Withdrawal of alcohol promotes regression while continued alcohol intake promotes persistence of LPS-induced pancreatic injury in alcohol-fed rats

Background and aims Administration of repeatedlipopolysaccharide (LPS) injections in alcohol-fed ratsleads to significant pancreatic injury including fibrosis.However, it remains unknown whether alcoholic(chronic) pancreatitis has the potential to regress whenalcohol is withdrawn. The aims of the study were (1) tocompare the effect of alcohol withdrawal/continuation onpancreatic acute injury and fibrosis; and (2) to assess theeffects of alcohol 6 LPS on pancreatic stellate cell (PSC)apoptosis in vivo and in vitro.Methods Rats fed isocaloric LiebereDeCarli liquid diets6 alcohol for 10 weeks were challenged with LPS(3 mg/kg/week for 3 weeks) and then either switched tocontrol diet or maintained on an alcohol diet for 3 days,7 days or 3 weeks. Pancreatic sections were assessedfor acute tissue injury, fibrosis, PSC apoptosis andactivation. Cultured rat PSCs were exposed to 10 mMethanol 6 1 mg/ml LPS for 48 or 72 h and apoptosis wasassessed (Annexin V, caspase-3 and terminaldeoxynucleotidyl transferase dUTP nick end labelling(TUNEL)).Results Withdrawal of alcohol led to resolution ofpancreatic lesions including fibrosis and to increased PSCapoptosis. Continued alcohol administration perpetuatedpancreatic injury and prevented PSC apoptosis. Alcoholand LPS significantly inhibited PSC apoptosis in vitro, andthe effect of LPS on PSC apoptosis could be blocked byToll-like receptor 4 small interfering RNA.Conclusions Induction of PSC apoptosis upon alcoholwithdrawal is a key mechanism mediating the resolutionof pancreatic fibrosis. Conversely, continued alcoholintake perpetuates pancreatic injury by inhibitingapoptosis and promoting activation of PSCs.Characterisation of the pathways mediating PSCapoptosis has the potential to yield novel therapeuticstrategies for chronic pancreatitis

Stellate Cells and the Pancreas

The past decade has seen rapid advances in our understanding of the fibrogenic process in the pancreas mainly due to the elucidation of the biology of the cells that are critical to this process. However, it is also becoming increasingly clear that PSCs do not merely exist to regulate ECM turnover in health and disease, but may also have other important roles in the normal pancreas as immune cells and/or progenitor cells. In vitro and in vivo experimental studies have provided encouraging results in terms of developing therapeutic strategies to target PSCs in chronic pancreatitis and pancreatic cancer. The challenge that remains is to translate these findings to the clinical situation so as to improve the outcome for patients afflicted with these diseases

The Fibrosis of Chronic Pancreatitis : New Insights into the Role of Pancreatic Stellate Cells

Significance : Prominent fibrosis is a major histological feature of chronic pancreatitis, a progressive necroinflammatory condition of the pancreas, most commonly associated with alcohol abuse. Patients with this disease often develop exocrine and endocrine insufficiency characterised by maldigestion and diabetes. Up until just over a decade ago, there was little understanding of the pathogenesis of pancreatic fibrosis in chronic pancreatitis. Recent Studies : In recent times, significant progress has been made in this area, mostly due to the identification, isolation and characterisation of the cells, namely pancreatic stellate cells (PSCs) that are now established as key players in pancreatic fibrogenesis. In health, PSCs maintain normal tissue architecture via regulation of the synthesis and degradation of extracellular matrix (ECM) proteins. During pancreatic injury, PSCs transform into an activated phenotype that secretes excessive amounts of the ECM proteins that comprise fibrous tissue. Critical Issues : This Review summarises current knowledge and critical aspects of PSC biology which have been increasingly well characterised over the past few years, particularly with respect to the response of PSCs to factors that stimulate or inhibit their activation and the intracellular signalling pathways governing these processes. Based on this knowledge, several therapeutic strategies have been examined in experimental models of pancreatic fibrosis, demonstrating that pancreatic fibrosis is a potentially reversible condition, at least in early stages. Future Directions : These will involve translation of the laboratory findings into effective clinical approaches to prevent/inhibit PSC activation so as to prevent, retard or reverse the fibrotic process in pancreatitis