Alcohol consumption is a risk factor for
chronic pancreatitis (CP), but the mechanism in humans remains obscure because prolonged alcohol consumption in most humans and animal models fails to produce alcoholic
chronic pancreatitis (ACP). We hypothesize that the process leading to ACP is triggered by a sentinel
acute pancreatitis (AP) event; this event causes recruitment of inflammatory cells, which initiates
fibrosis driven by the anti-inflammatory response to recurrent AP and/or chronic oxidative stress. The aim was to determine whether chronic alcohol consumption accelerates
fibrosis in response to
cerulein-induced
pancreatitis in the rat. Wistar male rats were pair-fed control (C) or 5%
ethanol (E) Lieber-DeCarli liquid diets. Animals were studied without
pancreatitis (P0), with
cerulein pancreatitis induced once (P1), or with
cerulein-induced
pancreatitis weekly for 3 weeks (P3). AP markers,
inflammation, and
fibrosis were measured histologically, by gene expression profiling and
protein expression. Macrophage infiltration was reduced in EP0 versus CP0 rats, but the pattern was reversed after AP. Microabscess, severe
necrosis, and early calcification were only induced in the EP3 rats.
Fibrosis was significantly induced in the EP3 rats versus EP1, CP1, and CP3 by histology,
hydroxyproline content, and
mRNA expression for
collagen alpha1(1) and
procollagen alpha2(1). Proinflammatory
cytokine mRNAs were up-regulated shortly after induction of AP, while the anti-inflammatory
cytokines (
interleukin-10 and
transforming growth factor-beta) were strongly up-regulated later and in parallel with fibrogenesis, especially in the EP3 rats. Pancreatic
fibrosis develops after repeated episodes of AP and is potentiated by alcohol. Expression of
fibrosis-associated genes was associated with expression of anti-inflammatory
cytokines in alcohol-fed rats.