Document Detail

Withdrawal of alcohol promotes regression while continued alcohol intake promotes persistence of LPS-induced pancreatic injury in alcohol-fed rats.
MedLine Citation:
PMID:  20870739     Owner:  NLM     Status:  In-Process    
BACKGROUND AND AIMS: Administration of repeated lipopolysaccharide (LPS) injections in alcohol-fed rats leads to significant pancreatic injury including fibrosis. However, it remains unknown whether alcoholic (chronic) pancreatitis has the potential to regress when alcohol is withdrawn. The aims of the study were (1) to compare the effect of alcohol withdrawal/continuation on pancreatic acute injury and fibrosis; and (2) to assess the effects of alcohol ± LPS on pancreatic stellate cell (PSC) apoptosis in vivo and in vitro.
METHODS: Rats fed isocaloric Liebere-De-Carli liquid diets ± alcohol for 10 weeks were challenged with LPS (3 mg/kg/week for 3 weeks) and then either switched to control diet or maintained on an alcohol diet for 3 days, 7 days or 3 weeks. Pancreatic sections were assessed for acute tissue injury, fibrosis, PSC apoptosis and activation. Cultured rat PSCs were exposed to 10 mM ethanol 6 1 mg/ml LPS for 48 or 72 h and apoptosis was assessed (Annexin V, caspase-3 and terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL)).
RESULTS: Withdrawal of alcohol led to resolution of pancreatic lesions including fibrosis and to increased PSC apoptosis. Continued alcohol administration perpetuated pancreatic injury and prevented PSC apoptosis. Alcohol and LPS significantly inhibited PSC apoptosis in vitro, and the effect of LPS on PSC apoptosis could be blocked by Toll-like receptor 4 small interfering RNA.
CONCLUSIONS: Induction of PSC apoptosis upon alcohol withdrawal is a key mechanism mediating the resolution of pancreatic fibrosis. Conversely, continued alcohol intake perpetuates pancreatic injury by inhibiting apoptosis and promoting activation of PSCs. Characterisation of the pathways mediating PSC apoptosis has the potential to yield novel therapeutic strategies for chronic pancreatitis.
Alain Vonlaufen; Phoebe A Phillips; Zhihong Xu; Xuguo Zhang; Lu Yang; Romano C Pirola; Jeremy S Wilson; Minoti V Apte
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-09-24
Journal Detail:
Title:  Gut     Volume:  60     ISSN:  1468-3288     ISO Abbreviation:  Gut     Publication Date:  2011 Feb 
Date Detail:
Created Date:  2011-01-05     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  2985108R     Medline TA:  Gut     Country:  England    
Other Details:
Languages:  eng     Pagination:  238-46     Citation Subset:  AIM; IM    
Pancreatic Research Group, South Western Sydney Clinical School and School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia
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