Jinjun Bian

Serum miR-146a and miR-223 as potential new biomarkers for sepsis.

OBJECTIVE Current biomarkers cannot completely distinguish sepsis from systemic inflammatory response syndrome (SIRS) caused by other non-infectious diseases. Circulating microRNAs (miRNAs) are promising biomarkers for several diseases, but their correlation with sepsis is not totally clarified. METHODS Seven miRNAs related to inflammation or infection were included in the present study. Serum miRNA expression was investigated in 50 patients diagnosed with sepsis, 30 patients with SIRS and 20 healthy controls to evaluate the diagnostic and prognostic value. Expression levels of serum miRNAs were determined by quantitative PCR using the Qiagen miScript system. Serum CRP and IL-6 levels were determined by enzyme linked immunosorbent assay. RESULTS Serum miR-146a and miR-223 were significantly reduced in septic patients compared with SIRS patients and healthy controls. The areas under the receiver operating characteristic curve of miR-146a, miR-223 and IL-6 were 0.858, 0.804 and 0.785, respectively. CONCLUSION Serum miR-146a and miR-223 might serve as new biomarkers for sepsis with high specificity and sensitivity. (ClinicalTrials.gov number, NCT00862290.).

Propofol vs traditional sedative agents for endoscopic retrograde cholangiopancreatography: A meta-analysis

AIM To investigate the efficacy and safety of propofol sedation for endoscopic retrograde cholangiopancreatography (ERCP). METHODS Databases including PubMed, Embase, and the Cochrane Central Register of Controlled Trials updated as of October 2010 were searched. Main outcome measures were ERCP procedure duration, recovery time, incidence of hypotension and hypoxia. RESULTS Six trials with a total of 663 patients were included. The pooled mean difference in ERCP procedure duration between the propofol and traditional sedative agents was -8.05 (95% CI: -16.74 to 0.63), with no significant difference between the groups. The pooled mean difference in the recovery time was -18.69 (95% CI: -25.44 to -11.93), which showed a significant reduction with use of propofol sedation. Compared with traditional sedative agents, the pooled OR with propofol sedation for ERCP causing hypotension or hypoxia was 1.69 (95% CI: 0.82-3.50) and 0.90 (95% CI: 0.55-1.49), respectively, which indicated no significant difference between the groups. CONCLUSION Propofol sedation during ERCP leads to shorter recovery time without an increase of cardiopulmonary side effects. Propofol sedation can provide adequate sedation during ERCP.

Methane limit LPS-induced NF-κB/MAPKs signal in macrophages and suppress immune response in mice by enhancing PI3K/AKT/GSK-3β-mediated IL-10 expression

Inflammatory diseases such as sepsis and autoimmune colitis, characterized by an overwhelming activation of the immune system and the counteracting anti-inflammatory response, remain a major health problem in worldwide. Emerging evidence suggests that methane have a protective effect on many animal models, like ischaemia reperfusion injury and diabetes-associated diseases. Whether methane could modulating inflammatory diseases remains largely unknown. Here we show that methane-rich saline (MS) ip treatment (16 ml/kg) alleviated endotoxin shock, bacteria-induced sepsis and dextran-sulfate-sodium-induced colitis in mice via decreased production of TNF-α and IL-6. In MS-treated macrophages, LPS-induced activation of NF-κb/MAPKs was attenuated. Interestingly, MS treatment significantly elevated the levels of IL-10 both in vitro and in vivo. Neutralization of IL-10 abrogated the therapeutic effect of MS. Moreover, anti-IL10 blockade partially restored the MS-mediated attenuation of NF-κb/MAPKs phosphorylation. We further found that MS resulted in markedly enhanced phosphorylation of GSK-3β and AKT, which both mediate the release of Il-10. Additionally, inhibition of PI3K attenuated MS-mediated p-GSK-3β and IL-10 production and reversed the suppressed activation of NF-κb/ MAPKs in response to LPS. Our results reveal a novel effect and mechanisms of methane and support the potential value of MS as a therapeutic approach in innate inflammatory diseases.

Up-regulation of programmed cell death 1 ligand 1 on neutrophils may be involved in sepsis-induced immunosuppression: an animal study and a prospective case-control study.

Background:Recent studies have shown that neutrophils may display an antigen-presenting function and inhibit lymphocyte proliferation by expressing programmed cell death 1 ligand 1 (PD-L1). The current study was performed to investigate the effect of neutrophils and their pathophysiological significance during sepsis. Methods:Neutrophil PD-L1 expression was determined in both septic mice (n = 6) and patients (n = 41). Neutrophils from septic mice were subtyped into PD-L1− and PD-L1+ populations to determine their phenotypes and functions. Septic neutrophils were cocultured with lymphocytes to observe the effect of septic neutrophils on lymphocyte apoptosis. Results:The PD-L1 level on neutrophils from septic mice was significantly up-regulated (21.41 ± 4.76%). This level increased with the progression of sepsis and the migration of neutrophils from the bone marrow to the blood and peritoneal cavity. The percentages of CD11a, CD62L, and C-C chemokine receptor type 2 were lower, whereas the percentages of CD16 and CD64 were higher on PD-L1+ neutrophils than on PD-L1− neutrophils. The migratory capacity of PD-L1+ neutrophils was compromised. Septic neutrophils induced lymphocyte apoptosis via a contact mechanism, and this process could be reversed by anti-PD-L1 antibody. PD-L1 was also up-regulated on neutrophils from patients with severe sepsis (14.6% [3.75%, 42.1%]). The levels were negatively correlated with the monocyte human leukocyte antigen-DR level and positively correlated with the severity of septic patients. Neutrophil PD-L1 was a predictor for the prognosis of severe sepsis, with an area of 0.74 under the receiver operating curve. Conclusions:PD-L1 is up-regulated on neutrophils during sepsis, which may be related to sepsis-induced immunosuppression.

Methane ameliorates spinal cord ischemia-reperfusion injury in rats: Antioxidant, anti-inflammatory and anti-apoptotic activity mediated by Nrf2 activation

ABSTRACT Methane is reported to have antioxidant, anti‐inflammatory and anti‐apoptotic properties. We investigated the potential neuroprotective effects of methane‐rich saline (MS) on spinal cord ischemia‐reperfusion injury and determined that its therapeutic benefits are associated with the activation of nuclear factor erythroid 2‐related factor 2 (Nrf2). Rats received 9 min of spinal cord ischemia induced by occlusion of the descending thoracic aorta plus systemic hypotension followed by a single MS treatment (10 ml/kg, ip) and 72 h reperfusion. MS treatment attenuated motor sensory deficits and produced high concentrations of methane in spinal cords during reperfusion, which increased Nrf2 expression and transcriptional activity in neurons, microglia and astrocytes in the ventral, intermediate and dorsal gray matter of lumbar segments. Heme oxygenase‐1, superoxide dismutase, catalase and glutathione were upregulated; and glutathione disulfide, superoxide, hydrogen peroxide, malondialdehyde, 8‐hydroxy‐2‐deoxyguanosine and 3‐nitrotyrosine were downregulated in MS‐treated spinal cords. MS treatment reduced neuronal apoptosis in gray matter zones, which was consistent with the suppression of cytochrome c release to the cytosol from the mitochondria and the activation of caspase‐9 and ‐3. Throughout the gray matter, the activation of microglia and astrocytes was inhibited; the nuclear accumulation of phosphorylated nuclear factor‐kappa B p65 was reduced; and tumor necrosis factor &agr;, interleukin 1&bgr;, chemokine (C‐X‐C motif) ligand 1, intercellular adhesion molecule 1 and myeloperoxidase were decreased. MS treatment attenuated blood‐spinal cord barrier dysfunction by preventing the expression and activity of matrix metallopeptidase‐9 and disrupting tight junction proteins. Consecutive intrathecal injection of specific siRNAs targeting Nrf2 at 24‐h intervals 3 days before ischemia reduced the beneficial effects of MS. Our data indicate that MS treatment prevents IR‐induced spinal cord damage via antioxidant, anti‐inflammatory and anti‐apoptotic activities that involve the activation of Nrf2 signaling. Thus, methane may serve as a novel promising therapeutic agent for treating ischemic spinal cord injury. Graphical abstract Figure. No Caption Available. HighlightsMethane exerts neuroprotective effects on spinal cord ischemia‐reperfusion injury.Methane activates Nrf2 in neurons, microglia and astrocytes in the spinal cord.The increased Nrf2 signaling inhibits oxidative stress and neuronal apoptosis.It also reduces proinflammatory response and blood‐spinal cord barrier dysfunction.Our results elucidate Nrf2‐dependent benefits of methane for spinal cord injury.

Plasma HSPA12B Is a Potential Predictor for Poor Outcome in Severe Sepsis

Introduction Endothelium-derived molecules may be predictive to organ injury. Heat shock protein (HSP) A12B is mainly located in endothelial cells, which can be detected in the plasma of septic patients. Whether it is correlated with prognosis of sepsis remains unclear. Methods Extracellular HSPA12B (eHSPA12B) was determined in plasma of septic mice at 6h, 12h, 24h and 48h after cecal ligation and puncture (CLP). It was also detected in plasma of patients with severe sepsis, sepsis, systemic inflammatory response syndrome and healthy volunteers. The predictive value for prognosis of severe sepsis was assessed by receiver operating curve (ROC) and Cox regression analyses. Results eHSPA12B was elevated in plasma of CLP mice at 6h and peaked at 24h after surgery. A total of 118 subjects were included in the clinical section, including 66 patients with severe sepsis, 21 patients with sepsis, 16 patients with SIRS and 15 volunteers. Plasma eHSPA12B was significantly higher in patients with severe sepsis than in patients with sepsis, SIRS and volunteers. The level of eHSPA12B was also higher in non-survivals than survivals with severe sepsis. The area under the curve (AUC) of eHSPA12B in predicting death among patients with severe sepsis was 0.782 (0.654–0.909) in ROC analysis, much higher than that of IL-6 and IL-10. Cox regression analysis showed that cardiovascular diseases, IL-6 and eHSPA12B were risk factors for mortality in patients with severe sepsis. Survival curve demonstrated a strikingly significant difference between 28-day survival rates of patients with an eHSPA12B lower or not lower than 1.466ng/ml. Conclusions Plasma eHSPA12B is elevated in both septic mice and patients. It may be a good predictor for poor outcome in patients with severe sepsis.

Effect of diltiazem and lidocaine on arterial pressure or heart rate and the quality of extubation in patients undergoing uvulopalato-pharyngoplasty

Abstract Objective To evaluate the effect of diltiazem and lidocaine on arterial pressure or heart rate and the quality of extubation in patients undergoing uvulopalatopharyngoplasty. Methods Sixty patients were randomly divided into 4 groups: In the control group patients were given saline; in the lidocaine group patients were given 1.0 mg/kg lidocaine; in the diltiazem group patients were given 0.2 mg/kg diltiazem; and in the lidocaine plus diltiazem group patients were given 1.0 mg/kg lidocaine and 0.2 mg/kg diltiazem. These drugs were given 2 min before tracheal extubation. Values for SBP, DBP, and HR were recorded, on arriving at the operating room, immediately at the end of the surgery, at the time of injection of the study drugs, at tracheal extubation, at 1 min and 5 min after extubation. The quality of extubation according to the Sebels grading scale were compared among the 4 groups. Results During extubation in the control group HR, SBP and DBF increased significantly when compared to baseline levels. Both lidocaine (1.0 mg/kg) and diltiazem (0.2 mg/kg) successfully alleviated these increases. The suppressive effect of diltiazem was greater than that of lidocaine. The combinative use of the two drugs minimized the increases. The administration of lidocaine significantly suppressed bucking or coughing compared with the other groups. Conclusions The pressor responses and tachycardia occurring in patients with uvulopalatopharyngoplasty during emergence from anesthesia and tracheal extubation, can be easily blocked by a bolus dose of 1.0 mg/kg lidocaine, 0.2 mg/kg diltiazem or the combinative use of the two drugs. And the concurrent use of lidocaine and diltiazem alleviated the hemodynamic changes more obviously.

Nitric oxide and ATP-sensitive potassium channels mediate lipopolysaccharide-induced depression of central respiratory-like activity in brain slices.

Infection may result in early abnormalities in respiratory movement, and the mechanism may involve central and peripheral factors. Peripheral mechanisms include lung injury and alterations in electrolytes and body temperature, but the central mechanisms remain unclear. In the present study, brainstem slices harvested from rats were stimulated with lipopolysaccharide at different doses. Central respiratory activities as demonstrated by electrophysiological activity of the hypoglossal rootlets were examined and the mechanisms were investigated by inhibiting nitric oxide synthase and ATP-sensitive potassium channels. As a result, 0.5 µg/ml lipopolysaccharide mainly caused inhibitory responses in both the frequency and the output intensity, while 5 µg/ml lipopolysaccharide caused an early frequency increase followed by delayed decreases in both the frequency and the output intensity. At both concentrations the inhibitory responses were fully reversed by inhibition of nitric oxide synthase with Nω-nitro-L-arginine methyl ester hydrochloride (20 µM), and by inhibition of ATP- sensitive potassium channels with glybenclamide (100 µM). These results show that direct lipopolysaccharide challenge altered central respiratory activity in dose- and time- related manners. Nitric oxide synthase and ATP-sensitive potassium channels may be involved in the respiratory changes.

Activated protein C inhalation: A novel therapeutic strategy for acute lung injury

Summary Acute lung injury (ALI) is a critical illness syndrome with a mortality rate of 25–40%. Despite recent advances of our understanding of the pathophysiology of ALI, no pharmacologic therapies have been proven effective. The key pathogenesis of ALI is the activation of the coagulation cascade and impaired fibrinolysis, resulting in extensive fibrin and hyaline membrane deposition. Activated protein C (APC), an endogenous protein that promotes fibrinolysis and inhibits thrombosis, can modulate the coagulation and inflammation associated with ALI. It is therefore reasonable to suggest that preventing the progression of pulmonary coagulopathy, by restoring normal intraalveolar levels of protein C, will be of therapeutic benefit to patients with ALI. However, a recent clinical trial demonstrated that APC did not improve outcomes from ALI, raising the possibility that the method of APC administration, intravenous infusion or inhalation, may influence the outcomes. In this article we propose the hypothesis that APC inhalation might be a promising and novel choice in the treatment of ALI.

Sophocarpine Attenuates LPS-Induced Liver Injury and Improves Survival of Mice through Suppressing Oxidative Stress, Inflammation, and Apoptosis

Septic liver injury/failure that is mainly characterized by oxidative stress, inflammation, and apoptosis led to a great part of terminal liver pathology with limited effective intervention. Here, we used a lipopolysaccharide (LPS) stimulation model to simulate the septic liver injury and investigated the effect of sophocarpine on LPS-stimulated mice with endotoxemia. We found that sophocarpine increases the survival rate of mice and attenuates the LPS-induced liver injury, which is indicated by pathology and serum liver enzymes. Further research found that sophocarpine ameliorated hepatic oxidative stress indicators (H2O2, O2∙−, and NO) and enhanced the expression of antioxidant molecules such as superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH). In addition, sophocarpine also attenuated regional and systematic inflammation and further reduced apoptosis of hepatocytes. Mechanistic evidence was also investigated in the present study as sophocarpine inhibited hepatic expression of the CYP2E/Nrf2 pathway during oxidative stress, inactivated p38/JNK cascade and NF-κB pathway, and, meanwhile, suppressed PI3K/AKT signaling that reduced apoptosis. Conclusively, the present study unveiled the protective role of sophocarpine in LPS-stimulated oxidative reaction, inflammation, and apoptosis by suppressing the CYP2E/Nrf2/ROS as well as PI3K/AKT pathways, suggesting its promising role in attenuating inflammation and liver injury of septic endotoxemia.