Discussion

This study demonstrated the reversibility of fibrosis in ethionine-induced pancreatitis in dogs in the early stages. Destruction of the exocrine parenchyma and decreased number and size of zymogen granules in acinar cells were mainly found in early stages of injury. Infiltration of lymphocytes was slight. Activated PSCs and a-SMA positive cells (myofibroblasts) play a central role in pancreatic fibrogenesis. Morphologically these cells produce and secrete the extracellular matrix proteins collagen and fibronectin. It is therefore likely that the

Fig. 5. Group 3. a Week 2. Fibrosis in the periductal and intra- and inter-lobular areas with atrophic exocrine parenchyma. Azan. b Week 3 Mild fibrosis in the periductal and interlobular areas. Azan.

formation of collagen bundles and resolution of fibrous depositions occur simultaneously between 2 and 4 weeks after the last feeding of ethionine, and that only the resolution of fibrous depositions occurs thereafter. These findings support the view that fibrosis in acute pancreatitis does not generally progress

Fig. 6. Group 3. Week 26. a Focal mild fibrosis in the periductal, perivascular and interlobular areas. HE. b Mild proliferation of collagen bundle. Azan.

to that in chronic pancreatitis and that fibrosis in chronic pancreatitis probably occurs due to continuous pancreatic injury, which causes the release of pancreatic enzymes. Mild fibrosis remained only in the periductule, interlobular and perivascular areas. It is likely that collagen bundles bound to existing fibrous

Fig. 7. Group 3. Week 26. a Mild fibrosis in the periductal area. Aggregation of ductules in the regenerated pancreas. b Mild proliferation of a-SMA positive spindle cells in the periductal and periacinar areas.

tissues such as pancreatic duct wall, vascular wall and interlobular stroma were slowly resolved.

In activated PSCs, a cell-cycle inhibitory protein p21Cip1/WAF1 was present in the nucleus. With conversion of PSCs to fibroblasts, p21Cip1/WAF1 translocated to the cytoplasm [12]. It is proposed that the fibroblastic phenotype of the stellate cell is resistant to apoptosis and a terminally differentiated state, due to similarities in the pattern of changes in p2lCip1/WAF1 associated with differentiation in monocytic cells and neuronal cells [13]. Fibroblastic cells not expressing a-SMA also play a role in pancreatic fibrosis in experimental models of pancreatitis. This phenotype is resistant to apoptosis. In this study fibroblastic cells were also found in fibrotic foci. However, a-SMA-positive stellate cells and also fibroblastic cells were decreased in number after removal of the injury.

In addition, PSCs were activated on exposure to ethanol in an in vitro model [14]. PSCs also have a capacity to metabolize ethanol to acetaldehyde and to synthesize collagen.

Pancreatic fibrosis in the animal model depends on the dose and duration of exposure to the metabolic agent. Activated PSCs play a central role in fibro-genesis, especially in early stages of the pancreas injury. PSCs were activated on exposure to cytokines, such as transforming growth factor-^ and platelet derived growth factor, and also ethanol. Activation of PSCs occurs early in long-term pancreatic injury.

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