The mechanism underlying ICAM-1 and E-selectin-mediated hypertriglyceridemic pancreatitis-associated lung injury.

PURPOSE: To investigate the possible mechanism by which adhesion molecules ICAM-1 and E-selectin mediate hypertriglyceridemic pancreatitis (HTGP)-associated lung injury. METHODS: C57BL/6 mice were randomly divided into five groups: control group (Con), severe acute pancreatitis group (SAP), HTGP group (HTGP), A-205804 group (A-205804), and apocynin group (Apo). Serum biochemical markers related to pancreatitis, such as inflammatory cytokines, amylase and lipase, were measured by enzyme-linked immunosorbent assay (ELISA) kits. Hematoxylin and eosin (HE) staining was used to analyze the histopathology changes in the pancreas and lung, and myeloperoxidase (MPO) activity in lung was detected by immunohistochemistry (IHC). Molecules related to NF-κB signaling pathway and adhesion molecules were assessed by western blotting (WB), IHC and immunofluorescence staining. The levels of malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione (GSH) in lung tissues and serum were measured with reagent kits, respectively. RESULTS: The severity of pancreatitis and lung injury in HTGP group was more severe than that in SAP group, and the expression levels of adhesion molecules ICAM-1 and E-selectin in lung tissues of HTGP mice were significantly increased. After HTGP mice were treated with adhesion molecule inhibitor A-205804, the expression of ICAM-1 and E-selectin in A-205804 group significantly decreased, and the lung injury was alleviated. The HTGP group had higher levels of oxidative stress and NF-κB pathway-related protein p-p65 expression compared with the SAP group. Apocynin treatment resulted in suppression of p-p65, ICAM-1, and E-selectin expression. CONCLUSION: In HTGP, hypertriglyceridemia may exacerbate pancreatitis-related lung injury by regulating oxidative stress and activating the NF-κB proinflammatory pathway to upregulate ICAM-1 and E-selectin levels.

Development an Inflammation-Related Factor-Based Model for Predicting Organ Failure in Acute Pancreatitis: A Retrospective Cohort Study.

Several inflammation-related factors (IRFs) have been reported to predict organ failure of acute pancreatitis (AP) in previous clinical studies. However, there are a few shortcomings in these models. The aim of this study was to develop a new prediction model based on IRFs that could accurately identify the risk for organ failure in AP. Methods. 100 patients with their clinical information and IRF data (levels of 10 cytokines, percentages of different immune cells, and data obtained from white blood cell count) were retrospectively enrolled in this study, and 94 patients were finally selected for further analysis. Univariate and multivariate analysis were applied to evaluate the potential risk factors for the organ failure of AP. The area under the ROC curve (AUCs), sensitivity, and specificity of the relevant model were assessed to evaluate the prediction ability of IRFs. A new scoring system to predict the organ failure of AP was created based on the regression coefficient of a multivariate logistic regression model. Results. The incidence of OF in AP patients was nearly 16% (15/94) in our derivation cohort. Univariate analytic data revealed that IL6, IL8, IL10, MCP1, CD3+ CD4+ T lymphocytes, CD19+ B lymphocytes, PCT, APACHE II score, and RANSON score were potential predictors for AP organ failure, and IL6 (P = 0.038), IL8 (P = 0.043), and CD19+B lymphocytes (P = 0.045) were independent predictors according to further multivariate analysis. In addition, a preoperative scoring system (0-11 points) was constructed to predict the organ failure of AP using these three factors. The AUC of the new score system was 0.86. The optimal cut-off value of the new scoring system was 6 points. Conclusions. Our prediction model (based on IL6, IL8, and CD19+ B Lymphocyte) has satisfactory working efficiency to identify AP patients with high risk of organ failure.

Dexmedetomidine attenuates inflammation and pancreatic injury in a rat model of experimental severe acute pancreatitis via cholinergic anti-inflammatory pathway.

BACKGROUND: Excessive inflammatory responses play a critical role in the development of severe acute pancreatitis (SAP), and controlling such inflammation is vital for managing this often fatal disease. Dexmedetomidine has been reported to possess protective properties in inflammatory diseases. Therefore, this study aimed to investigate whether dexmedetomidine pre-treatment exerts an anti-inflammatory effect in rats with SAP induced by sodium taurocholate, and if so, to determine the potential mechanism. METHODS: SAP was induced with sodium taurocholate. Rats received an intraperitoneal injection of dexmedetomidine 30 min before sodium taurocholate administration. α-bungarotoxin, a selective alpha-7 nicotinic acetylcholine receptor (α7nAchR) antagonist, was injected intra-peritoneally 30 min before dexmedetomidine administration. The role of the vagus nerve was evaluated by performing unilateral cervical vagotomy before the administration of dexmedetomidine. Efferent discharge of the vagal nerve was recorded by the BL-420F Data Acquisition & Analysis System. Six hours after onset, serum pro-inflammatory cytokine (tumor necrosis factor α [TNF-α] and interleukin 6 [IL-6]) levels and amylase levels were determined using an enzyme-linked immunosorbent assay and an automated biochemical analyzer, respectively. Histopathological changes in the pancreas were observed after hematoxylin and eosin staining and scored according to Schmidt criteria. RESULTS: Pre-treatment with dexmedetomidine significantly decreased serum levels of TNF-α, IL-6, and amylase, strongly alleviating pathological pancreatic injury in the rat model of SAP (TNF-α: 174.2 ±â€Š30.2 vs. 256.1±42.4 pg/ml; IL-6: 293.3 ±â€Š46.8 vs. 421.7 ±â€Š48.3 pg/ml; amylase: 2102.3 ±â€Š165.3 vs. 3186.4 ±â€Š245.2 U/L). However, the anti-inflammatory and pancreatic protective effects were abolished after vagotomy or pre-administration of α-bungarotoxin. Dexmedetomidine also significantly increased the discharge frequency and amplitude of the cervical vagus nerve in the SAP rat model (discharge frequency: 456.8 ±â€Š50.3 vs. 332.4 ±â€Š25.1 Hz; discharge amplitude: 33.4 ±â€Š5.3 vs. 20.5 ±â€Š2.9 µV). CONCLUSIONS: Dexmedetomidine administration attenuated the systemic inflammatory response and local pancreatic injury caused by SAP in rats through the cholinergic anti-inflammatory pathway involving vagus- and α7nAChR-dependent mechanisms.

Diabetes and Younger Age Are Vital and Independent Risk Factors for Acute Pancreatitis in Patients with Severe Hypertriglyceridemia.

Background. The incidence of hypertriglyceridemia-induced acute pancreatitis (HIAP) is increasing worldwide, and now it is the third leading cause of acute pancreatitis in the United States. But, there are only 5% of patients with severe hypertriglyceridemia (>1000 mg/dl) which might generate acute pancreatitis. In order to explore which part of the patients is easy to develop into pancreatitis, a case-control study was performed by us to consider which patient population tend to develop acute pancreatitis in patients with severe hypertriglyceridemia. To perform a retrospective case-control study, we identified severe hypertriglyceridemia patients without AP (HNAP) and with HIAP with a fasting triglyceride level of >1000 mg/dl from The First Affiliated Hospital of Nanjing Medical University during January 1, 2014, to December 31, 2016. Baseline patient characteristics, comorbidities, and risk factors were recorded and evaluated by the univariate and multivariate logistic regression analysis for HIAP and HNAP patients. A total of 124 patients with severe hypertriglyceridemia were included in this study; of which, 62 patients were in the HIAP group and 62 were in the HNAP group. Univariate logistic regression analysis showed that there was no gender difference in both groups; however, there were more younger patients in the HIAP group than in the HNAP group ( P value < 0.001), and the HIAP group had low level of high-density lipoprotein compared to the HNAP group ( P < 0.05 ). Meanwhile, the presence of pancreatitis was associated with higher level of glycemia and a history of diabetes ( P < 0.05 ). Multivariate logistic regression analysis indicated that a history of diabetes and younger age were independent risk factors for acute pancreatitis in patients with severe hypertriglyceridemia. Uncontrolled diabetes and younger age are potential risk factors in patients with severe hypertriglyceridemia to develop acute pancreatitis.

Minimally invasive drainage versus open surgical debridement in SAP/SMAP - a network meta-analysis.

BACKGROUND: The efficacy of some therapeutic methods (open surgical debridement (OSD), conservative treatment (CST) and minimally invasive drainage (MID)) for severe acute pancreatitis (SAP) and moderately severe acute pancreatitis (MSAP) has been widely evaluated. However, the results remained controversial. We performed this study to illuminate whether any difference in incidence exists on patients with SAP/MSAP treated with OSD and MID. METHODS: Eligible articles were collected base of a comprehensive review of PUBMED, EMBASE, COCHRANE, CKNI and WANGFANG for published randomized controlled trials. Two steps of meta-analysis were performed, routine pair-wise meta-analysis and network meta-analysis. RESULTS: Thirteen studies were included in this study. Participants were classed as 5 groups, CST, early MID (EMID), late MID (LMID), early OSD (EOSD) and late OSD (LOSD). And MID contains endoscopic drainage (ESD), percutaneous catheter drainage (PCD) and minimally invasive surgery (MIS). Compared with CST, MID could decrease both mortality and multiple organ dysfunction syndrome (MODS) rate but OSD couldn't. Both EMID and MID can significantly decrease the mortality and MODS rate compared to CST. PCD might be most likely to have a benefit compared to CST. CONCLUSION: Existing evidence for the use of MID in SAP/MSAP is reliable and it can be used as early treatment. OSD, if necessary, should be avoided or delayed as long as possible.

Iguratimod (T-614) attenuates severe acute pancreatitis by inhibiting the NLRP3 inflammasome and NF-κB pathway.

Severe acute pancreatitis (SAP) is an acute abdominal disease that can develop locally to the multiple organs. It is characterized by pancreatic tissue self-digestion, and the rapid release of inflammatory cytokines, which play a dominant role in local or even systemic inflammation. In this study, we investigate the protective effect of T-614 against SAP induced by cerulein plus LPS in mice. Biochemical markers associated with pancreatitis in serum such as inflammatory cytokines, amylase and lipase activities were measured. Related proteins of NLRP3 inflammasome and NF-κB signaling pathway were evaluated by western blotting. Hematoxylin-eosin staining (HE) and immunohistochemistry (IHC) were used to evaluate changes of inflammation in pancreatic tissue. T-614 significantly alleviated the elevation markers of pancreatitis and suppresses the pancreatic tissue damage, including histopathological and molecular manifestations. In conclusion, T-614 plays a protective role in experimental SAP mice model via anti-inflammatory effects.

Gene polymorphisms in the interleukins gene and the risk of acute pancreatitis: A meta-analysis.

Single nucleotide polymorphisms (SNPs) within the interleukins (IL) gene may affect the risk of acute pancreatitis. Many epidemiological studies have reported an association between the IL gene and acute pancreatitis risk, but the results remain inconsistent. Given the controversial available data, we carried out a meta-analysis to systematically evaluate and clarify the association between IL gene polymorphisms and AP. A systematic search of studies for this association was obtained from the PubMed, EMBASE, Web of Science and Chinese National Knowledge Infrastructure (CNKI) databases until June 1, 2017. We also searched the references of the included studies to identify additional studies. Odds ratios (ORs) with 95% confidence intervals (95% CIs) were used to pool the effect size. Stata12.0 was used for whole statistical analysis. Fifteen studies that contained 3371 AP cases and 3506 controls were included in final combination. Overall, a significant association was found between the IL-8-251 T/A (rs4073) polymorphism, the IL-10-1082 A/G (rs1800896) polymorphism and the AP risk in four genetic models (homozygote model, recessive model, dominant model, allele model). Meanwhile, individuals with IL-1ß+3954 C/T (rs1143634, (homozygote model, recessive model)), IL-1ß -511 C/T (rs16944, (dominant model)) and IL-6-634C/G (rs1800796, (allele model)) polymorphism were associated with an increased risk of AP. No evidence of an association was found between IL and 10-592 C/A (rs1800872) and IL-10-819 C/T (rs1800871) polymorphism and AP risk.

SRT1720 ameliorates sodium taurocholate-induced severe acute pancreatitis in rats by suppressing NF-κB signalling.

Severe acute pancreatitis (SAP) is a medical emergency that is often associated with multiple organ failure and high mortality. Although an SAP diagnosis requires prompt treatment, therapeutic options remain limited. SRT1720 is a newly formulatedSIRT1 activator that exerts multiple pharmacological activities with beneficial health effects. However, its potential as an SAP treatment has not been explored. The current study assessed the effect of SRT1720 on a rat model of sodium taurocholate-induced SAP and explored the underlying mechanism. SAP was induced in rats by retrograde injection of a 3.5% sodium taurocholate solution (1 ml/kg) in the biliopancreatic duct. SRT1720 (5 mg/kg) was administered intraperitoneally after sodium taurocholate exposure. Serum samples were analysed for inflammatory cytokine levels and select enzymatic activities using the enzyme-linked immunosorbent assay and commercial enzyme activity assay kits, respectively; protein expression levels were evaluated by western blotting; mRNA levels of biomarkers were determined by quantitative real-time PCR; histopathological changes were analysed by haematoxylin and eosin staining and immunohistochemistry.SRT1720 treatment significantly reduced serum amylase, lipase, pancreatic histological scores, proinflammatory cytokine (TNF-α and IL-6) levels, and expression of NF-κB and p65 in sodium taurocholate-induced SAP rats. Importantly, the treatment stimulated SIRT1 and IκBα levels in pancreatic tissue. Our data suggest that SRT1720 protects rats from sodium taurocholate-induced SAP by suppressing the NF-κB signalling pathway.

New Predictor of Organ Failure in Acute Pancreatitis: CD4+ T Lymphocytes and CD19+ B Lymphocytes.

OBJECTIVE: Lymphocytes are one of the main effector cells in the inflammatory response of acute pancreatitis (AP). The purpose of the study was to evaluate whether peripheral blood lymphocyte (PBL) subsets at admission change during AP based on clinical outcomes and to explore whether these changes vary by aetiology of AP. Hence, we performed a prospective study to find a predictor in lymphocyte subsets that might allow easier, earlier, and more accurate prediction of clinical outcomes. METHODS: Patients with AP were enrolled from December 2017 to June 2018 at the First Affiliated Hospital of Nanjing Medical University. Age, sex, clinical and biochemical parameters, and aetiology of AP were obtained at admission. PBL counts were assessed within 24 hours after admission. Clinical outcomes were observed as endpoints. The areas under the curve (AUCs) of different predictors were calculated using the receiver operating characteristic (ROC) curve. RESULTS: Overall, 133 patients were included. Patients (n=24) with organ failure (OF) had significantly lower CD4+ T lymphocyte levels than those (n=109) with No OF (NOF) (39.60 (33.94-46.13) vs. 32.41 (26.51-38.00), P=0.004). The OF group exhibited significantly higher CD19+ B lymphocytes than the NOF group (16.07 (10.67-21.06) vs. 23.78 (17.84-29.45), P=0.001). Of the AP cases, 68.8% were caused by gallstones; 10.1% were attributed to alcohol; 16.5% were due to hyperlipidaemia; and 4.6% had other causes. Across all aetiologies, a lower CD4+ T lymphocyte level was significantly related to OF (P<0.05). However, CD19+ B lymphocytes were significant only in gallstone pancreatitis (P<0.05). The ROC curve results showed that the AUC values of CD4+T lymphocytes, CD19+ B lymphocytes, and combined CD4+T lymphocytes and CD19+ B lymphocytes were similar to those of traditional scoring systems, such as APACHEII and Ranson. CONCLUSIONS: CD4+ T and CD19+ B lymphocytes during the early phase of AP can predict OF.

Thymidine kinase 1 silencing retards proliferative activity of pancreatic cancer cell via E2F1-TK1-P21 axis.

OBJECTIVES: Thymidine kinase 1 (TK1) is one of the salvage enzymes engaged in the synthesis of DNA. Although a pro-carcinogenetic role of TK1 has been reported in various types of cancers, its role in pancreatic ductal adenocarcinoma (PDAC) is still unknown. The study is aimed to elaborate the function of TK1 in PDAC and the potential mechanisms in the following study. MATERIALS AND METHODS: TK1 expression was analysed by immunohistochemistry, real-time PCR and Western blot, and its relationship with clinicopathological characteristics of PDAC patients was further investigated. To verify the function of TK1 and potential mechanism, TK1 siRNA was used to transfect PDAC cells and performed a series of assays in cell and animal models. RESULTS: The level of TK1 expression was higher in cancerous tissues compared with matched adjacent tissues. TK1 overexpression was associated with progression of PDAC and poor prognosis. Knockdown of TK1 could suppress cell proliferation via inducing S phase arrest mediated by upregulation of P21. Further mechanism investigation suggested that transcription factor E2F-1 could directly regulate the TK1 and promote tumour proliferation. CONCLUSIONS: The results suggested that TK1 might be involved in the development and progression of PDAC by regulating cell proliferation and show that TK1 may work as a promising therapeutic target in patients with PDAC.

A multichannel decision-level fusion method for T wave alternans detection.

Sudden cardiac death (SCD) is one of the most prominent causes of death among patients with cardiac diseases. Since ventricular arrhythmia is the main cause of SCD and it can be predicted by T wave alternans (TWA), the detection of TWA in the body-surface electrocardiograph (ECG) plays an important role in the prevention of SCD. But due to the multi-source nature of TWA, the nonlinear propagation through thorax, and the effects of the strong noises, the information from different channels is uncertain and competitive with each other. As a result, the single-channel decision is one-sided while the multichannel decision is difficult to reach a consensus on. In this paper, a novel multichannel decision-level fusion method based on the Dezert-Smarandache Theory is proposed to address this issue. Due to the redistribution mechanism for highly competitive information, higher detection accuracy and robustness are achieved. It also shows promise to low-cost instruments and portable applications by reducing demands for the synchronous sampling. Experiments on the real records from the Physikalisch-Technische Bundesanstalt diagnostic ECG database indicate that the performance of the proposed method improves by 12%-20% compared with the one-dimensional decision method based on the periodic component analysis.