Acinar Cells

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Abnormalities Related to Alcohol Intake

At the initial stage of periacinar collagenization, abnormalities related to alcohol intake were found in zymogen granules, lysosomes, lipid droplets and the endoplasmic reticulum. A decreased number of zymogen granules and electron-dense zymogen granules were found in patients with chronic alcoholism. Decreased electron-dense zymogen granules were sometimes seen with peripheral halos and centric or eccentric cores (fig. 3). An increased number of lysosomes was found in patients with chronic alcoholism. Lysosomes were

Fig. 4. Higher-powered view of the acinar cell shown in figure 3. Note the presence of many lysosomes and degenerative zymogen granules close to the basal lamina (arrowheads). Some zymogen granules form peripheral halos and reduced the electron-dense contents. Lipid droplets are also found in secondary lysosomes. Uranyl acetate, lead citrate and tannic acid stain. From [10] with permission.

Fig. 4. Higher-powered view of the acinar cell shown in figure 3. Note the presence of many lysosomes and degenerative zymogen granules close to the basal lamina (arrowheads). Some zymogen granules form peripheral halos and reduced the electron-dense contents. Lipid droplets are also found in secondary lysosomes. Uranyl acetate, lead citrate and tannic acid stain. From [10] with permission.

derived both from the Golgi apparatus and from degenerative zymogen granules (fig. 4). Some lysosomes consisted of lipid droplets and highly electron-dense granules, which seemed to be lipofuscin. An increased number of lipid droplets was found in patients with chronic alcoholism. Dilatation of the endoplasmic reticulum was also found in patients with chronic alcoholism. In areas where the degeneration was advanced, dilatation and vesiculation were often observed in the rough endoplasmic reticulum (RER). The vesicles contained medium electron-dense materials similar to mucin, and were sometimes closely packed near the basal lamina (fig. 5). The basal lamina was sometimes obscured by some degenerative acinar cells. Medium electron-dense materials in dilated cisternae of the RER occasionally leaked out via the damaged membranes (fig. 6).

Very thin Filaments in Chronic Alcoholics

In the tissue samples from patients with chronic alcoholism, in addition to the above-mentioned changes, very thin filaments in zymogen granules were found.

Fig. 5. Degenerative acinar cell from a 58-year-old male with chronic alcoholism. Note the dilation and vesiculation of the RER containing amorphous and medium electron-dense contents similar to mucinous materials. The vesiculated endoplasmic reticulum is sometimes closely packed near the basal lamina (arrows).

Fig. 5. Degenerative acinar cell from a 58-year-old male with chronic alcoholism. Note the dilation and vesiculation of the RER containing amorphous and medium electron-dense contents similar to mucinous materials. The vesiculated endoplasmic reticulum is sometimes closely packed near the basal lamina (arrows).

These very thin filaments, approximately 3-6 nm in diameter, replaced the osmophilic contents of some zymogen granules. The very thin filaments often spread out to neighboring zymogen granule spaces via a fused limiting membrane (fig. 7). The filamentous structures found near the basal lamina occasionally leaked out from the zymogen granules via the disrupted limiting membrane (fig. 8).

Intracellular Transportation of Materials Related to

Periacinar Collagenization

In terms of ultrastructural changes in acinar cells related to alcoholism, various changes were seen in zymogen granules, as well as dilatation and vesicula-tion of the endoplasmic reticulum containing medium electron-dense material, and an increased number of lysosomes and lipid granules. In normal acinar cells, the secretory proteins are synthesized on ribosomes attached to the membrane of the RER, and the contents of the RER are transported to the Golgi complex where they are condensed and modified. Lysosomes are also transported and

Fig. 6. Degenerative acinar cell from the same patient as figure 5. At (a), note the group of zymogen granules and dilated RER containing various electron-dense contents. At (b) is a higher-powered view of part of the acinar cell shown at (a). Note the obscure membranes of some zymogen granules, a markedly dilated RER (asterisks) and the presence of many microvesicles of the endoplasmic reticulum (arrowheads) close to the destroyed basal lamina. The intracisternal contents flowing out via the damaged membrane of the endoplasmic reticulum can be observed (arrow). Uranyl acetate, lead citrate and tannic acid stain. From [10] with permission.

Fig. 6. Degenerative acinar cell from the same patient as figure 5. At (a), note the group of zymogen granules and dilated RER containing various electron-dense contents. At (b) is a higher-powered view of part of the acinar cell shown at (a). Note the obscure membranes of some zymogen granules, a markedly dilated RER (asterisks) and the presence of many microvesicles of the endoplasmic reticulum (arrowheads) close to the destroyed basal lamina. The intracisternal contents flowing out via the damaged membrane of the endoplasmic reticulum can be observed (arrow). Uranyl acetate, lead citrate and tannic acid stain. From [10] with permission.

formed in a manner similar to the secretory proteins. Primary lysosomes are thought to produce not only secondary lysosomes, but also zymogen granules. From our studies, various abnormalities in zymogen granules have been reported. Medium electron-dense materials in dilated cisternae of the RER and very thin filaments in the zymogen granules were also found. The abnormalities of zymogen granules, increased lysosomes and lipid droplets were already observed by electron microscope previous to the periacinar fibrosis. Therefore, the Golgi apparatus-endoplasmic reticulum-lysosome (GERL) abnormality and the zymogen granules were considered to disturb the intracellular transportation of various secretory proteins, lipoproteins and lipids and to play an important role in progression towards the advanced stage of periacinar collagenization followed by intralobular fibrosis. The series of changes in GERL and zymogen granules are illustrated in figure 9. The changes in zymogen granules were recognized to have been caused by alcohol-enhanced metabolic injury to acinar cells [5, 30, 31]. Similar changes in zymogen granules, except for the very thin filaments, were previously reported in acute pancreatitis in humans and laboratory animals and in genetic exocrine pancreatic insufficiency syndrome in mice [32, 33]. Medium electron-dense materials in the dilated cisternae of the RER also suggested the blockage of transporting proteins. Normally, the proteina-

Fig. 7. Degenerative acinar cell from a 52-year-old male with chronic alcoholism. Note the decreased contents of the zymogen granules and the presence of very thin filaments (F), which measure approximately 3-6 nm in diameter, arranged in parallel and sometimes present along the limiting membranes. The thin filaments also occupy the space of the zymogen granules that are without any osmophilic contents. Uranyl acetate, lead citrate and tannic acid stain. From [10] with permission.

Fig. 7. Degenerative acinar cell from a 52-year-old male with chronic alcoholism. Note the decreased contents of the zymogen granules and the presence of very thin filaments (F), which measure approximately 3-6 nm in diameter, arranged in parallel and sometimes present along the limiting membranes. The thin filaments also occupy the space of the zymogen granules that are without any osmophilic contents. Uranyl acetate, lead citrate and tannic acid stain. From [10] with permission.

ceous substances produced in the RER are transported to the Golgi complex and condensed to form zymogen granules. Zymogen granules contain glycosamino-glycans, mainly heparan sulfate and chondroitin sulfate, which are known to be involved in the mechanism by which collagen fibrils bind these structures together [34, 35]. In addition, heparan sulfate, one of the heparan-related proteoglycans, participates in the differentiation of myofibroblasts [36-39]. In our ongoing study, some filamentous structures of different diameters were identified not only in acinar cells, but also outside them. With reference to the intracy-toplasmic process of collagen formation in fibroblasts or the basement membrane formation by epithelial cells, a complex triple helix is formed from an a-chain, a simple amino acid constitution including praline, by hydroxylation of praline with the chains entwining and being transported to the Golgi complex. In the Golgi complex, carbohydrate subunits are synthesized and procollagen molecules are assembled, resulting in tropocollagen formation. Tropocollagen molecules are transported to primary and secondary lisosomes and finally are

Fig. 8. Leakage of filamentous materials (asterisk) through the disrupted limiting membrane of zymogen granules in a 53-year-old male with chronic alcoholism. Uranyl acetate, lead citrate and tannic acid stain. From [10] with permission.

released from the cell. The morphological changes in a series of filaments in our studies might indicate a similar process to intracytoplasmic collagen formation in fibroblasts or formation of the basement membrane by epithelial cells. Lysosomes are known to play an important role in the turnover of intracellular organelles [39, 40]. Therefore, cell damage, with destruction of the membranes of zymogen granules and GERL, and various filamentous formations, plus the loss of the acinar cell-basal lamina barrier, might enhance periacinar collagenization and lead to intralobular sclerosis. Furthermore, swelling of mitochondria and irregular shaped nuclei with enlarged nucleoli were seen in our studies as abnormalities of organelles in acinar cells. These changes were thought to be related to the severity of the acinar cell damage regardless of alcohol intake. The meaning of these changes is less well understood at present.

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