Pancreatitis: The Acid Test Rodger A. Liddle  Gastroenterology  Volume 139, Issue 5, Pages 1457-1460 (November 2010) DOI: 10.1053/j.gastro.2010.09.021 Copyright © 2010 AGA Institute Terms and Conditions

Figure 1 Exocytosis acidifies the apical surface of the pancreatic acinar cell. (A) CCK, or its analog cerulein, at physiologic concentrations, binds to the high-affinity site of the CCK1 receptor on pancreatic acinar cells and initiates a series of downstream signaling events that increase cytoplasmic Ca2+ levels. A characteristic pattern of Ca2+ oscillations is associated with secretion of pancreatic enzymes that results from fusion of zymogen granules with the apical membrane of the acinar cell. As zymogen granules fuse with the plasma membrane, they also fuse with one another, a process known as compound exocytosis. The contents of zymogen granules are acidic; therefore, as exocytosis occurs the pH of the luminal surface of the acinar cell declines. This low pH activates the PMCA which exchanges intracellular Ca2+ ions for extracellular H+ ions, thus lowering the intracellular Ca2+ concentration. This restoration of Ca2+ to basal levels, reduces the stimulus for enzyme secretion. (B) Supraphysiologic concentrations of cerulein bind to both the high and low affinity sites of CCK1 receptor. Activation of the low-affinity CCK1 receptor produces high intracellular Ca2+ levels throughout the cell and physiologic Ca2+ oscillations are lost. Apparently this causes a brief burst in zymogen secretion and extensive acidification of the acinar lumen. The high and widespread H+ ion concentration disrupts the tight junctions between acinar cells leading to cellular damage. Gastroenterology 2010 139, 1457-1460DOI: (10.1053/j.gastro.2010.09.021) Copyright © 2010 AGA Institute Terms and Conditions

Figure 2 Contribution of extracellular acidification to pancreatitis. Zymogen granules have a low pH, which provides an ideal environment of activation of trypsinogen. An extracellular acid load from any cause may damage intercellular junctions and increase paracellular permeability. The fall in local pH that accompanies secretagogue hyperstimulation or other causes of pancreatic injury may also activate acid-sensitive ion channels (eg, TRPV1) on primary sensory nerves which release inflammatory neurotransmitters (eg, substance P). In the pancreas, substance P causes vasodilation, plasma extravasation, neutrophil infiltration, and inflammatory cell activation, whereas, in the spinal cord, substance P signals pain. Gastroenterology 2010 139, 1457-1460DOI: (10.1053/j.gastro.2010.09.021) Copyright © 2010 AGA Institute Terms and Conditions