.

A gloves-associated outbreak of imipenem-resistant Acinetobacter baumannii in an intensive care unit in Guangdong, China

BackgroundImipenem-resistant Acinetobacter baumannii (IRAB) is an important cause of hospital-acquired infection. We aimed to describe an outbreak of IRAB infection and to investigate its possible source in an intensive care unit.MethodsAn environmental investigation was undertaken. Antimicrobial susceptibility testing was performed by microdilution. These isolates were genotyped by use of repetitive extragenic palindromic polymerase chain reaction (rep-PCR; DiversiLab). The study included 11 patients infected with IRAB and 14 control patients free of IRAB. Case and control patients were compared for possible predisposing factors. A multifaceted intervention was implemented to control the outbreak.ResultsThirty-nine IRABs were isolated from patients and the environmental surveillance culture in August, November, and December 2011. All isolates were resistant to imipenem. The IRAB strains belonged to seven clones (A–G) by the use of rep-PCR. There were four epidemic clones (D–G) in the outbreak, and Clone D was predominant. For the case–control study, patients with chronic obstructive pulmonary disease were susceptible to infection with IRAB. The hospital mortality of the case group was significantly higher than that of the control group.ConclusionsThe outbreak strains were transmitted among infected patients and equipment by inappropriate use of gloves. A combination of aggressive infection control measures is essential for preventing recurrent nosocomial outbreaks of IRAB.

Survival Predictors for Severe ARDS Patients Treated with Extracorporeal Membrane Oxygenation: A Retrospective Study in China

Extracorporeal membrane oxygenation (ECMO) is increasingly being applied as life support for acute respiratory distress syndrome (ARDS) patients. However, the outcomes of this procedure have not yet been characterized in severe ARDS patients. The aim of this study was to evaluate the outcomes of severe ARDS patients supported with ECMO and to identify potential predictors of mortality in these patients. A total of 38 severe ARDS patients (aged 51.39±13.27 years, 32 males) who were treated with ECMO in the specialized medical intensive care unit of Guangzhou Institute of Respiratory Diseases from July 2009 to December 2014 were retrospectively reviewed. The clinical data of the patients on the day before ECMO initiation, on the first day of ECMO treatment and on the day of ECMO removal were collected and analyzed. All patients were treated with veno-venous ECMO after a median mechanical ventilation duration of 6.4±7.6 days. Among the 20 patients (52.6%) who were successfully weaned from ECMO, 16 patients (42.1%) survived to hospital discharge. Of the identified pre-ECMO factors, advanced age, a long duration of ventilation before ECMO, a higher Acute Physiology and Chronic Health Evaluation II (APACHE II) score, underlying lung disease, and pulmonary barotrauma prior to ECMO were associated with unsuccessful weaning from ECMO. Furthermore, multiple logistic regression analysis indicated that both barotrauma pre-ECMO and underlying lung disease were independent predictors of hospital mortality. In conclusion, for severe ARDS patients treated with ECMO, barotrauma prior to ECMO and underlying lung disease may be major predictors of ARDS prognosis based on multivariate analysis.

The Predictive Value of Plasma Galectin-3 for Ards Severity and Clinical Outcome.

Background: Galectin-3 is a &bgr;-galactoside-binding lectin implicated as a mediator in a variety of inflammatory and fibrotic diseases. However, information about galectin-3 release in patients with acute respiratory distress syndrome (ARDS) is very limited. We sought to determine whether plasma galectin-3 levels were increased in ARDS patients and were associated with disease severity. Methods: Patients admitted to intensive care unit (ICU) within 48 h and diagnosed with ARDS were identified. In addition, healthy subjects were assigned to a control group. Plasma samples were collected from patients within 48 h after ICU admission as well as healthy subjects. Plasma galectin-3 levels were measured by enzyme-linked immunosorbent assay. The primary outcome was mortality at 28 days. Results: Sixty-three ARDS patients were identified. Among these, 27 patients died within 28 days of admission. The plasma galectin-3 levels of the patients were significantly higher than those of control subjects (median [IQR]: 12.37 [7.94–18.79] vs. 5.01 [4.15–5.69] ng/mL, respectively, P <0.0001). Furthermore, galectin-3 levels were significantly higher in non-surviving patients than in those who survived (15.38 [11.59–22.98] vs. 10.07 [7.39–15.54] ng/mL, respectively, P = 0.0136). Plasma galectin-3 levels were significantly correlated with acute physiology and chronic health evaluation II scores and arterial oxygen tension/inspiratory oxygen fraction ratios (Spearman rho = 0.44, P <0.0001 and −0.616, P <0.0001, respectively). At an optimal cutoff of 10.59 ng/mL, the sensitivity and specificity of galectin-3 for prediction of 28-day mortality were 81.48% (95% CI 0.62–0.94) and 55.56% (95% CI 0.38–0.72), respectively. Conclusions: Higher levels of galectin-3 were significantly associated with disease severity and worse outcomes in ARDS patients.

Interleukin-10/lymphocyte ratio predicts mortality in severe septic patients

Background Immunosuppression is common even in the early stage of severe sepsis. Interleukin-10 (IL-10) secretion and lymphocyte exhaustion are the main features of sepsis-induced immunosuppression. However, the relationship between IL-10 and the lymphocyte is still unclear. We investigated if IL-10/lymphocyte ratio (IL10LCR) were associated with mortality in severe septic patients. Methods Adult patients with severe sepsis admitted to ICU of the First Affiliated Hospital of Guangzhou Medical University were identified from October 2012 to August 2013. Within 24 hours of ICU admission, peripheral whole blood was collected for the measurement of IL-10 using commercial multiplex bead-based assay kits and determination of lymphocyte count from laboratory data. The primary outcome was 28-day mortality. Results A total of 63 severe sepsis patients were identified. There were 20 (32%) patients died within 28 days. IL10LCR in non-survival patients was significantly higher than survival patients (median (IQR) 36.78 (12.34–79.63) ng/ml2 versus 11.01(5.41–27.50) ng/ml2, P = 0.002). Correlation analysis showed that IL10LCR was significantly correlated with APACHE II score (Spearman’s rho = 0.424, P<0.001). The receiver operating characteristic (ROC) curves showed the area under the curve was 0.749 for IL10LCR level to predict 28-day mortality with sensitivity and specificity at 70.0% and 74.4%, respectively. At an optimal cutoff of 23.39ng/ml2, Kaplan-Meier curve showed survival in patients with IL10LCR level above 23.39ng/ml2 was significantly lower than in patients with IL10LCR level less than 23.39ng/ml2 (P = 0.001 by log-rank test). Conclusion IL10LCR level is significantly associated with the severity and outcome of severe septic patients. It may serve as a biomarker for sepsis-induced immunosuppression.

Identification of a novel HLA‐DRB1 allele, HLA‐DRB1*12:51, in a Chinese Cord Blood Donor

HLA-DRB1*12:51 has a single nucleotide difference to DRB1*12:02:01 at position 208, G > T.

MicroRNA-19b Mediates Lung Epithelial-Mesenchymal Transition via Phosphatidylinositol-3,4,5-Trisphosphate 3-Phosphatase in Response to Mechanical Stretch

&NA; Lung epithelial‐mesenchymal transition (EMT) plays an important role in ventilation‐associated lung fibrosis, which may contribute to the poor outcome of patients with acute respiratory distress syndrome. Because microRNAs control and modulate normal physiological and pathophysiological processes, we investigated the role of microRNAs in the development of acute respiratory distress syndrome‐associated EMT in response to mechanical stress. In the current study, primary human alveolar epithelial type II (AEII) cells were subjected to cyclic stretch that resulted in EMT profiles with decreased gene expression of cytokeratin‐8, E‐cadherin, and surfactant protein B, and increased expression of vimentin, &agr;‐smooth muscle actin, and N‐cadherin. Microarray analysis revealed that the expression of microRNA‐19b (miR‐19b) was up‐regulated in the AEII cells, and real‐time polymerase chain reaction showed that the expression of miR‐19b increased in both the AEII cells and the primary human small‐airway epithelial cells. Overexpression of miR‐19b in small‐airway epithelial cells promoted the mechanical stretch‐induced EMT phenotypes, whereas inhibition of miR‐19b attenuated it. The inhibitory effect of miR‐19b was attributed to enhanced signaling of phosphatidylinositol‐3,4,5‐trisphosphate 3‐phosphatase (PTEN), leading to inactivation of the AKT pathway. Restoration of PTEN expression or inhibition of AKT phosphorylation suppressed the mechanical stretch‐induced EMT phenotypes. We further demonstrated that the mechanical stretch‐induced miR19 expression was regulated by the focal adhesion kinase‐Rho pathway. In conclusion, we found that miR‐19b plays a key role in the development of the EMT phenotype through down‐regulation of PTEN in human lung epithelial cells in response to mechanical stretch. The miR‐19b‐PTEN signaling pathway may serve as a novel therapeutic target in the context of ventilator‐associated lung fibrosis.

973: THE EFFICACY OF HIGH-FLOW NASAL CANNULA OXYGEN THERAPY IN ADULT RESPIRATORY FAILURE: A META-ANALYSIS.

Learning Objectives: High-flow nasal cannula oxygen therapy is the most recent mode of respiratory support in adult respiratory failure. However, the evidence supporting its efficacy has not yet been established. We conducted a systematic review and meta-analysis of clinical trials comparing the efficacy of high-flow nasal cannula(HFNC) therapy compared with conventional oxygen therapy(COT) and noninvasive ventilation (NIV) in adults. Methods: Articles were indexed by using Pubmed, Embase, Scopus and Web of Science. Randomized clinical trials involving adults, comparing HFNC with COT or NIV, and reporting extractable data on relevant outcomes, were selected. Data on efficacy and other common outcomes, including intubation rates and odds of death, were extracted on predesigned forms. Results: In this analysis, we included 2,386 adults participating in 8 clinical trials. HFNC therapy had significantly superior in efficacy to COT in adults with respiratory failure when used as primary support (odds ratio of failure of therapy, 0.45 [95% confidence interval: 0.26 to 0.77], p=0.005; I2=55%), as well as after extubation (OR, 0.32, 95%CI [0.19 to 0.54], p<0.0001; I2=8%). There were no significant differences in odds of death (OR, 0.72 95%CI [0.39, 1.32]; p=0.28; I2=0%) between the groups. When compared to NIV treatment, HFNC had shown similar efficacy in treating adults with respiratory failure (odds ratio of failure of therapy, 0.84, 95%CI [0.63, 1.11]; p=0.23; I2=48%). Conclusions: High-flow therapy had shown greater efficacy than conventional oxygen therapy in treating adult patients with respiratory failure. And it appears to be similar in efficacy to NIV in adult patients with respiratory failure.