Professor Chris Day
Based: University of Newcastle upon Tyne
Donor: British Liver Trust
Amount: £21,100 (payable over two years)
Start date: 1st March 1995
Title of study: Hepatocyte proliferation and apoptosis - An investigation of the role of lipid-derived second messengers in the signal transduction pathways controlling hepatocyte proliferation and apoptosis
Download: Final report.pdf
Introduction
Liver cirrhosis is a major cause of morbidity and mortality world wide and yet the precise biochemical mechanisms involved in its pathogenesis remain unclear. Elucidation of these mechanisms is likely to be a major advance towards the design of rational treatment modalities which at present are largely restricted to liver transplantation for patients with advanced disease.
Despite the recent identification of several growth factors and cytokines that appear to play a role in initiating the liver fibrosis (scarring) that ultimately leads to cirrhosis, little information exists on the precise signalling mechanisms by which these factors actually tell the scar-producing cells of the liver (hepatic stellate cells, HSC) to activate and produce scar tissue. The principal aim of this project was to investigate the nature of these ‘signals’ which might eventually lead to the development of new forms of therapies based on their manipulation.
Results
1. We have shown that a particular family of signalling molecules (the stress-activated protein kinases, SAPKs) are activated by stimuli known to ‘switch on’ HSC (e.g. tumour necrosis factor-?, TNF?), and are inhibited by conditions known to block this switch (antioxidants). Furthermore, we have shown that inhibiting one of the SAPK family of signals (the p38 kinase) blocks the activation of HSC, suggesting a novel therapeutic approach to the treatment of liver fibrosis.
2. We have also investigated the signals important in the proliferation of already activated HSC. We have shown that, in contrast to less potent stimulators of HSC proliferation, platelet-derived growth factor (PDGF) activates a completely different set of signals derived from the breakdown of the lipids in cell walls. These signals may prove to be another target for therapeutic intervention.
3. Finally, we have also shown that the known anti-fibrotic effect of the anti-viral agent, interferon-? (IFN?), reflects inhibition of PDGF-stimulated proliferation of HSC, and that this effect may be via inhibition of the p38 SAPK signalling molecule. This result clearly further supports a role for specific P38 inhibitors in the treatment of liver fibrosis.