Bacterial endotoxin: a trigger factor for alcoholic pancreatitis? Evidence from a novel, physiologically relevant animal model.
OBJECTIVE
This study examined the possible role of endotoxinemia (from increased gut permeability) as an additional trigger factor for overt pancreatic disease and as a promoter of chronic pancreatic injury in alcoholics by using a rat model of chronic alcohol feeding and in vitro experiments with cultured pancreatic stellate cells (PSCs), the key mediators of pancreatic fibrosis.


METHODS
In the in vivo model, Sprague-Dawley rats fed isocaloric Lieber-DeCarli liquid diets +/- alcohol for 10 weeks were challenged with a single dose or 3 repeated doses of the endotoxin lipopolysaccharide (LPS) and the pancreas was examined. In the in vitro studies, rat PSCs were assessed for activation on exposure to LPS +/- ethanol. The expression of LPS receptors TLR4 and CD14 also was assessed in rat and human PSCs.


RESULTS
In the in vivo model, single or repeated LPS challenge resulted in significantly greater pancreatic injury in alcohol-fed rats compared with rats fed the control diet without alcohol. Notably, repeated LPS injections caused pancreatic fibrosis in alcohol-fed rats, but not in rats fed the control diet. In the in vitro studies, PSCs were activated by LPS. Alcohol + LPS exerted a synergistic effect on PSC activation. Importantly, both rat and human PSCs expressed TLR4 and CD14.


CONCLUSIONS
This study describes, for the first time, a clinically relevant animal model of alcohol-related pancreatic injury and provides strong in vivo and in vitro evidence that suggests that LPS is a trigger factor in the initiation and progression of alcoholic pancreatitis.
Vonlaufen
Alain
A
Pancreatic Research Group, South Western Sydney Clinical School, Sydney, Australia.
Xu
Zhihong
Z
Daniel
Balu
B
Kumar
Rakesh K
RK
Pirola
Romano
R
Wilson
Jeremy
J
Apte
Minoti V
MV
D000199:Actins / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D019446:Endotoxemia / Q000139:chemically induced / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D000431:Ethanol; D005355:Fibrosis; D006801:Humans; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008070:Lipopolysaccharides; D008297:Male; D009336:Necrosis; D010179:Pancreas / Q000378:metabolism / Q000473:pathology*; D019512:Pancreatitis, Alcoholic / Q000139:chemically induced / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012307:Risk Factors; D012720:Severity of Illness Index; D013997:Time Factors; D051197:Toll-Like Receptor 4 / Q000378:metabolism
D000199:Actins; D000431:Ethanol; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D051197:Toll-Like Receptor 4; C495345:TLR4 protein, human; C495347:Tlr4 protein, rat; C498862:Acta2 protein, rat