Pancreas fibrosis is the result of a dynamic cascade of mechanisms beginning with acinar cell (AC) injury and necrosis and followed by inflammation, activation of macrophages, aggregation of platelets, release of growth factors and reactive oxygen species (ROS), activation of pancreatic stellate cells (PSC), stimulated synthesis of extracellular matrix and reduced matrix degradation. The result is a net matrix accumulation. Numerous in vivo and in vitro studies have provided strong evidence of a central role for PSC in fibrogenesis associated with acute and chronic pancreatitis. The PSC share homologies with hepatic stellate cells (HSC). In normal pancreas, the fat-storing phenotype of PSC is found in low numbers (approx. 4% of the cells) in the periacinar and interlobular space. Similar to the stellate cell-activating mechanisms in the liver, in pancreas injury PSC change their phenotype from the fat-storing to a highly active matrix-producing cell type (activated PSC). The induction of the activated phenotype of PSC has been shown to involve a number of diverse extra- and intracellular effector molecules, including inflammatory cytokines, growth factors, ethanol, acetaldehyde, and oxidative stress.

MG. Stimulation of stellate cells by injured acinar cells: a model of acute pancreatitis induced by alcohol and fat (VLDL). Am J Physiol Gastrointest Liver Physiol 297: G1163-G1171, 2009. First published September 24, 2009 doi:10.1152/ajpgi.90468.2008.-Mechanisms leading to acute pancreatitis after a fat-enriched meal combined with excess alcohol are incompletely understood. We have studied the effects of alcohol and fat (VLDL) on pancreatic acinar cell (PAC) function, oxidative stress, and repair mechanisms by pancreatic stellate cells (PSC) leading to fibrogenesis. To do so, PAC (rat) were isolated and cultured up to 24 h. Ethanol and/or VLDL were added to PAC. We measured PAC function (amylase, lipase), injury (lactic dehydrogenase), apoptosis (TUNEL, Apo2.7, annexin V binding), oxidative stress, and lipid peroxidation (conjugated dienes, malondialdehyde, chemoluminescence); we also measured PSC proliferation (bromodeoxyuridine incorporation), matrix synthesis (immunofluorescence of collagens and fibronectin, fibronectin immunoassay), and fatty acids in PAC supernatants (gas chromatography). Within 6 h, cultured PAC degraded and hydrolyzed VLDL completely. VLDL alone (50 g/ml) and in combination with alcohol (0.2, 0.5, and 1% vol/vol) induced PAC injury (LDL, amylase, and lipase release) within 2 h through generation of oxidative stress. Depending on the dose of VLDL and alcohol, apoptosis and/or necrosis were induced. Antioxidants (Trolox, Probucol) reduced the cytotoxic effect of alcohol and VLDL. Supernatants of alcohol/VLDL-treated PAC stimulated stellate cell proliferation and extracellular matrix synthesis. We concluded that, in the presence of lipoproteins, alcohol induces acinar cell injury. Our results provide a biochemical pathway for the clinical observation that a fat-enriched meal combined with excess alcohol consumption can induce acinar cell injury (acute pancreatitis) followed by repair mechanisms (proliferation and increased matrix synthesis in PSC).ethanol; free radicals; pancreas THE MECHANISM OF ALCOHOLIC PANCREATITIS is incompletely understood. Despite the fact that about 40% of acute pancreatitis and 70% of chronic pancreatitis in humans are induced by alcohol, most alcoholics will never be affected by any of these diseases. As calculated by Ammann et al. (1), only 5% of all alcohol abusers will develop alcoholic pancreatitis. Interestingly enough, this can also be observed in setups with animals where acute pancreatitis cannot be induced by alcohol itself (8,15,25). Therefore, additional factors accompanying alcohol intake must be coresponsible for the induction of the disease. Some of these cofactors such as stimulation of pancreatic secretion and/or obstruction of pancreatic outflow have been experimentally observed by us and others (8,12,25,26).Clinical experience has taught us that a large number of patients presenting an acute event of alcoholic pancreatitis have drunk lots of alcohol together with an opulent (fat enriched) meal the day before onset of the disease. In the present ...

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Question: A 64-year-old man with a 4-month history of intermittent abdominal pain, fevers to 38 C, chills, fatigue, anorexia, and weight loss visited our clinic because the discomforts have gotten worse over the past week. Physical examination was unremarkable. His medical and surgical history included right hemicolectomy 23 years ago for adenocarcinoma of the ascending colon, coronary atherosclerotic heart disease, kidney stones, cholecystolithiasis, and type II diabetes. He had a 40year history of cigarette smoking and no family history of cancer. Notable laboratory studies included a white blood cell count of 13.9 Â 10 9 /L with neutrophil 82.5%, hemoglobin 89 g/L, alkaline phosphatase 151 IU/L, gamma glutamyl transferase 116 IU/L, albumin 34.9 g/L, creatinine 136.5mmol/L, carcinoembryonic antigen 25.59 ng/mL, squamous cell carcinoma (SCC) antigen 19.8 ng/mL, cytokeratin 19 fragment 9.61 ng/mL, carbohydrate antigen 72-4 300 U/mL, tissue polypeptide antigen 292.5 U/L, positive for fecal occult blood test, and negative for hepatitis B and C tests. Colonoscopy revealed an anastomotic tubular adenoma. Gastroscopy revealed reflux esophagitis and chronic nonatrophic gastritis. A computed tomography (CT) scan of the chest showed small nodules in the bilateral interlobular