Apoptosis and proliferation of acinar and islet cells in chronic pancreatitis: evidence for differential cell loss mediating preservation of islet function

Abstract

Background: Chronic pancreatitis is characterised clinically by early exocrine insufficiency, with diabetes mellitus occurring as a late phenomenon. This is mirrored pathologically by extensive acinar cell destruction and islet preservation. The mechanisms underlying this differential rate of cellular destruction are unknown.

Aims: To test the hypothesis that acinar loss and islet preservation in chronic pancreatitis occurs due to differential epithelial kinetics and investigate the role of inflammatory cells and cell cycle associated molecules.

Methods: Archival tissue from six chronic pancreatitis cases was compared with six normal controls using TUNEL and immunohistochemistry for CD3, CD20, CD68, MIB-1, Bcl-2, Bax, Fas, Fas ligand, retinoblastoma protein (Rb), and tissue inhibitor of metalloproteinases 1 (TIMP-1) and 2 (TIMP-2).

Results: The acinar cell apoptotic index (AI) and proliferation index were higher in chronic pancreatitis than controls. T lymphocytes diffusely infiltrated fibrous bands and acini but rarely islets. Acinar Bcl-2 expression exceeded islet expression in chronic pancreatitis and controls while Bax was strongly expressed by a subset of islet cells and weakly by centroacinar cells. Islet Fas and Fas ligand expression exceeded acinar expression in chronic pancreatitis and controls. Acinar Rb expression was higher in chronic pancreatitis than in controls. Islets in chronic pancreatitis and controls showed intense TIMP-1 and TIMP-2 expression.

Conclusion: Apoptosis plays a significant role in acinar loss in chronic pancreatitis. Acinar Bcl-2 and islet Bax expression indicates complex AI control. Increased acinar Rb expression in chronic pancreatitis may differentially promote acinar loss. Fas ligand expression may be restricted to islet cell membranes through TIMP-1 expression and inhibit islet damage by promoting apoptosis of cytotoxic T lymphocytes.

Figure 1

Haematoxylin and eosin stained section of pancreas (chronic pancreatitis) showing two apoptotic bodies (arrowed) within acinar epithelial cells. Magnification ×500.

Figure 2

Section of pancreas (chronic pancreatitis) stained using the TUNEL technique showing darkly labelled nuclear material within an apoptotic acinar epithelial cell (arrowed). Magnification ×500.

Figure 3

Section of pancreas (chronic pancreatitis) stained using MIB-1 immunohistochemistry showing several positively labelled nuclei within acinar epithelial cells. Magnification ×500.

Figure 4

Section of pancreas (normal) stained using immunohistochemistry for Bcl-2 protein, showing cytoplasmic Bcl-2 expression within acinar cells but not within islets. Magnification ×250.

Figure 5

Section of pancreas (chronic pancreatitis) stained using immunohistochemistry for Bax protein, showing intense cytoplasmic Bax expression within a subset of islet cells as well as within centroacinar cells (on either side of the islet). Labelling of the latter cells is accentuated within this section of chronic pancreatitis since many of the outer acinar cells have been destroyed. Magnification ×500.

Figure 6

Section of pancreas (chronic pancreatitis) stained using immunohistochemistry for Fas protein, showing cytoplasmic Fas expression within islet cells. Magnification ×500.

Figure 7

Section of pancreas (normal) stained using immunohistochemistry for Fas ligand protein, showing intense cytoplasmic Fas ligand expression within islet cells. Magnification ×500.

Figure 8

Section of pancreas (chronic pancreatitis) stained using immunohistochemistry for tissue inhibitor of metalloproteinase (TIMP)-1 protein, showing intense cytoplasmic TIMP-1 expression within islet cells. A very similar expression pattern was identified for TIMP-2. Magnification ×250.