New Advances in Cell Physiology and Pathophysiology of the Exocrine Pancreas

Abstract

This review provides some aspects on the physiology of stimulation and inhibition of pancreatic digestive enzyme secretion and the pathophysiology of pancreatic acinar cell function leading to pancreatitis. Cholecystokinin (CCK) stimulates both directly via CCK-A receptors on acinar cells and indirectly via CCK-B receptors on nerves, followed by acetylcholine release, pancreatic enzyme secretion. It is still not known whether CCK-A receptors exist in human acinar cells, in contrast to acinar cells of rodents where CCK-A receptors have been well described. CCK has numerous actions both in the periphery and in the central nervous systems. CCK inhibits gastric motility and regulates satiety. Another major function of CCK is stimulation of gallbladder contraction. This function enables that bile acids act simultaneously with pancreatic lipolytic enzymes. Secretin is a major stimulator of bicarbonate secretion. Trypsinogen is activated by the gut mucosal enzyme enterokinase. The other pancreatic proenzymes are activated by trypsin. Termination of enzyme secretion may be regulated by negative feedback mechanisms via destruction of CCK-releasing peptides by trypsin. Furthermore, the ileum may act as a brake by release of inhibitory hormones such as PYY and somatostatin. In the pathophysiology of acute pancreatitis, fusion of zymogen granules with lysosomes leading to intracellular activation of trypsinogen is regarded as an initiation step. This activation of trypsinogen may be caused by the lysosomal enzyme cathepsin B. However, autoactivation of trypsinogen itself may be a possibility in pathogenesis. Autoactivation is enhanced in certain mutations of trypsinogen. Furthermore, an imbalance of protease inhibitors and active proteases may be involved. The role of pancreatic lipolytic enzymes, the role of bicarbonate secretion, and toxic Ca²⁺ signals by excessive liberation from the endoplasmic reticulum have to be discussed in the pathogenesis of acute pancreatitis.

The digestive tract as the origin of systemic inflammation

“…These are converted by the intestinal microflora to yield secondary bile acids, deoxycholic acid (DCA), lithocholic acid, and ursodeoxycholic acid (UDCA) [ 80 ]. Bile is released in the duodenal lumen in response to cholecystokinin (CCK) produced by duodenal cells postprandially [ 81 ]. The bile acids are reabsorbed with dietary lipids and returned to the liver via the enterohepatic circulation, whereas saturated digestive enzymes are normally excreted and eliminated [ 80 ].…”

Species- and Dose-Specific Pancreatic Responses and Progression in Single- and Repeat-Dose Studies with GI181771X

“…The pathogenesis and molecular mechanisms of CCK-induced pancreatic changes have been extensively evaluated and reported in the literature. Readers are encouraged to refer to these suggested review papers for details (Saluja et al 2007; Mossner 2010; Sah, Garg, and Saluja 2012; Yu and Kim 2012). The pathologic cellular events are summarized below.…”

Pancreatic Stellate Cells

“…The primary site of injury in acute pancreatitis is thought to be the acinar cell [80]. Regardless of the causative factor (commonly gallstone disease or alcohol abuse), the prevailing view, based on extensive studies with a variety of experimental animal models, is that the initial insult causes subcellular changes in the acinar cell that predispose the cell to autodigestion via premature intracellular activation of pancreatic digestive enzymes.…”