Showing papers by "John P. Iredale published in 2002"

Expression of Transforming Growth Factor-β1 by Pancreatic Stellate Cells and Its Implications for Matrix Secretion and Turnover in Chronic Pancreatitis

Abstract: Pancreatic stellate cells mediate fibrosis in chronic pancreatitis. Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs)-1 and -2 are crucial modulators of fibrosis. Transforming growth factor-β (TGF-β) is a key regulator of extracellular matrix production and myofibroblast proliferation. We have examined MMP and TIMP synthesis by transformed cultured pancreatic stellate cells and their regulation by TGF-β1. By Northern analysis they expressed mRNAs for procollagen 1, TIMP-1, TIMP-2, and MMP-2. Expression of membrane type-1 MMP was confirmed by Western blotting. By immunohistochemistry these enzymes localized to fibrotic areas in human chronic pancreatitis. Active TGF-β1 constitutes 2 to 5% of total TGF-β1 secreted by pancreatic stellate cells; they express TGF-β receptors I and II. Exogenous TGF-β1 (10 ng/ml) significantly increased procollagen-1 mRNA by 69% and collagen protein synthesis by 34%. Similarly TGF-β1 at 0.1, 1, and 10 ng/ml significantly reduced cellular proliferation rate by 37%, 44%, and 44%, respectively, whereas pan-TGF-β-neutralizing antibody increased proliferation by 40%. TGF-β1 (10 ng/ml) down-regulated MMP-9 by 54% and MMP-3 by 34% whereas TGF-β1-neutralizing antibody increased MMP-9 expression by 39%. Pancreatic stellate cells express both mediators of matrix remodeling and the regulatory cytokine TGF-β1 that, by autocrine inhibition of MMP-3 and MMP-9, may enhance fibrogenesis by reducing collagen degradation.

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.

Developing strategies for liver fibrosis treatment

Abstract: Liver fibrosis represents a major worldwide healthcare burden. Current therapy is limited to removing the causal agent. This approach is successful in some diseases; particularly haemochromatosis and chronic viral hepatitis. However, for many patients treatment is not possible, while other patients present to medical attention at an advanced stage of fibrosis. There is therefore a great need for novel therapies for liver fibrosis. The hepatic stellate cell has been recognised to be responsible for most of the excess extracellular matrix observed in chronic liver fibrosis. The detailed understanding of hepatic stellate cell biology has allowed the rational design of novel antifibrotic therapies. This review describes for the general reader the novel emerging therapies for liver fibrosis.