The acinar cell and early pancreatitis responses

Abstract

Pathologic responses arising from the pancreatic acinar cell appear to have a central role in initiating acute pancreatitis. Environmental factors that sensitize the acinar cell to harmful stimuli likely have a critical role in many forms of pancreatitis, including that induced by alcohol abuse. Activation of zymogens within the acinar cell and an inhibition of secretion are critical, but poorly understood, early pancreatitis events. While there is firm evidence relating trypsinogen activation to pancreatitis, the importance of other zymogens has been less studied. Preliminary studies suggest that trypsin may be activated by mechanisms that are distinct from other zymogens. Further, unlike the small intestine, it may not catalyze the activation of other zymogens. These features could affect strategies aimed at inhibiting proteases to treat pancreatitis. Specific intracellular signals are required to activate pancreatitis pathways in the acinar cell. The most important is calcium. Recent studies have suggested that calcium release through specific calcium channels in the endoplasmic reticulum is the means by which pathological elevations in cytosolic calcium occur. Although the targets of abnormal calcium signaling are unknown, calcineurin, a calcium-dependent phosphatase, may serve such a role. Finally, recent work suggests that an acute acid load might sensitize the acinar cell to pancreatitis responses. Therapies aimed at preventing or reversing the effects of an acid load on the pancreas may be important for treatment.

Figure 1

Trypsinogen activation, trypsin inhibition, and degradation in the acinar cell. The acinar cell has evolved specific mechanisms that regulate the processing of trypsinogen and trypsin within the acinar cell that are distinct from its metabolism in the intestine. Thus, cathepsin B has a central role in regulating trypsinogen activation (A). Two mechanisms have evolved to reduce trypsin activity when generated in the acinar cell. SPINK1 is an endogenous trypsin inhibitor that is present in the secretory pathway; the basal levels of SPINK1 would inhibit very small amounts of trypsin (B). Some proteases (anionic trypsin, chymotrypsin C) within the secretory pathway, and perhaps some lysosomal proteases, can degrade trypsin (C). Notably, mutations in proteins in these pathways have been found to either cause (cationic trypsinogen) or predispose to (eg, SPINK1, chymotrypsin C) the development of pancreatitis (model suggested by Szmola R).

Figure 2

Pancreatic secretion is inhibited by multiple mechanisms in acute pancreatitis. In physiologic conditions, zymogen granules are concentrated at the apical pole of the acinar cell where secretion occurs. Secretion from the basolateral region is inhibited. Tight paracellular barriers prevent the flux of secretory products from the lumen to the interstitium. In acute pancreatitis, apical secretion is inhibited, zymogen granules redistribute away from the apical pole, and exocytosis at the basolateral membrane is no longer inhibited. Disruption of the tight junctions allows flux of luminal contents into the interstitium.

Figure 3

An acute acid load can affect many pancreatitis responses.