Does alcohol directly stimulate pancreatic fibrogenesis? Studies with rat pancreatic stellate cells.
OBJECTIVE
Activated pancreatic stellate cells have recently been implicated in pancreatic fibrogenesis. This study examined the role of pancreatic stellate cells in alcoholic pancreatic fibrosis by determining whether these cells are activated by ethanol itself and, if so, whether such activation is caused by the metabolism of ethanol to acetaldehyde and/or the generation of oxidant stress within the cells.


METHODS
Cultured rat pancreatic stellate cells were incubated with ethanol or acetaldehyde. Activation was assessed by cell proliferation, alpha-smooth muscle actin expression, and collagen synthesis. Alcohol dehydrogenase (ADH) activity in stellate cells and the influence of the ADH inhibitor 4-methylpyrazole (4MP) on the response of these cells to ethanol was assessed. Malondialdehyde levels were determined as an indicator of lipid peroxidation. The effect of the antioxidant vitamin E on the response of stellate cells to ethanol or acetaldehyde was also examined.


RESULTS
Exposure to ethanol or acetaldehyde led to cell activation and intracellular lipid peroxidation. These changes were prevented by the antioxidant vitamin E. Stellate cells exhibited ethanol-inducible ADH activity. Inhibition of ADH by 4MP prevented ethanol-induced cell activation.


CONCLUSIONS
Pancreatic stellate cells are activated on exposure to ethanol. This effect of ethanol is most likely mediated by its metabolism (via ADH) to acetaldehyde and the generation of oxidant stress within the cells.
Apte
M V
MV
Pancreatic Research Group, Prince of Wales Hospital and University of New South Wales, Sydney, Australia.
Phillips
P A
PA
Fahmy
R G
RG
Darby
S J
SJ
Rodgers
S C
SC
McCaughan
G W
GW
Korsten
M A
MA
Pirola
R C
RC
Naidoo
D
D
Wilson
J S
JS
D000079:Acetaldehyde / Q000494:pharmacology; D000199:Actins / Q000378:metabolism; D000818:Animals; D001205:Ascorbic Acid / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen / Q000096:biosynthesis; D004338:Drug Combinations; D000431:Ethanol / Q000378:metabolism / Q000494:pharmacology*; D005290:Ferric Compounds / Q000494:pharmacology; D005355:Fibrosis; D008054:Lipid Peroxides / Q000378:metabolism; D008315:Malondialdehyde / Q000378:metabolism; D009130:Muscle, Smooth / Q000378:metabolism; D018384:Oxidative Stress; D010179:Pancreas / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D051381:Rats
D000199:Actins; D004338:Drug Combinations; D005290:Ferric Compounds; D008054:Lipid Peroxides; C024823:ferric sulfate; D000431:Ethanol; D008315:Malondialdehyde; D003094:Collagen; D000079:Acetaldehyde; D001205:Ascorbic Acid