Does alcohol directly stimulate pancreatic fibrogenesis? Studies with rat pancreatic stellate cells

Background & Aims: Activated pancreatic stellate cells have recently been i mplicated in pancreatic fibrogenesis. This study examined the role of pancr eatic stellate cells in alcoholic pancreatic fibrosis by determining whethe r these cells are activated by ethanol itself and, if so, whether such acti vation is caused by the metabolism of ethanol to acetaldehyde and/or the ge neration of oxidant stress within the cells. Methods: Cultured rat pancreat ic stellate cells were incubated with ethanol or acetaldehyde. Activation w as assessed by cell proliferation, a-smooth muscle actin expression, and co llagen synthesis. Alcohol dehydrogenase (ADH) activity in stellate cells an d the influence of the ADH inhibitor 4-methylpyrazole (4MP) on the response of these cells to ethanol was assessed. Malondialdehyde levels were determ ined as an indicator of lipid peroxidation. The effect of the antioxidant v itamin E on the response of stellate cells to ethanol or acetaldehyde was a lso examined. Results: Exposure to ethanol or acetaldehyde led to cell acti vation and intracellular lipid peroxidation. These changes were prevented b y the antioxidant vitamin E. Stellate cells exhibited ethanol-inducible ADH activity. Inhibition of ADH by 4MP prevented ethanol-induced cell activati on. Conclusions: Pancreatic stellate cells are activated on exposure to eth anol. This effect of ethanol is most likely mediated by its metabolism (via ADH) to acetaldehyde and the generation of oxidant stress within the cells .