Chronic Obstructive Pancreatitis

In the case of chronic obstructive pancreatitis, pressure or enzymatic effects of pancreatic juice may cause damage to the pancreatic acinar cells and ductal epithelial cells. The pancreatic acini show a declining number of acinar cells and transformation of acinar cells into ductular cells, resembling the proliferation of cholangioles in chronic cholestasis of the liver. In the intermediate or late stage of obstructive pancreatitis, the ductules transformed from centroacinar cells proliferate at the centers of the pancreatic lobules. These ductules are surrounded by

Fig. 2. A few myofibroblasts are observed around the pancreatic ducts, but not in the pancreatic lobules (a). Activated myofibroblasts are observed in the periacinar areas in the early stage of chronic obstructive pancreatitis (b) and also in the perilobular areas in the mid stage (c). In the late stage, diffuse proliferation of activated myofibroblasts is observed in the fibrosis, especially around the pancreatic ducts (d). Immunostaining for a-SMA.

Fig. 2. A few myofibroblasts are observed around the pancreatic ducts, but not in the pancreatic lobules (a). Activated myofibroblasts are observed in the periacinar areas in the early stage of chronic obstructive pancreatitis (b) and also in the perilobular areas in the mid stage (c). In the late stage, diffuse proliferation of activated myofibroblasts is observed in the fibrosis, especially around the pancreatic ducts (d). Immunostaining for a-SMA.

myxomatous stroma and collagen fibers. In the late stage, the pancreatic parenchyma, except for the ducts, disappears and the collagenous matrix increases. Immunohistochemistry reveals that myofibroblasts proliferate around the lobules in the early stage of pancreatic obstruction, similar to interlobular fibrosis, which is frequently observed in chronic alcoholic pancreatitis. In the intermediate stage, myofibroblasts are present in and around the lobules, similar to mixed fibrosis. In the final stage, fibrosis is extended into all pancreatic parenchyma except for the pancreatic duct. A number of myofibroblasts are observed in the fibrotic parenchyma, especially around the pancreatic ducts, at this stage. This indicates that myofibroblasts are induced by diverse stimuli at each stage during progression of fibrosis in chronic obstructive pancreatitis (fig. 2). We focused on expression of TGF-^1, 2 and 3, PDGF and IGF-1 in the paracrine mechanism of chronic obstructive pancreatitis. Interestingly, TGF-^1 expresses on neutrophils, and TGF-^2 and 3 on ductal or ductular cells. All subtypes of TGF-P are expressed on myofibroblasts [20]. PDGF and IGF-1 are

Fig. 3. In situ hybridization of TGF-ß mRNA in chronic obstructive pancreatitis. Centroacinar cells or pancreatic ductular cells express TGF-ß mRNA in chronic obstructive pancreatitis. a Positive centroacinar cells in the early stage. b Positive ductular cells in the late stage.

Fig. 4. In situ hybridization of PDGF mRNA in chronic obstructive pancreatitis. a Many centroacinar cells express platelet-derived growth factor mRNA in the mid stage. b A few ductular cells express it in the late stage.

Fig. 4. In situ hybridization of PDGF mRNA in chronic obstructive pancreatitis. a Many centroacinar cells express platelet-derived growth factor mRNA in the mid stage. b A few ductular cells express it in the late stage.

Fig. 5. In situ hybridization of IGF-1 mRNA in chronic obstructive pancreatitis. Centroacinar cells strongly express IGF-1 mRNA in the early stage. a Anti-sense probe. b Sense probe.

Fig. 6. Immunohistochemistry for IGF-1 and its receptor in chronic obstructive pancreatitis. Normal pancreatic tissue is negative for immunostaining of IGF-1 (a), while centroacinar cells in the normal pancreatic tissue are positive for immunostaining of its receptor (b, immunopositive for IGF-1 receptor indicated by arrow). In chronic obstructive pancreatitis, centroacinar cells are immunopositive for both IGF-1 (c, immunopositive for IGF-1 indicated by arrow) and its receptor (d, immunopositive for IGF-1 receptor indicated by arrow).

Fig. 6. Immunohistochemistry for IGF-1 and its receptor in chronic obstructive pancreatitis. Normal pancreatic tissue is negative for immunostaining of IGF-1 (a), while centroacinar cells in the normal pancreatic tissue are positive for immunostaining of its receptor (b, immunopositive for IGF-1 receptor indicated by arrow). In chronic obstructive pancreatitis, centroacinar cells are immunopositive for both IGF-1 (c, immunopositive for IGF-1 indicated by arrow) and its receptor (d, immunopositive for IGF-1 receptor indicated by arrow).

Fig. 7. Double immunostaining of a-SMA and TGF-ß in chronic obstructive pancreatitis. A few myofibroblasts, which are immunopositive for a-SMA, express TGF-ß around the pancreatic duct (white arrows).

expressed on centroacinar cells, but not inflammatory cells (figs. 3-6). Myofibroblasts around the pancreatic ductules express TGF-P (fig. 7), suggesting that chronic obstructive pancreatitis has an autocrine mechanism.

In conclusion, autocrine and paracrine mechanisms play a crucial role in pancreatic fibrosis. However, many cells express different growth factors or growth factor subtypes in chronic pancreatitis and fibrosis, indicating that these may lead to different morphologies, such as interlobular and intralobular fibrosis.

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