Cases categorized as focal pancreatitis (FP) showed localized stenosis of the main pancreatic duct on endoscopic retrograde pancreatography and histological findings of localized acinar atrophy with massive fibrosis with scanty inflammatory cell infiltration. All cases with FP showed fibrous thickening of the wall of the main pancreatic duct without atypical epithelium at the stenotic portion. In 6 cases with FP, a-SMA-positive and desmin-negative cells, i.e. myofibroblasts, proliferated between the duct epithelium and preexisting elastic fibers in the duct wall (fig. 3). The other cases showed no proliferation of myofibroblasts, but showed collagen-fiber accumulation in the subepithelium space, resulting in dissociation of elastic fibers from the duct epithelium . Because myofibroblasts play an important role in wound healing [1, 16], the same phenomena might occur at the duct wall with localized inflammation or ulceration by any causes. In 4 cases without myofibroblast proliferation, apo-ptosis observed to be negative for a-SMA might occur after collagen fiber synthesis in the late phase of wound healing  or cytoskeletal transformation
In our study, the distribution of interlobular fibrosis, one characteristic finding in alcoholic chronic pancreatitis (CP)  showed good agreement with the distribution of proliferating myofibroblasts (fig. 4). However, no proliferation of myofibroblasts was found in stenosed duct walls with inflammatory cell infiltration. Many studies have attempted to elucidate the mechanism of CP [36-39]. Functional disorder of acinar cells and ductal epithelial cells in the early stages
of CP have been reported. Formation of protein plugs and stones in the pancreatic duct system due to change of character of pancreatic juice, abnormality of the microcirculation [40, 41], and formation of autocrine and paracrine loops of cytokines such as transforming growth factor-^1 [40, 42-49, 50-52], and other factors have been thought to be related to progression of CP [53, 54]. Particularly the activation of cells producing several kinds of extracellular matrixes is an important factor in pancreatic fibrosis [18, 20, 21, 55]. Casini et al. reported acceleration of lipid peroxidation in acinar cells adjacent to interlobular fibrosis and acceleration of collagen fiber production in pancreatic stellate cells adjacent to them in human pancreas tissue with CP .
We did not identify myofibroblast proliferation in the duct walls of the pancreas of alcoholic liver cirrhosis patients without CP. Myofibroblasts uniformly proliferated in the periacinar space (fig. 5), where fibrosis was observed, in pancreas tissues obtained from autopsy cases with alcoholic liver cirrhosis . These cells are thought to be derived from pancreatic stellate cells similar to Ito cells in the liver. Moroboshi et al. reported that periacinar fibrosis accompanied with no inflammatory changes were observed in the pancreata of hard drinkers, and suggested the existence of not only secondary fibrosis due to parenchymal inflammation but also primary fibrosis . In the livers of cases
Fig. 5. Myofibroblasts, a-SMA-positive cells, proliferating in the periacinar area of a patient with alcoholic liver cirrhosis. Immunostain for a-SMA. X200. Reproduced with permission .
with alcoholism, similar fibrosis in absence of hepatitis, which is called pericellular fibrosis, occurs by activation of Ito cells . Several investigators have explained the mechanism of periacinar fibrosis. Portal hypertension due to liver cirrhosis may be a cause of myofibroblast activation , as congestive heart failure can induce Ito cells to transform into myofibroblasts . Kuroda et al. suggested a contribution of the intracellular transport blockage of protein, as represented by abnormalities of zymogen granules, endoplasmic reticulum and lysosomes, to the development of acinar collagenization in patients with chronic alcoholism . Recently, Apte et al. showed that rat pancreatic stellate cells were directly activated by exposure to ethanol or acetaldehyde, and generation of oxidant stress within the cells .
The pancreatic tissue of patients with carcinoma of the papilla of Vater (VPCa) showed various degrees of inter- and intralobular fibrosis with acinar atrophy that correspond to obstructive CP [63, 64]. The 56 specimens of VPCa were classified into five patterns of myofibroblast distribution, as follows: (1) no proliferation, same as normal tissue (n = 6); (2) proliferation only in the duct wall (n = 10); (3) proliferation in the duct wall and periductal area (n = 15) (fig. 6); (4) proliferation in the interlobular and periacinar areas in addition to the duct wall (n = 15), and (5) diffuse proliferation in the
parenchyma (n = 10). Myofibroblasts proliferating in the duct wall were distributed mainly in the subepithelial space, resulting in dissociation of elastic fibers from the duct epithelium as seen in cases with FP. The distribution of myofibroblasts coinicided with that of fibrosis in each case, but 10 cases with myofibroblast proliferation only in the duct wall showed no fibrosis in the interlobular and periacinar areas. Myofibroblasts that contain stress fibers in their cytoplasm and connect to the extracellular matrix with microtendons participate in tissue contraction [1, 7, 65]. In VPCa cases, myofibroblasts might proliferate in the duct wall against the increase in intraductal pressure due to disturbance of the flow of pancreatic juice. When intraductal pressure rises beyond the limitation of compensation by the contractile force of proliferating myofibroblasts, pancreatitis may occur .
At the stenotic portion of the main pancreatic duct, where carcinoma cells invaded into the duct wall, no myofibroblast proliferation was observed in any cases, whereas myofibroblasts proliferated in duct walls upstream from the stenotic portions, accompanied by inter- and intralobular fibrosis and acinar atrophy in various degrees.
Degeneration and disappearance of the pancreatic ductal epithelium, intraluminal aggregation of bacilli, and diffuse interlobular fibrosis were observed in the pancreas of some cases with pancreaticobiliary maljunction . Therefore, direct and/or indirect activation of pancreatic enzymes by infected bile is considered to be the mechanism of damage to acinar cells [67, 68]. In our cases with pancreaticobiliary maljunction, fibrosis was observed in the interlobular and periductal spaces, while myofibroblast proliferation was observed in the duct wall and periductal space (fig. 7). Our results indicate that apoptosis or transformation into a-SMA-negative cells might occur in proliferating myofibroblasts in the interlobular space, but on the other hand fibrosis might persist in the periductal space in bile pancreatitis due to pancreaticobiliary maljunction.
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