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Anecdotal evidence suggests that abstinence from alcohol is an important factor in inhibiting progression in chronic pancreatitis. However, experimental evidence assessing this issue is lacking.1) To compare the effects of alcohol withdrawal with those of alcohol continuation on the extent and pattern of pancreatic injury in a novel rat model of alcoholic chronic pancreatitis induced by repeated endotoxin (LPS) injections in alcohol-fed rats. 2) To assess the effect of alcohol ± LPS on pancreatic stellate cell (PSC) apoptosis in vitro.1) SD rats fed isocaloric Lieber-DeCarli diets ± alcohol for 10 weeks were challenged with LPS (3 mg/kg; 1 IV injection/week x 3 wks). Alcohol-fed rats were then either switched to a non-alcohol diet or continued on alcohol for 3 wks. Thus, the experimental groups (n = 5 rats/group) included: control diet + LPS (CL); alcohol diet + LPS (AL), alcohol diet + LPS continued on alcohol (AL+A), alcohol diet + LPS switched to control diet (AL+C). H&E sections of the head, body and tail of each pancreas (20 HPF/section) were scored for oedema, acinar vacuolization and necrosis, haemorrhage and inflammation. Pancreatic fibrosis (collagen deposition) was scored (30 HPF/section) using Sirius Red stained sections. 2) Rat PSCs were exposed to ethanol 10mM (E10) ± LPS 1μg/ml (L1) for 48h and apoptosis assessed by Annexin V and Caspase-3 staining.Pancreatic injury and fibrosis were significantly greater in AL rats than in CL rats. Withdrawal of alcohol led to complete normalisation of the pancreas with disappearance of fibrosis, while continuation of alcohol resulted in persistent acinar injury and fibrosis [Histological score (mean ± SEM): CL 1.29 ± 0.51; AL 6.36 ± 0.38*; AL+A 5.6 ± 0.22*; AL+C 0.67 ± 0.15#; *p < 0.001 vs CL; #p < 0.001 vs AL and AL+A. Fibrosis score (% total area, mean ± SEM): CL 0.56 ± 0.15; AL 2.19 ± 0.36ˆ; AL+A 1.62 ± 0.18ˆ; AL+C 0.53 ± 0.12¥; ˆp < 0.05 vs CL; ¥p < 0.01 vs AL and AL+A; n = 5 animals / group]. Both alcohol and LPS significantly reduced PSC apoptosis [% of control (mean ± SEM); E10: 70 ± 10.2; L1: 45.01 ± 11.8; E10+L1: 38.43 ± 9.38; p < 0.03 vs Control and E10+L1 vs E10; n = 3 separate PSC preparations]. Similar results were obtained for Caspase-3.1) Continuation of alcohol after LPS-induced pancreatic injury in alcohol-fed rats perpetuates the disease. In contrast, withdrawal of alcohol reverses pancreatic damage. 2) Both alcohol and LPS inhibit PSC apoptosis. Our findings are the first to support the concept that abstinence improves patient outcome in chronic pancreatitis. Perpetuation of fibrosis when alcohol is continued may be due to decreased PSC apoptosis.