Mechanisms of Fibrous Regression in Animal Models

We have had some experience in investigating the mechanisms involved in the process of fibrous regression after the peak of fibrous formation in animal models of chronic pancreatitis [66]. In our studies, it became apparent that fibrous regression depends on a change in the balance between factors promoting fibrosis and those causing its dissolution. That is to say, the WBN/Kob rats used in the study, showed accelerated collagenase activity in the pancreas after the fibrosis had occurred. On the other hand, the activity leading to fibrosis seemed to remain, because the amount of prolyl hydroxylase, which plays a role in collagen synthesis, was still maintained at a high level. We hence concluded that the reversibility of fibrosis in the WBN/Kob rats was partly due to the ability of the pancreas to elevate its collagen-degrading activity above its collagen-forming activity. In recent years, there have appeared a growing number of reports on studies that have analyzed the mechanism underlying the resolution of pancreatic fibrosis in relation to both formation and degradation [147-150].

Also, we immunohistochemically investigated pancreatic fibrosis in animal models of pancreatic fibrosis. We compared fibrosis in WBN/Kob rats with that in the DBTC model. Fibrosis in WBN/Kob rats, which is reversible, was due to fibers composed of type III collagen (fig. 11a, b). In contrast, in the DBTC model, the fibrosis around the pancreatic ducts is irreversible, and was due to fibers composed of type I collagen (fig. 11c). However, the interlobular or intralobular fibrosis in the DBTC model, which resolved with time, was immunohistochemically positive for type III collagen (fig. 11d). As type I collagen is known to be more resistant to enzymic degradation than type III [151, 152], fibrosis involving type III collagen would be more easily disrupted or resolved. This indicates that the irreversible fibrosis seen in human chronic pancreatitis may be due to the fact that the fibers involved are mostly type I collagen [150, 153] and that approaches to limit synthesis of type I collagen may be very significant for establishing treatment guidelines. If it is possible that

Fig. 11. Immunohistochemical characteristics of pancreatic fibrosis from male WBN/Kob rats and DBTC model rats. a Type I collagen immunohistochemistry of pancreas from a WBN/Kob rat at 4 months of age. Scarcely any positive immunoreaction is seen in the area of fibrosis. b Type III collagen immunohistochemistry of the pancreas from the same animal as in (a). It is evident that the fibrosis in WBN/Kob rat is mostly due to fibers composed of type- III collagen. c Type I collagen immunohistochemistry of pancreas from a DBTC model rat at 2 weeks after the treatment. Positive staining is seen in fibrous elements around the pancreatic ducts, indicating a great difference between the fibrosis in WBN/Kob rats and that in DBTC model rats. d Type III collagen immunohistochemistry of pancreas from the same animal as in (c). As in the case of the WBN/Kob rats, type III collagen is

Fig. 11. Immunohistochemical characteristics of pancreatic fibrosis from male WBN/Kob rats and DBTC model rats. a Type I collagen immunohistochemistry of pancreas from a WBN/Kob rat at 4 months of age. Scarcely any positive immunoreaction is seen in the area of fibrosis. b Type III collagen immunohistochemistry of the pancreas from the same animal as in (a). It is evident that the fibrosis in WBN/Kob rat is mostly due to fibers composed of type- III collagen. c Type I collagen immunohistochemistry of pancreas from a DBTC model rat at 2 weeks after the treatment. Positive staining is seen in fibrous elements around the pancreatic ducts, indicating a great difference between the fibrosis in WBN/Kob rats and that in DBTC model rats. d Type III collagen immunohistochemistry of pancreas from the same animal as in (c). As in the case of the WBN/Kob rats, type III collagen is fibrosis in human pancreatitis could be controlled by promoting the formation of type III collagen while inhibiting that of type I collagen, it might be possible to prevent acute pancreatitis from progressing to pancreatic fibrosis or to treat recrudescence of chronic pancreatitis.

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