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Human pancreatitis and the role of cathepsin B
  1. M M Lerch1,
  2. W Halangk2
  1. 1Department of Gastroenterology, Endocrinology, and Nutrition, Ernst-Moritz-Arndt Universität Greifswald, Germany
  2. 2Department of Surgery, Division of Experimental Surgery, Otto-von-Guericke- Universität, Magdeburg, Germany
  1. Correspondence to:
    Professor M M Lerch
    Department of Gastroenterology, Endocrinology, and Nutrition, Ernst-Moritz-Arndt Universität Greifswald, Friedrich-Loeffler-Str 23A, 17487 Greifswald, Germany; lerch{at}

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Any assumption about the role of the newly detected cathepsin B polymorphisms in pancreatitis must, for now, remain speculative

Acute pancreatitis has long been considered an autodigestive disorder in which the pancreas is destroyed by its own digestive proteases.1 Under physiological conditions pancreatic proteases are synthesised as inactive precursor zymogens and stored by acinar cells in zymogen granules. Autodigestion of the gland would therefore require premature activation of these zymogens. How and where such a premature and intrapancreatic activation of digestive proenzymes is initiated in the course of pancreatitis has been the subject of several investigations.2,3 Recent studies strongly suggest that the early pathophysiological events that eventually lead to necrosis of pancreatic tissue originate in acinar cells3–5 and involve the intracellular presence of active trypsin,5,6 a serine proteinase capable of activating other pancreatic zymogens. Within pancreatic acinar cells cytoplasmic vesicles have been identified as the subcellular compartment in which premature trypsinogen activation begins within minutes after induction of experimental pancreatitis.3,7,8

The molecular mechanisms responsible for the intracellular activation of trypsinogen, however, have remained elusive. One hypothesis predicts that the lysosomal cysteine proteinase cathepsin B (CTSB) plays an essential role in this process.9 The largely circumstantial evidence for this “cathepsin B hypothesis” is based on the following observations: (a) CTSB has been shown to activate trypsinogen in vitro10; (b) during the initial phase of acute pancreatitis in several animal models, redistribution of CTSB into a zymogen granule containing subcellular compartment was detected by density gradient centrifugation11; and (c) in the same pancreatitis models lysosomal enzymes were detected by immunogold electron microscopy in secretory organelles that also contained digestive enzymes (for example, trypsinogen).12 Experimental approaches to show an essential role for CTSB in premature zymogen activation …

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