The acinar-ductal tango in the pathogenesis of acute pancreatitis

Abstract

There is an unacceptably high mortality in acute pancreatitis, which is due to the lack of specific treatments for the disease. A major reason stated to account for the inability to develop effective treatments is that there are multiple pathobiologic pathways activated in the acinar cell mediating pancreatitis making it difficult to choose molecular targets for therapeutic strategies. However, this reasoning limits opportunities for therapeutic development because it does include another important participant in pancreatitis - the pancreatic duct cells. The most recent advance in pancreatitis research is that depletion of both glycolytic and oxidative ATP synthesis is a common event in both acinar and ductal cells. Although ATP has a very short half-life in the blood and is hydrolysed to ADP, there is clear evidence that encapsulating ATP into liposomes can effectively drive ATP into the cells which can be effective in protecting them from necrosis. In this review, we will examine the effects of different insults associated with pancreatitis on both the acinar and ductal components of the exocrine pancreas pointing out the role of the ductal epithelial responses in both attenuating and increasing the severity of pancreatitis. In addition, we propose that exogenous ATP administration may restore ductal and acinar function providing therapeutic benefit.

Figure 1

Effects of bile acids on the exocrine pancreas. Ductal cells. Bile acids have dual effects on the ductal fluid and HCO₃⁻ secretion. First, when the non-conjugated bile acids reach the ductal cells in low concentration, they induce a dose-dependent elevation of Ca²⁺_i concentration via an inositol 1,4,5-triphosphate receptor (IP₃R) and phospholipase C-mediated pathway and stimulate HCO₃⁻ secretion through the luminal Cl⁻/HCO₃⁻ exchanger. Theoretically, ductal cells may try to wash out the toxic acids and thus defend the acinar cells. If this defence mechanism is inefficient and bile acids reach the ductal cells in high concentration, they induce a toxic sustained Ca²⁺_i concentration signal and decrease [ATP]_i, which will inhibit all of the acidebase transporters including the basolateral Na⁺/H⁺ exchanger, Na⁺/HCO₃⁻ cotransporter and the luminal Cl⁻/HCO₃⁻ exchanger. Acinar cells. Most probably when the ductal defence mechanism is damaged, bile acids can reach the acinar cells at high concentrations. The key point in the toxic effects of bile acid on acinar cells is the generation of global sustained Ca²⁺ waves. Bile acids elevate the Ca²⁺_i concentration by stimulating Ca²⁺ efflux from the (i) endoplasmic reticulum (ER) via IP₃R and ryanodine receptors, from the (ii) acidic Ca²⁺ stores (AS) and by (iii) stimulating indirectly the opening of store-operated Ca²⁺ channels (SOCC). In addition, bile acids inhibit Ca²⁺ restoration to the basal level by blocking both the sarco/endoplasmic reticulum Ca²⁺ ATPase (SERCA)-dependent Ca²⁺ reloading into intracellular pools and the plasma membrane Ca²⁺ ATPase (PMCA)-dependent Ca²⁺ excretion. Depletion of Ca²⁺_i defends the acinar cells from death. CaCC, Ca²⁺-activated Cl⁻ channel; CFTR, cystic fibrosis transmembrane conductance regulator Cl⁻ channel; N, nucleus; Z, zymogen granule; +, stimulation; −, inhibition.

Figure 2

Effects of ethanol on pancreatic ductal cells. Acinar cells. Ethanol (ETOH) or fatty acid ethyl esters (FAEE) can enter the cells by diffusion. Ethanol will be metabolised by FAEE synthase (synth.). FAEE and their metabolites fatty acids (FA) strongly elevate the intracellular Ca²⁺ (Ca²⁺_i) concentration by stimulating Ca²⁺ efflux from the (i) endoplasmic reticulum (ER) via inositol 1,4,5-triphosphate receptor (IP₃R) and ryanodine receptor-dependent pathways, from the (ii) acidic Ca²⁺ stores (AS) and by (iii) indirectly stimulating the opening of store-operated Ca²⁺ channels (SOCC). FA strongly damage the mitochondria and decrease [ATP]_i. This energetic breakdown will inhibit the Ca²⁺ restoration to the basal level by blocking both the sarco/endoplasmic reticulum Ca²⁺ ATPase-dependent Ca²⁺ reloading into intracellular pools and the plasma membrane Ca²⁺ ATPase (PMCA)-dependent Ca²⁺ excretion. Restoration of [ATP]_i can defend the acinar cells from death. Ductal cells. Low concentration of ethanol and secretin together cause elevation of Ca²⁺_i concentration and cAMP level. Ethanol augments the secretin-stimulated pancreatic ductal fluid and HCO₃⁻ secretion. However, high concentration of ethanol inhibits HCO₃⁻ secretion induced by physiological concentration of secretin. CaCC, Ca²⁺-activated Cl⁻ channel; CFTR, cystic fibrosis transmembrane conductance regulator Cl⁻ channel; N, nucleus; Z, zymogen granule; +, stimulation; −, inhibition.