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Most patients with acute pancreatitis develop their disease in association with either biliary tract stones or abuse of ethanol, whereas chronic pancreatitis is most commonly the result of prolonged ethanol abuse. Attempts to study the pathogenesis and pathophysiology of these inflammatory conditions have been hampered by the relative inaccessibility of the pancreas to study in humans, as well as the difficulty in identifying appropriate patients during the earliest stages of their disease.
Over the past two decades, several models of acute pancreatitis induced in laboratory animals have been developed.1-3 Use of these models has permitted the performance of studies that have advanced our understanding of the early cellular events that underlie the development of acute pancreatitis.4 Unfortunately, similar progress in the area of chronic pancreatitis has not been made, mainly because no good models of that disease have been developed.
The hallmarks of chronic pancreatitis are the combined presence of chronic inflammatory changes, pancreatic fibrosis, and loss of pancreatic acinar cell mass. Several recent reports have suggested that the cytokine transforming growth factor (TGF) β1 may play an important role in regulating these events in the pancreas and in other organs including the liver. Evidence supporting a role for TGF-β1 includes the following observations: intrapancreatic expression of TGF-β1 is increased in clinical chronic pancreatitis5; administration of TGF-β1 to animals during acute pancreatitis promotes pancreatic fibrosis6; transgenic mice that overexpress TGF-β1 in the pancreas develop pancreatic fibrosis7; and administration of anti-TGF-β1 antibodies during acute pancreatitis in animals reduces extracellular matrix formation.8 The prevailing dogma suggests that TGF-β1 promotes fibrogenesis by (a) favouring the proliferation and/or activation of collagen forming stellate cells (i.e. myofibroblasts) in the pancreas and other tissues9and (b) increasing the production of collagenase inhibitors.10
The immunosuppressant cyclosporin has been shown to stimulate TGF-β1 production.11 In this issue, Vagueroet al (see page 269) report that administration of cyclosporin to rats increases TGF-β1 levels in the pancreas. More importantly, however, they show that administration of cyclosporin to rats subjected to repeated episodes of secretagogue induced acute pancreatitis results in the development of chronic pancreatitis, characterised by the loss of pancreatic mass, proliferation of intrapancreatic myofibroblasts, increase in pancreatic hydroxyproline (i.e. collagen) content, development of pancreatic fibrosis, and appearance of a chronic inflammatory cell infiltrate within the pancreas.
These observations are of potential importance because they suggest that administration of cyclosporin to animals during experimental acute pancreatitis could provide the model of chronic pancreatitis which is so badly needed for studies probing the mechanisms underlying that disease. Clearly, the clinical relevance of the model described by Vaguero et al can be questioned as there is no reason to believe that clinical chronic pancreatitis is related to the combined effects of supramaximal secretagogue stimulation and exposure to cyclosporin. Similarly, there is no evidence that patients given cyclosporin for immunosuppression after non-pancreatic transplantation develop chronic pancreatitis and, in those given cyclosporin after pancreas transplantation, pancreatic atrophy, when it occurs, probably reflects rejection rather than chronic pancreatitis.
At the same time, however, it must be pointed out that the effective use of an animal model of disease is not dependent upon that model’s recapitulation of the clinical events believed to be critical to the development of the disease. There are many examples of important insights gained using animal models of disease which are induced by interventions that may be, themselves, clinically irrelevant. Indeed, the most commonly used models of acute pancreatitis involve either administration of a choline deficient ethionine supplemented diet to young female mice1 or the exposure of rodents to a supramaximally stimulating dose of the cholecystokinin analogue caerulein.2 Neither of these models would pass the “clinical relevance” test as few if any patients develop acute pancreatitis as the result of either ingesting an ethionine containing diet or being exposed to a supramaximally stimulating dose of a secretagogue. Yet both models have permitted performance of many studies that have elucidated basic cellular events that are critical to the development of acute pancreatitis.
It should be hoped that the model described by Vagueroet al will be similarly exploited for studies directed at elucidating early critical events in chronic pancreatitis. In this regard, evaluating the effects of cyclosporin administration during other forms of acute pancreatic injury might indicate whether the effects seen by Vaguero et al in the caerulein model are specific to that model or, alternatively, characteristic of pancreatic injury regardless of its cause. Similarly use of this model in transgenic or knockout mouse strains could permit dissection of the events which couple TGF-β1 overexpression to chronic pancreatitis.
See article on page 269
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