Chronic alcohol consumption accelerates fibrosis in response to cerulein-induced pancreatitis in rats.
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.
Deng
Xiaoying
X
Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Wang
Lin
L
Elm
Mary S
MS
Gabazadeh
David
D
Diorio
Greg J
GJ
Eagon
Patricia K
PK
Whitcomb
David C
DC
D000428:Alcohol Drinking / Q000473:pathology; D000437:Alcoholism / Q000150:complications*; D000818:Animals; D002108:Ceruletide / Q000633:toxicity*; D002908:Chronic Disease; D017931:DNA Primers; D004195:Disease Models, Animal; D005355:Fibrosis; D005786:Gene Expression Regulation; D008297:Male; D010195:Pancreatitis / Q000139:chemically induced / Q000235:genetics / Q000473:pathology*; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar
D017931:DNA Primers; D012333:RNA, Messenger; D002108:Ceruletide