Maochun Tang

Increased interleukin-23/17 axis and C-reactive protein are associated with severity of acute pancreatitis in patients.

Objective The interleukin (IL)-23/IL-17 axis plays an important role in various inflammatory conditions but its function in acute pancreatitis (AP) is not well understood. The present study investigated the relationship between serum levels of IL-23, IL-17, and C-reactive protein (CRP) in patients and the severity of AP. Methods Eighty-five patients with AP were categorized into mild group, moderately severe group, and severe group according to the revised Atlanta classification, 2012. Serum levels of IL-23 and IL-17 were measured by enzyme-linked immunosorbent assay in patients 48 hours after admission. The CRP levels of patients were also measured on admission and 48 hours after admission. Results The serum levels of CRP of patients on admission and 48 hours after admission and levels of IL-23 and IL-17 of patients 48 hours after admission increased alone with the severity of AP, respectively (P < 0.01). The serum levels of IL-23 and IL-17 in the patients were correlated with CRP levels (r2 = 0.234, r2 = 0.552, P < 0.001, respectively). Conclusions The serum levels of IL-17, IL-23, and CRP are correlated with the severity of AP and represent valuable prognostic factors in the assessment of disease severity of patients with AP.

C-reactive protein: rethinking its role in evaluating the severity of hyperlipidemic acute pancreatitis.

Objectives The goal of this study is to evaluate the role of C-reactive protein (CRP) in predicting the severity of hyperlipidemic acute pancreatitis (HLAP) compared with non-HLAP (NHLAP). Methods A total of 1073 episodes of acute pancreatitis between July 2009 and June 2013 were retrospectively studied. The clinical characteristics and laboratory data of HLAP and NHLAP were statistically analyzed on days 1, 2, 3, 4, and 6, especially the CRP level. Results There was a significant difference in CRP levels between HLAP and NHLAP (P < 0.01) on days 1, 2, 3, 4, and 6. The cutoff value for CRP in HLAP should be greater than NHLAP to obtain an accurate prediction of severity. Higher serum CRP levels in HLAP cases were correlated with higher incidences of diabetes and fatty liver and lower incidences in women, elevated very-low-density lipoprotein levels, and lower high-density lipoprotein levels. Conclusions The significant difference in CRP cutoff values in predicting severity between patients with HLAP and NHLAP should be noted in the clinic.

Different Clinical Presentations of Hyperlipidemic Acute Pancreatitis: A Retrospective Study.

Objectives The goal of this study was to summarize the clinical features of hyperlipidemic acute pancreatitis (HLAP), and help clinicians understand the characteristic presentations of HLAP. Methods From July 2009 to June 2013, 1073 cases of acute pancreatitis were retrospectively assessed. The clinical characteristics of HLAP and non-HLAP were statistically analyzed. Results The etiologic ratio of HLAP in acute pancreatitis rose from 13% in 2009 to 25.6% in 2013. Diabetes mellitus, fatty liver, and acute pancreatitis recurrence were positively correlated with HLAP, and female sex, age (>60 years), and alkaline phosphatase level were negatively correlated with HLAP. The diagnostic accuracy of amylase in HLAP was only 40.38%, compared with lipase (91.83%). Different cutoff points of serum triglyceride on day 1 (5.33 mmol/L), day 2 (2.77 mmol/L), and day 3 (2.18 mmol/L) could be used to obtain an accurate diagnosis of HLAP. Higher incidences of acute peripancreatic fluid collection, renal failure, and severe acute pancreatitis were also observed in patients with HLAP. Conclusions Different clinical presentations of HLAP should be applied to be distinguished from non-HLAP in the clinic.

Role of Microvesicles From Bone Marrow Mesenchymal Stem Cells in Acute Pancreatitis

Objectives Mesenchymal stem cells (MSCs) have shown an obvious protective effect on acute pancreatitis (AP). The purpose of the present study was to analyze the effect of bone marrow MSC-derived microvesicles (bmMSC-MVs) on AP and explore the underlying mechanisms. Methods Bone marrow MSCs and bmMSC-MVs were isolated from Sprague-Dawley rats. Cerulein-induced mild AP (MAP) and sodium taurocholate-induced severe AP (SAP) were used as AP models in vivo and in vitro. Pancreatic injury was evaluated by measuring serum levels of amylase, lipase, chemokines, and interleukins, and by pancreatic histology, reverse transcription-polymerase chain reaction, Western blotting, and immunohistochemistry. The effects of bmMSC-MVs on the survival rates of pancreatic acinar cells in vitro were also assessed. Results Bone marrow MSC-MVs attenuated acute pancreatic injury in MAP and SAP by regulating IL-1&agr;, IL-6, and TNF-&agr;, and dramatically attenuated the nuclear translocation of NF-&kgr;B p65 in MAP and SAP. Bone marrow MSC-MVs improved the survival rates of pancreatic acinar cells in MAP and SAP models in vitro. Conclusions Bone marrow MSC-MVs played a protective role in AP by reducing the levels of proinflammatory cytokines and regulating the nuclear translocation of NF-&kgr;B p65. Bone marrow MSC-MVs could be developed as a strategy for the clinical treatment of SAP.OBJECTIVES Mesenchymal stem cells (MSCs) have shown an obvious protective effect on acute pancreatitis (AP). The purpose of the present study was to analyze the effect of bone marrow MSC-derived microvesicles (bmMSC-MVs) on AP and explore the underlying mechanisms. METHODS Bone marrow MSCs and bmMSC-MVs were isolated from Sprague-Dawley rats. Cerulein-induced mild AP (MAP) and sodium taurocholate-induced severe AP (SAP) were used as AP models in vivo and in vitro. Pancreatic injury was evaluated by measuring serum levels of amylase, lipase, chemokines, and interleukins, and by pancreatic histology, reverse transcription-polymerase chain reaction, Western blotting, and immunohistochemistry. The effects of bmMSC-MVs on the survival rates of pancreatic acinar cells in vitro were also assessed. RESULTS Bone marrow MSC-MVs attenuated acute pancreatic injury in MAP and SAP by regulating IL-1α, IL-6, and TNF-α, and dramatically attenuated the nuclear translocation of NF-κB p65 in MAP and SAP. Bone marrow MSC-MVs improved the survival rates of pancreatic acinar cells in MAP and SAP models in vitro. CONCLUSIONS Bone marrow MSC-MVs played a protective role in AP by reducing the levels of proinflammatory cytokines and regulating the nuclear translocation of NF-κB p65. Bone marrow MSC-MVs could be developed as a strategy for the clinical treatment of SAP.

Pancreatic acinar cells-derived cyclophilin A promotes pancreatic damage by activating NF-κB pathway in experimental pancreatitis

Inflammation triggered by necrotic acinar cells contributes to the pathophysiology of acute pancreatitis (AP), but its precise mechanism remains unclear. Recent studies have shown that Cyclophilin A (CypA) released from necrotic cells is involved in the pathogenesis of several inflammatory diseases. We therefore investigated the role of CypA in experimental AP induced by administration of sodium taurocholate (STC). CypA was markedly upregulated and widely expressed in disrupted acinar cells, infiltrated inflammatory cells, and tubular complexes. In vitro, it was released from damaged acinar cells by cholecystokinin (CCK) induction. rCypA (recombinant CypA) aggravated CCK-induced acinar cell necrosis, promoted nuclear factor (NF)-κB p65 activation, and increased cytokine production. In conclusion, CypA promotes pancreatic damage by upregulating expression of inflammatory cytokines of acinar cells via the NF-κB pathway.

Astragaloside IV ameliorates acute pancreatitis in rats by inhibiting the activation of nuclear factor-κB

This study aimed to investigate the effects of astragaloside IV (AS-IV; 3-O-β-D-xylopyranosyl-6-O-β-D-glucopyranosylcycloastragenol), which has been reported to have comprehensive pharmacological functions, on sodium taurocholate (NaTc)/L-arginine (L-Arg)-induced acute pancreatitis (AP) in rats in vivo and in rat pancreatic acinar cells in vitro. NaTc-induced experimental AP was induced in rats by injecting 4% NaTc (0.1 ml/100 g) in the retrograde direction of the biliopancreatic duct. L-Arg-induced experimental AP was induced in rats by 2 intraperitoneal injections of 20% L-arg (3 g/kg), with an interval of 1 h between the injections. The rats were pre-treated AS-IV (50 mg/kg) or the vehicle (DMSO) 2 h prior to the induction of AP. Enzyme-linked immunosorbent assay, H&E staining, myeloperoxidase (MPO) activity, reverse transcription-quantitative PCR, western blot analysis and immunohistochemistry were used to evaluate the effects of AS-IV on AP. The results revealed that treatment with AS-IV significantly reduced serum amylase and lipase levels, pancreatic pathological alterations, the secretion of pro-inflammatory cytokines, MPO activity, and the protein expression of nuclear factor-κB (NF-κB) in vivo. Moreover, pre-treatment with AS-IV significantly increased the expression levels of manganese superoxide dismutase and cuprum/zinc superoxide dismutase. In the in vitro experiment, treatment of the cells with AS-IV aslo reduced rat pancreatic acinar cell necrosis and nuclear NF-κB activity, and enhanced the protein expression of superoxide dismutase. In conclusion, this study indicates that the protective effects of AS-IV on experimental AP in rats may be closely related to the inhibition of NF-κB. In addition, our results indicate that AS-IV may exert potential antioxidant effects on AP. Therefore, AS-IV may be an effective therapeutic agent for AP.

Downregulation of CD9 promotes pancreatic cancer growth and metastasis through upregulation of epidermal growth factor on the cell surface

The expression of CD9 has been shown to be inversely associated with pancreatic cancer metastasis but the underlying mechanism remains incompletely understood. Using the two closely associated pancreatic cancer cell lines, PaTu-8898s and PaTu-8898t, which are metastatic and non-metastatic, respectively, we showed that the PaTu-8988s cells expressed a lower level of CD9 but had higher proliferation and migration rates than the PaTu-8898t cells. An inverse correlation between CD9 expression and the cell surface level of epidermal growth factor receptor (EGFR) was observed in both cell lines. In the PaTu-8898s cells, overexpression of CD9 decreased the cell surface expression of EGFR, associated with increased expression of dynamin-2, whereas in the PaTu-8898t cells, knockdown of CD9 with RNA interference (RNAi) increased the cell surface expression of EGFR, associated with decreased expression of dynamin-2. However, the total EGFR level did not change by manipulation of CD9 expression, suggesting that CD9 plays a role in EGFR endocytosis. Furthermore, in the PaTu-8898ts cells, CD9 overexpression decreased the cell proliferation and migration, which were reversed by EGFR overexpression, whereas in the PaTu-8898t cells, CD9 knockdown enhanced the cell proliferation and migration which were blocked by EGFR RNAi both in vitro and in vivo. Thus, in pancreatic cancer cells, downregulation of CD9 may play a role in cancer growth and metastasis through, at least in part, enhancing cell surface expression of EGFR.

Impact of Seasons and Festivals on the Onset of Acute Pancreatitis in Shanghai, China.

Objectives Seasonal variation on acute pancreatitis (AP) has not been investigated in Eastern Asia. The aims of the study were to assess the association of the onset of AP with the occurrence of seasons and Chinese festivals and to investigate trends in AP incidence in Shanghai, China. Methods From January 2009 to December 2014, a total of 1780 patients with AP were considered. The incidence was assessed by different etiology and severity. Monthly disease prevalence was investigated to explore the seasonal variation. The prevalence on weekdays, weekends, and festivals was evaluated to establish any weekly or festival influences in AP. Results Acute pancreatitis increased from 30.5 per 100,000 in 2009 to 39.2 in 2014 (5.1% annual increase), with greatest increases in alcoholic (19.8% annually) and severe AP (13.7% annually). Time series analysis indicated that prevalence was significantly higher form February to May (spring) and from September to October (autumn). Acute pancreatitis increased during Chinese festivals, 17% and 28% greater than that observed on weekdays and weekends, respectively. Prevalence was greatest in Chinese Spring Festival week. Conclusions Acute pancreatitis increased in Shanghai and had a seasonal variation, with a higher frequency of events in the spring and autumn. Chinese festivals are associated with a high prevalence of AP.

MiRNA-155 Regulates the Th17/Treg Ratio by Targeting SOCS1 in Severe Acute Pancreatitis

Acute pancreatitis (AP) is a serious condition associated with intestinal barrier disruption or inflammation of the pancreatic tissue. Specific microRNAs are involved in the pathogenesis of AP, during which IL-17-producing CD4+ T helper (Th17) cells accumulate in the pancreas. In this study, significantly increased levels of miR-155 were detected in clinical samples from patients with AP, and overexpression of miR-155 correlated with severe AP (SAP). To identify the effect of miR-155 on T cell differentiation, we isolated CD4+ T lymphocytes and in vitro experiments showed that inhibition of miR-155 significantly reversed the stress-induced increase in the Th17/Treg ratio. The results also showed that miR-155 increased the Th17-mediated inflammatory response by targeting SOCS1. The interaction between miR-155 and the 3′-UTR of SOCS1 was confirmed by a dual luciferase reporter assay and RT-PCR. Experimental AP of varying severity was induced in BALB/c mice by caerulein hyperstimulation and miR-155 expression was found to increase with disease progression. Inhibition of miR-155 expression significantly improved the pathology of the pancreas. We also observed downregulation of expression of inflammatory factors, IL-17, SOCS1 and phosphorylated STAT1 after miR-155 inhibition. In summary, miR-155 regulates the Th17/Treg ratio by targeting SOCS1, most probably via direct binding to its 3′-UTR region, indicating that this microRNA may be a potential biomarker and/or therapeutic target for AP.

Lipoprotein lipase gene-deficient mice with hypertriglyceridaemia associated with acute pancreatitis.

PURPOSE: To investigate the severity of pancreatitis in lipoprotein lipase (LPL)-deficient hypertriglyceridaemic (HTG) heterozygous mice and to establish an experimental animal model for HTG pancreatitis study. METHODS: LPL-deficient HTG heterozygous mice were rescued by somatic gene transfer and mated with wild-type mice. The plasma amylase, triglyceride, and pathologic changes in the pancreas of the LPL-deficient HTG heterozygous mice were compared with those of wild-type mice to assess the severity of pancreatitis. In addition, acute pancreatitis (AP) was induced by caerulein (50 µg/kg) for further assessment. RESULTS: The levels of plasma amylase and triglyceride were significantly higher in the LPL-deficient HTG heterozygous mice. According to the pancreatic histopathologic scores, the LPL-deficient HTG heterozygous mice showed more severe pathologic damage than the wild-type mice. CONCLUSIONS: Lipoprotein lipase deficient heterozygous mice developed severe caerulein-induced pancreatitis. In addition, their high triglyceride levels were stable. Therefore, LPL-deficient HTG heterozygous mice are a useful experimental model for studying HTG pancreatitis.