Protein kinase D: A therapeutic target in experimental alcoholic pancreatitis.

BACKGROUND: Alcohol abuse, a main cause of pancreatitis, has been known to augment NF-κB activation and cell necrosis in pancreatitis. However, the underlying mechanisms are unclear. We recently reported that inhibition of protein kinase D (PKD) alleviated NF-κB activation and severity of experimental pancreatitis. Here we investigated whether PKD signaling mediated the modulatory effects of alcohol abuse on pathological responses in alcoholic pancreatitis. METHODS: Alcoholic pancreatitis was provoked in two rodent models with pair-feeding control and ethanol-containing Lieber-DeCarli diets for up to 8 weeks followed by up to 7 hourly intraperitoneal injections of cerulein at 1 µg/kg (rats) or 3 µg/kg (mice). Effects of PKD inhibition by PKD inhibitors or genetic deletion of pancreatic PKD isoform (PKD3Δpanc mice) on alcoholic pancreatitis parameters were determined. RESULTS: Ethanol administration amplified PKD signaling by promoting expression and activation of pancreatic PKD, resulted in augmented/promoted pancreatitis responses. Pharmacological inhibition of PKD or with PKD3Δpanc mice prevented the augmenting/sensitizing effect of ethanol on NF-κB activation and inflammatory responses, cell necrotic death and the severity of disease in alcoholic pancreatitis. PKD inhibition prevented alcohol-enhanced trypsinogen activation, mRNA expression of multiple inflammatory molecules, the receptor-interacting protein kinase activation, ATP depletion, and downregulation of pro-survival Bcl-2 protein in alcoholic pancreatitis. Furthermore, PKD inhibitor CID755673 or CRT0066101, administrated after the induction of pancreatitis in mouse and rat alcoholic pancreatitis models, significantly mitigated the severity of pancreatitis. CONCLUSION: PKD mediates effect of alcohol abuse on pathological process of pancreatitis and constitutes a novel therapeutic target to treat this disease.

Ulinastatin in the Management of Severe Acute Alcoholic Pancreatitis: A Case Series.

Severe acute alcoholic pancreatitis is a second common form of pancreatitis that requires intensive care unit care and has high morbidity and mortality due to lacking specific treatment. Management of alcoholic pancreatitis is generally non- specific and supportive. We hereby present a case-series of three patients that describes the successful treatment of severe acute alcoholic pancreatitis with ulinastatin and other supportive treatment. From this we want to emphasize that ulinastatin a protease inhibitor can be used in the treatment of alcoholic pancreatitis.

[Protective Effect of a Dihydroflavonol Glycoside from Coreopsis tinctoria Nutt. in Mouse Model of Alcoholic Acute Pancreatitis].

OBJECTIVE: To investigate the protective effect of (2R, 3R)-dihydroquercetin 7-O-ß-D-glucopyranose (C1) extracted from Coreopsis tinctoria Nutt. in a mouse model of alcoholic acute pancreatitis (FAEE-AP) induced byfatty acid ethyl ester (FAEE). METHODS: The 30 healthy SPF mice were randomly divided into control group, model group, low dose group, middle dose group and high dose group, 6 in each group. Alcoholic pancreatitis was induced by ethanol and palmitoleic acid administration (1.75 g/kg ethanol, 200 mg/kg palmitoleic acid, 2 times peritoneal injections). The three treatment groups were given C1 (0 h, 4 h, 8 h) at the dose of 12.5, 25 and 50 mg/kg, respectively. After 24 h of molding, the serum amylase, lipase and IL-6 levels were detected. The trypsin level in pancreatic tissue and myeloperoxidase (MPO) level in pancreatic and lung tissue were detected. Hematoxylin-eosin (HE) staining was used to observe the pathological changes of pancreatic tissue and immunohistochemical (IHC) staining was used to detect the expression of nuclear factor-erythroid 2 related factor 2 (Nrf2) in pancreatic tissue. RESULTS: The pancreatic histopathological scores, serum amylase and lipase activity, trypsin level in pancreatic tissue, serum IL-6 level, MPO level of pancreas and lung were significantly higher in the model group than in the control group (P < 0.01). Compared with the model group, the pancreatic histopathologies of the low dose group was significantly improved (P < 0.05), as well as the serum amylase and lipase activity, trypsin level of pancreas, serum IL-6 level, the pancreas andthe lung's MPO level decreased significantly (P < 0.05), and up-regulate that expression of Nrf2 in pancreatic tissue. CONCLUSION: 12.5 mg/kg of (2R, 3R) -dihydroquercetin 7-O-ß-D-glucopyranose (C1) improved the expression of Nrf2, reduced the expression of inflammatory factor IL-6, and protected acute pancreatitis caused by FAEE.

New-Onset Diabetes Mellitus After Chronic Pancreatitis Diagnosis: A Systematic Review and Meta-analysis.

OBJECTIVES: The aim of this study was to assess the occurrence of new-onset diabetes mellitus (DM) after chronic pancreatitis (CP) diagnosis via systematic review and meta-analysis. METHODS: A systematic review of literature and meta-analysis of relevant reports were performed. The primary outcome measures studied were newly diagnosed DM and DM treated with insulin. For the binary outcomes, pooled prevalence and 95% confidence interval (CI) were calculated. METHODS: Fifteen studies involving 8970 patients were eligible. The incidence of new-onset DM after CP diagnosis was 30% (95% CI, 27%-33%). Among all patients, 17% (95% CI, 13%-22%) developed insulin-dependent new-onset DM. The prevalence of newly diagnosed DM after CP diagnosis increased from 15% within 36 months to 33% after 60 months. The proportion of alcoholic CP, sex, age, and body mass index had minimal effect on the studied outcomes. CONCLUSIONS: This systematic review identified a clinically relevant risk of new-onset DM after CP diagnosis. Therefore, patients should be informed of the risk of DM and monitored.

Two Cases of Liver Abscesses Derived from Dental Disease in Patients with Alcoholic Chronic Pancreatitis.

Among the etiologies of pyogenic liver abscess (PLA), bacterial spread from the biliary tract or portal flow is the major cause, while the onset of PLA due to arterial bacterial transmission is rare. We herein report two cases of PLA thought to be caused by arterial transmission from dental disease. In both cases, there was benign biliary stricture as a result of alcoholic chronic pancreatitis, although normal oral flora was detected as the causative bacteria and oral hygiene was poor in both patients. We presumed that the origin of PLA was dental disease and successfully treated the patients with percutaneous drainage, antibiotics and dental procedures.

Pharmacological attenuation of chronic alcoholic pancreatitis induced hypersensitivity in rats.

AIM: To characterize an alcohol and high fat diet induced chronic pancreatitis rat model that mimics poor human dietary choices. METHODS: Experimental rats were fed a modified Lieber-DeCarli alcohol (6%) and high-fat (65%) diet (AHF) for 10 wk while control animals received a regular rodent chow diet. Weekly behavioral tests determined mechanical and heat sensitivity. In week 10 a fasting glucose tolerance test was performed, measuring blood glucose levels before and after a 2 g/kg bodyweight intraperitoneal (i.p.) injection of glucose. Post mortem histological analysis was performed by staining pancreas and liver tissue sections with hematoxylin and eosin. Pancreas sections were also stained with Sirius red and fast green to quantify collagen content. Insulin-expressing cells were identified immunohistochemically in separate sections. Tissue staining density was quantified using Image J software. After mechanical and heat sensitivity became stable (weeks 6-10) in the AHF-fed animals, three different drugs were tested for their efficacy in attenuating pancreatitis associated hypersensitivity: a Group II metabotropic glutamate receptor specific agonist (2R,4R)-4-Aminopyrrolidine-2,4-dicarboxylate (APDC, 3 mg/kg, ip; Tocris, Bristol, United Kingdom), nociceptin (20, 60, 200 nmol/kg, ip; Tocris), and morphine sulfate (3 mg/kg, µ-opioid receptor agonist; Baxter Healthcare, Deerfield, IL, United States). RESULTS: Histological analysis of pancreas and liver determined that unlike control rats, AHF fed animals had pancreatic fibrosis, acinar and beta cell atrophy, with steatosis in both organs. Fat vacuolization was significantly increased in AHF fed rats (6.4% ± 1.1% in controls vs 23.8% ± 4.2%, P < 0.05). Rats fed the AHF diet had reduced fasting glucose tolerance in week 10 when peak blood glucose levels reached significantly higher concentrations than controls (127.4 ± 9.2 mg/dL in controls vs 161.0 ± 8.6 mg/dL, P < 0.05). This concurred with a 3.5 fold higher incidence of single and small 2-10 cell insulin-positive cell clusters (P < 0.05). Insulin expressing islet of Langerhans cells appeared hypertrophied while islet number and area measurements were not different from controls. Weekly behavioral tests determined that mechanical and heat sensitivities were significantly increased by 4 wk on AHF diet compared to controls. Hypersensitivity was attenuated with efficacy similar to morphine with single dose treatment of either metabotropic glutamate receptor 2/3 agonist APDC, or nociceptin, the endogenous ligand for opioid-receptor-like 1 receptor. CONCLUSION: The AHF diet induces a chronic alcoholic pancreatitis in rats with measurable features resembling clinical patients with chronic pancreatitis and type 3c diabetes mellitus.

Small intestinal bacterial overgrowth is common both among patients with alcoholic and idiopathic chronic pancreatitis.

BACKGROUND: Small intestinal bacterial overgrowth (SIBO) is known to occur in patients with chronic pancreatitis, particularly of alcoholic etiology. There are, however, scanty data on frequency of SIBO in patients with chronic idiopathic pancreatitis and factors associated with its occurrence. METHODS: 68 patients with chronic pancreatitis and 74 age and gender-matched healthy subjects (HS) were evaluated for SIBO using glucose hydrogen breath test (GHBT). Persistent rise in breath hydrogen 12 ppm above basal (at least two recordings) was diagnostic of SIBO. RESULT: SIBO was diagnosed more often among patients with chronic pancreatitis than controls (10/68 [14.7%] vs. 1/74 controls [1.3%]; p = 0.003). Of 68 patients, 22 (32.3%) had alcoholic and 46 (67.6%) had idiopathic chronic pancreatitis. SIBO was as commonly detected among patients with alcoholic as idiopathic pancreatitis (3/22 [13.6%] vs. 7/46 [15.2%]; p = 0.86). Age, gender, body mass index (BMI), steatorrhoea, pain, analgesic use, pancreatic calcifications and use of pancreatic enzyme supplements had no relationship with the presence of SIBO. Diabetes mellitus tended to be commoner among patients with chronic pancreatitis with than without SIBO (6/10 [60%] vs. 18/58 [31%]; p = 0.07). CONCLUSION: SIBO was commoner among patients with chronic pancreatitis, both alcoholic and idiopathic, than HS. Though presence of SIBO among patients with chronic pancreatitis tended to be commoner among those with diabetes mellitus, there was no relationship with age, gender, BMI, steatorrhoea, pain, analgesic use, pancreatic calcifications and use of pancreatic enzyme supplements.

Ca2+ release-activated Ca2+ channel blockade as a potential tool in antipancreatitis therapy.

Alcohol-related acute pancreatitis can be mediated by a combination of alcohol and fatty acids (fatty acid ethyl esters) and is initiated by a sustained elevation of the Ca(2+) concentration inside pancreatic acinar cells ([Ca(2+)]i), due to excessive release of Ca(2+) stored inside the cells followed by Ca(2+) entry from the interstitial fluid. The sustained [Ca(2+)]i elevation activates intracellular digestive proenzymes resulting in necrosis and inflammation. We tested the hypothesis that pharmacological blockade of store-operated or Ca(2+) release-activated Ca(2+) channels (CRAC) would prevent sustained elevation of [Ca(2+)]i and therefore protease activation and necrosis. In isolated mouse pancreatic acinar cells, CRAC channels were activated by blocking Ca(2+) ATPase pumps in the endoplasmic reticulum with thapsigargin in the absence of external Ca(2+). Ca(2+) entry then occurred upon admission of Ca(2+) to the extracellular solution. The CRAC channel blocker developed by GlaxoSmithKline, GSK-7975A, inhibited store-operated Ca(2+) entry in a concentration-dependent manner within the range of 1 to 50 µM (IC50 = 3.4 µM), but had little or no effect on the physiological Ca(2+) spiking evoked by acetylcholine or cholecystokinin. Palmitoleic acid ethyl ester (100 µM), an important mediator of alcohol-related pancreatitis, evoked a sustained elevation of [Ca(2+)]i, which was markedly reduced by CRAC blockade. Importantly, the palmitoleic acid ethyl ester-induced trypsin and protease activity as well as necrosis were almost abolished by blocking CRAC channels. There is currently no specific treatment of pancreatitis, but our data show that pharmacological CRAC blockade is highly effective against toxic [Ca(2+)]i elevation, necrosis, and trypsin/protease activity and therefore has potential to effectively treat pancreatitis.

[Inhibition of the stellate cells using lisinopril and lovastatin for prophylaxis of pancreatic stump fibrosis after performance of distal resection in a model of chronic alcoholic pancreatitis].

Complex application of lisinopril (inhibitor of angiotensin-converting enzyme) and lovastatin (inhibitor of HMG-CoA reductase) inhibits pancreatic fibrosis in the rats, having alcoholic chronic pancreatitis after distal pancreatic resection (DPR). Lisinopril and lovastatin were injected to the rats after DPR in dose 10 mg/kg during 3 weeks. Immunohistochemical markets, such as alpha-smooth-muscle actin (alpha-SMA), desmin, glial fibrillary acidic protein (GFAP), vimentin, and expression of matrix metalloproteinase-1 (MMP-1) as well as inhibitor of matrix metalloproteinase-2 (TIMP-2) were detected for estimation of therapeutic impact on activity and quantity of stellate pancreatic cells. Under the influence of lisinopril and lovastatin there were observed lowering in the stellate pancreatic cells activity and in expression of SMA, desmin, GFAP, vimentin and TIMP-2, the MMP-1 and TIMP-2 ratio have had increased significantly and severity of fibrotic pancreatic affection had reduced trustworthy in comparison w such, occurring in a control group.

Role of the chemokine fractalkine in a rat model of acute necrotizing pancreatitis and the interventional effect of ulinastatin.

BACKGROUND: Severe acute pancreatitis (SAP) is a serious systemic disease with high mortality. This study aims to investigate the role of the chemokine, fractalkine (FKN), in the pathogenesis of SAP and the effects of intervention by ulinastatin on FKN expression in an SAP rat model. METHODS: We randomly divided 72 Sprague Dawley rats into the following groups: SAP, ulinastatin treatment (UT), and control (C). The SAP model was induced by retrograde infusion of 4% sodium taurocholate into the bili-pancreatic ducts of the rats. Rats in the UT group were injected with ulinastatin immediately after establishment of the SAP model. Serum FKN levels were detected by ELISA at various time points. Histopathological analyses of the pancreas and lung were performed. Expressions of FKN mRNA in the tissues of the pancreas and lung were detected by real-time fluorescence quantitative polymerase chain reaction (RT-qPCR) at various time points for each group. RESULTS: Serum levels of FKN at 3 h after surgery in the SAP subgroup were significantly higher than those in the C group (P < 0.05). There were no significant differences between the UT and C groups observed at various time points. Expression levels of FKN mRNA in the pancreatic tissues of the SAP group increased gradually. Although we observed no difference between the SAP and C groups (P > 0.05) at 1 hour h after surgery, mRNA levels of FKN in the lung tissues at 3, 6, and 12 h post-surgery in the SAP subgroups were significantly higher than those in the C group for the same time points (P < 0.05). Pathological injury of the pancreatic tissues was more remarkable in the SAP group compared to the UT group. CONCLUSION: FKN may play an important role in the pathogenesis of SAP and SAP-related acute lung injury (ALI). Ulinastatin efficiently interferes with SAP and SAP-related ALI and may be related to inhibition of FKN expression.

A case of recurrent arrhythmia in an acute pancreatitis patient--pathophysiological explanation using shortage of 'repolarization reserve'.

We report a case of a patient with acute pancreatitis who developed serious heart rhythm abnormalities on three occasions, two of which were associated with administration of the first generation antihistamine chloropyramine, and the third one with hypomagnesemia and hypokalemia. Dysrhythmic events consisted of bigeminy, multifocal ventricular extrasystoles and torsades de pointes-like ventricular tachycardia. Electrocardiographic changes in acute pancreatitis in the absence of previous heart disease can occur in more than half of the cases. Antihistamines are medications that are known to produce heart rhythm disturbances, especially the second generation drugs astemizole and terfenadine. This is the first report of chloropyramine causing dysrhythmia. It seems that acute pancreatitis patients are especially prone to heart dysrhythmia caused by different factors such as electrolyte disturbances and pronounced vagal tone. Acute pancreatitis may be added to the list of risk factors with altered 'repolarization reserve', predisposing to drug-induced QT interval prolongation and possible torsades de pointes occurrence.

[Inhibition of pancreatic stellate cell activation by lisinopril for prevention fibrogenesis in experimental chronic alcoholic pancreatitis].

Lisinopril (angiotensin-converting enzyme inhibitor) attenuates fibrotic changes in pancreas after distal pancreatectomy in rats with experimental alcohol induced chronic pancreatitis. Lisinopril was administered after distal pancreatectomy in rats with experimental alcohol induced chronic pancreatitis. The animals were treated with lisinopril at the dose of 10 mg/kg body weight per day for 21 days after operation. To estimate the efficacy of the treatment on activity and number of pancreatic stellate cells the immunohistochemical investigation was made with alpha-smooth muscle actin (alpha-SMA), desmin, vimentin, glial fibrillary acidic protein (GFAP), matrix metalloproteinase-1 (MMP-1), tissue inhibitor of metalloproteinase-2 (TIMP-2) using. The treatment of rats after operation with lisinopril inhibite activity of pancreatic stellate cells and characterized by significant decrease of the alpha-SMA, desmin, GFAP, vimentin and TIMP-2 expression. The ratio of MMP-1/TIMP-2 was greater in the group with treatment then in the control group. This therapy had a trend to alleviate the fibrotic changes in pancreas.

Antioxidant therapy does not reduce pain in patients with chronic pancreatitis: the ANTICIPATE study.

BACKGROUND & AIMS: We investigated whether antioxidant therapy reduces pain and improves quality of life in patients with chronic pancreatitis. METHODS: We performed a double-blind, randomized, controlled trial that compared the effects of antioxidant therapy with placebo in 70 patients with chronic pancreatitis. Patients provided 1 month of baseline data and were followed for 6 months while receiving either antioxidant therapy (Antox version 1.2, Pharma Nord, Morpeth, UK) or matched placebo (2 tablets, 3 times/day). The primary analysis was baseline-adjusted change in pain score at 6 months, assessed by an 11-point numeric rating scale. Secondary analyses included alternative assessments of clinical and diary pain scores, scores on quality-of-life tests (the European Organization for Research and Treatment of Cancer [EORTC-QLQ-C30], Quality of Life Questionnaire-Pancreatic modification [QLQ-PAN28], European Quality of Life questionnaire [EuroQOL EQ-5D], and European Quality of Life questionnaire - Visual Analog Score [EQ-VAS]), levels of antioxidants, use of opiates, and adverse events. Analyses, reported by intention to treat, were prospectively defined by protocol. RESULTS: After 6 months, pain scores reported to the clinic were reduced by 1.97 from baseline in the placebo group and by 2.33 in the antioxidant group but were similar between groups (-0.36; 95% confidence interval [CI], -1.44 to 0.72; P = .509). Average daily pain scores from diaries were also similar (3.05 for the placebo group and 2.93 for the antioxidant group, a difference of 0.11; 95% CI, 1.05-0.82; P = .808). Measures of quality of life were similar between groups, as was opiate use and number of hospital admissions and outpatient visits. Blood levels of vitamin C and E, ß-carotene, and selenium were increased significantly in the antioxidant group. CONCLUSIONS: Administration of antioxidants to patients with painful chronic pancreatitis of predominantly alcoholic origin does not reduce pain or improve quality of life, despite causing a sustained increase in blood levels of antioxidants.