Alcohol, endotoxin and the pancreas (induction, progression and reversibility of alcoholic pancreatitis)

摘要

This thesis pertains to the pathogenesis of alcoholic pancreatitis, a considerable burden in terms of morbidity, mortality and health related costs. It has long been known that only a minority of alcoholics develop clinically evident pancreatitis, suggesting that (an) additional trigger factor(s) is required to elicit overt disease. Endotoxin (lipopolysaccharide LPS), from gut-derived gram negative bacteria may be one such trigger factor, since alcoholics exhibit increased levels of serum endotoxin. In addition, the degree of endotoxinaemia has been reported to correlate with the severity of pancreatitis. Studies described in this thesis report, i) the development of a novel rodent model of alcoholic pancreatitis produced by challenging alcohol-fed animals with single or repeated doses of LPS. The animals exhibit features of both acute (acinar vacuolisation, necrosis, pancreatic oedema, haemorrhage and inflammatory infiltration) and chronic (acinar atrophy and pancreatic fibrosis) pancreatitis; ii) the reversion of pancreatic injury (including fibrosis) upon withdrawal of alcohol in the model and the persistence of pancreatic damage with continuation of alcohol feeding; iii) activation of pancreatic stellate cells (PSCs, known to play a central role in fibrogenesis) in vivo and in vitro by alcohol and LPS; iv) the inhibition of PSC apoptosis in vivo and in vitro upon exposure to alcohol and LPS and the induction of PSC apoptosis in vivo upon withdrawal of alcohol from the diet and v) the presence of LPS receptors TLR4 and CD14 on PSCs, which would explain the responsiveness of PSCs to LPS.Thus the work in this thesis provides strong evidence in support of endotoxin as a clinically relevant trigger factor for the initiation of alcoholic pancreatitis and as a factor that promotes disease progression. The thesis also provides the first experimental evidence to support the clinical reports of a beneficial effect of abstinence on chronic pancreatitis. Delineation of the mechanisms mediating the induction, progression and reversibility of alcoholic pancreatitis has the potential to direct the development of new therapeutic interventions for alcohol-related pancreatic injury.