Trypsin in pancreatitis: The culprit, a mediator, or epiphenomenon?

Abstract

Pancreatitis is a common, life-threatening inflammatory disease of the exocrine pancreas. Its pathogenesis remains obscure, and no specific or effective treatment is available. Gallstones and alcohol excess are major etiologies of pancreatitis; in a small portion of patients the disease is hereditary. Pancreatitis is believed to be initiated by injured acinar cells (the main exocrine pancreas cell type), leading to parenchymal necrosis and local and systemic inflammation. The primary function of these cells is to produce, store, and secrete a variety of enzymes that break down all categories of nutrients. Most digestive enzymes, including all proteases, are secreted by acinar cells as inactive proforms (zymogens) and in physiological conditions are only activated when reaching the intestine. The generation of trypsin from inactive trypsinogen in the intestine plays a critical role in physiological activation of other zymogens. It was proposed that pancreatitis results from proteolytic autodigestion of the gland, mediated by premature/inappropriate trypsinogen activation within acinar cells. The intra-acinar trypsinogen activation is observed in experimental models of acute and chronic pancreatitis, and in human disease. On the basis of these observations, it has been considered the central pathogenic mechanism of pancreatitis - a concept with a century-old history. This review summarizes the data on trypsinogen activation in experimental and genetic rodent models of pancreatitis, particularly the more recent genetically engineered mouse models that mimic mutations associated with hereditary pancreatitis; analyzes the mechanisms mediating trypsinogen activation and protecting the pancreas against its' damaging effects; discusses the gaps in our knowledge, potential therapeutic approaches, and directions for future research. We conclude that trypsin is not the culprit in the disease pathogenesis but, at most, a mediator of some pancreatitis responses. Therefore, the search for effective therapies should focus on approaches to prevent or normalize other intra-acinar pathologic processes, such as defective autophagy leading to parenchymal cell death and unrelenting inflammation.

Keywords: Autophagy; Cathepsin; Cerulein; Cholecystokinin; Endolysosomal system; Hereditary pancreatitis; Pancreatic acinar cell.

Figure 1

Trypsin structure and functions. A: N-terminal amino acid sequence of the cationic trypsinogen; B: Schematic of trypsin-mediated activation of other digestive proteases during physiological process of digestion. SP: Signal peptide; TAP: Trypsinogen activation peptide.

Figure 2

Illustration of the main methods to measure trypsinogen activation in experimental pancreatitis. A and B: Time-course of changes in the levels of (A) trypsin activity and (B) trypsinogen activation peptide (TAP) measured in pancreas homogenates from rats subjected to i.v. infusion of 5 μg/kg cerulein (adapted from Hofbauer et al[21]), ^*P < 0.05 versus saline; C: Electron microscopic immunolocalization of TAP in pancreas was measured in (a) untreated rats and (b) 60 minutes after cerulein (5 μg/kg) infusion. Note intense punctate TAP immunoreactivity in small vesicles (arrowheads) and large vacuoles (arrows), which was absent in control[28]. C: Citation: Otani T, Chepilko SM, Grendell JH, Gorelick FS. Codistribution of TAP and the granule membrane protein GRAMP-92 in rat caerulein-induced pancreatitis. Am J Physiol 1998; 275: G999-G1009. Copyright© The American Physiological Society 1998. Published by American Physiological Society. Authors of American Physiological Society articles may reuse their content in reused new works (https://journals.physiology.org/publication-process#copyright).

Figure 3

Putative mechanisms whereby endolysosomal and autophagy dysfunctions mediate intra-acinar trypsin accumulation in pancreatitis. CTSB: Cathepsin B.