Events Inside the Pancreatic Acinar Cell in Acute Pancreatitis: Role of Secretory Blockade, Calcium Release, and Dehydration in the Initiation of Trypsinogen Activation and Autodigestion

Abstract

Recent studies offer new insight into the processes which may lead to protease activation and cell damage during acute pancreatitis. Several mechanisms which finally lead to cell damage in vitro and to acute pancreatitis in vivo cause a rapid increase of [Ca²⁺]_i in the acinar cells. This [Ca²⁺]_i increase is followed shortly thereafter by cell dehydration and a blockade of protein secretion. Recent studies suggest that the cell shrinkage may largely explain the secretory blockade, which is an early characteristic of acute pancreatitis. Several mechanisms that cause [Ca²⁺]_i increase, cell dehydration, and secretory blockade also result in activation of trypsinogen. Calcium chelators can reduce the trypsinogen activation, and cell dehydration can restore the secretory function. Thus, these cellular events are probably linked in a causal relationship (Fig. 1). Recent studies also show that trypsinogen activation occurs inside the acinar cell and may be the primary step leading to autodigestion. Once trypsin has become activated, its inhibition does not alter the course of pancreatitis, because other proteases which are activated by trypsin finally cause the subsequent cell damage. Clinical studies should therefore focus rather on new protease inhibitors, which more specifically also inhibit elastase and phospholipase in already established pancreatitis. Other studies should analyze means of inhibiting a pathological calcium release and of overcoming the secretory blockade. Re-hydration may be a crucial factor not only in preventing shock but also in restoring cellular functions.