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Research Article

Stimulation of stellate cells by injured acinar cells: A model of acute pancreatitis induced by alcohol and fat (VLDL)

¹Ostalb-klinikum Aalen ²The First Hospital of Peking University, China ^{3 4}University of Ulm ⁵Universitiy of Ulm ⁶Universitat Ulm-Klinikum

Submitted 4 August 2008 ; revision received 3 September 2009 ; accepted in final form 3 September 2009

ABSTRACT

Aims: 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 (very low density lipoproteins = VLDL) on pancreatic acinar cell (PAC) function, oxidative stress, and repair mechanisms by pancreatic stellate cells (PSC) leading to fibrogenesis. Methods: 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 (LDH), apoptosis (TUNEL, Apo2.7, Annexin V binding), oxidative stress and lipid peroxidation (conjugated dienes, malondialdehyde, chemoluminescence); PSC proliferation (BrdU-incorporation) and matrix synthesis (immunofluorescence of collagens and fibronectin, fibronectin immunoassay); fatty acids in PAC-supernatants (gas chromatography). Results: Within 6h cultured PAC degraded and hydrolyzed VLDL completely. VLDL alone (50µg/ml) and in combination with alcohol (0.2, 0.5, 1% v/v) 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. Conclusion: 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).

pancreas; ethanol; pancreatitis; free radicals