Bacterial endotoxin – a trigger factor for alcoholic pancreatitis? Evidence from a novel, physiologically relevant animal model
Background and Aims: 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, A., Xu, Z., Daniel, B., Kumar, R. K., Pirola, R., Wilson, J., & Apte, M. V. (2007). Bacterial endotoxin – a trigger factor for alcoholic pancreatitis? Evidence from a novel, physiologically relevant animal model. Gastroenterology, 133(4), 1293-1303. doi: 10.1053/j.gastro.2007.06.062