The exocrine pancreas synthesizes and secretes more protein per cell than any other exocrine organ. Much of its protein secretion consists of digestive proenzymes, called zymogens, that require cleavage of an activation peptide by a protease. After entering the small intestine, the pancreatic zymogen trypsinogen is first processed to trypsin by the intestinal protease, enterokinase. Trypsin then proteolytically processes the other pancreatic zymogens to their active forms. Under physiologic conditions, pancreatic proteases remain inactive during their synthesis, intracellular transport, secretion from acinar cells, and transit through the pancreatic duct. They become active only when they reach the lumen of the small intestine. About a century ago, Chiari suggested that the pancreas of patients who had died during episodes of acute necrotizing pancreatitis “had succumbed to its own digestive properties” and postulated that pancreatic autodigestion is the underlying pathophysiologic mechanism of the disease.<sup>8 Chiari H. Über die Selbstverdauung des menschlichen Pankreas Z Heilk 1896 ;  17 : 69-96

Cliquez ici pour aller à la section Références</sup> Since then, many attempts have been made to prove or disprove the role of a premature and intracellular zymogen activation as an initial or an initiating event in the course of acute pancreatitis. More recent advances in biochemical and molecular techniques have allowed investigators to address some of these questions conclusively.

Much of the current knowledge regarding the onset of pancreatitis was not gained from studies involving the human pancreas or patients with pancreatitis but from animal or isolated cell models. There are several reasons why these models have been used: (1) The pancreas is a rather inaccessible organ because of its anatomic location in the retroperitoneal space; in contrast to the colon or stomach, biopsy specimens of human pancreas are difficult to obtain for ethical and medical reasons. (2) Patients who are admitted to the hospital with acute pancreatitis have usually passed through the initial stages of the disease in which the triggering early events could have been studied. Particularly the autodigestive process that characterizes this disease has remained a significant impediment for investigations that address initiating pathophysiologic events. The issue of premature protease activation has mostly been studied in animal models of the disease.<sup>16 Gorelick F.S., Adler G., Kern H.F. Cerulein-induced pancreatitis The Pancreas: Biology, Pathobiology, and Disease New York: Raven Press (1993).  501-526

Cliquez ici pour aller à la section Références, 40 Lerch M.M., Adler G. Experimental pancreatitis Curr Opin Gastroenterol 1993 ;  9 : 752-759  [cross-ref]

Cliquez ici pour aller à la section Références, 41 Lerch M.M., Adler G. Experimental animal models of acute pancreatitis Int J Pancreatol 1994 ;  15 : 159-170

Cliquez ici pour aller à la section Références</sup> These models can be experimentally controlled, are highly reproducible, and recapitulate many of the cellular events that are associated with clinical disease.

Although this article focuses on zymogen activation within the acinar cell, other mechanisms undoubtedly contribute to pancreatic injury.<sup>16 Gorelick F.S., Adler G., Kern H.F. Cerulein-induced pancreatitis The Pancreas: Biology, Pathobiology, and Disease New York: Raven Press (1993).  501-526

Cliquez ici pour aller à la section Références</sup> The activation of extracellular proteases, an increased vascular permeability, and endothelial injury are all features of acute pancreatitis and have been shown to contribute to pancreatic edema, decreased pancreatic blood flow, ischemic injury, and disease progression.<sup>25 Hartwig W., Jimenez R.E., Werner J. , et al. Interstitial trypsinogen and its relevance to the transformation of mild into necrotizing pancreatitis in rats Gastroenterology 1999 ;  117 : 717-725  [cross-ref]

Cliquez ici pour aller à la section Références, 49 Lerch M.M., Weidenbach H.S., Gress T.M. , et al. Effect of kinin inhibition in experimental acute pancreatitis Am J Physiol 1995 ;  269 : G490-G499

Cliquez ici pour aller à la section Références</sup> Potentially damaging free radicals are detected within the pancreas soon after the induction of pancreatitis,<sup>58 Niederau C., Niederau M., Borchard F. , et al. Effects of antioxidants and free radical scavengers in three different models of acute pancreatitis Pancreas 1992 ;  7 : 486-496  [cross-ref]

Cliquez ici pour aller à la section Références</sup> and free radical scavengers have been reported to improve the course of experimental disease models.<sup>54 Neuschwander-Tetri B.A., Ferrell L.D., Sukhabote R.J. , et al. Glutathione monoethyl ester ameliorates caerulein-induced pancreatitis in the mouse J Clin Invest 1992 ;  89 : 109-116  [cross-ref]

Cliquez ici pour aller à la section Références</sup> Finally, the release of cytokines by acinar cells and activated inflammatory cells and the expression of adhesion factors promote the harmful inflammatory response that begins within hours after the onset of experimental pancreatitis.<sup>59 Norman J. The role of cytokines in the pathogenesis of acute pancreatitis Am J Surg 1998 ;  175 : 76-83  [cross-ref]

Cliquez ici pour aller à la section Références</sup> Although most of these factors contribute to the severity and ultimate clinical outcome of acute pancreatitis, they are probably not involved in the early phase of intracellular zymogen activation and are not discussed further here.