Abstract
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alcohol is withdrawn.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 6 LPS on pancreatic stellate cell (PSC)
apoptosis in vivo and in vitro.
Methods Rats fed isocaloric LiebereDeCarli liquid diets
6 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.