Dr JP Iredale
Based: University of Southampton
Donor: British Liver Trust
Amount: £26,655
Start date: November 1995
Title of study: An investigation into the relative roles of TIMP-1 and interstitial collagenase in the development of liver fibrosis and an evaluation of the effect of relaxin in reducing progression of fibrosis.
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Aim of Project:
1. To determine the relative roles of collagenase (the enzyme which breaks down scar tissue in the liver) and collagenase inhibitory tissue inhibitor of metalloproteinase 1 (TIMP-1) in regulating the breakdown of scar tissue which characterises liver fibrosis and cirrhosis.
2. To determine and define the factors which regulate spontaneous recovery from liver fibrosis, with emphasis on studies of hepatic stellate cell apoptosis (in effect hepatic stellate cell suicide).
Lay summary of research outcomes and implications for liver patients
Liver fibrosis and cirrhosis result from a spectrum of liver disease including viral damage, immune mediated damage e.g. primary biliary cirrhosis, and toxic damage including alcohol. At the level of the cell, liver fibrosis results from the proliferation of a specific liver cell type (the hepatic stellate cell) so that the numbers of this cell are greatly increased. In addition, the cell produces a large quantity of scar tissue.
By studying hepatic stellate cells in culture, we have demonstrated that a key feature of their behaviour after liver injury is that they produce TIMP-1, a powerful inhibitor of the enzymes which would otherwise degrade scar tissue. The effect of this production of TIMP-1 is that any tendency of the liver to degrade and remove excessive scar tissue is inhibited. In consequence, the scar tissue secreted by the hepatic stellate cells continues to accumulate with adverse effects. Furthermore, we have demonstrated that when we prevent cells from producing TIMP-1, they are able to utilise one or more related inhibitors from the same family (TIMPs –2 to –4).
These results indicate that the production of one or more members of the TIMP family is a feature of liver injury which may be central to the development of liver fibrosis and cirrhosis. By targeting the TIMPs with drug treatment we ultimately hope to be able to encourage the natural breakdown of scar tissue within injured, fibrotic and cirrhotic livers, thereby restoring normal liver architecture and function.
In order to facilitate these studies, we have developed a model of spontaneous recovery from liver fibrosis. Spontaneous recovery from even quite advanced fibrosis in patients with liver disease has been reported in the past; most commonly in treated autoimmune chronic active hepatitis, although other diseases including haemochromatosis may demonstrate similar resolution.
This model was developed primarily to further study the roles of TIMPs –1 and –2 in fibrogenesis, but has enabled us to define a number of events which are essential to recovery from fibrosis. During recovery, the scarring bands which link the vascular structures of the liver and cause cirrhosis are observed to become remodelled back to a pattern close to that seen in normal liver. In association with this, the scar forming cells (hepatic stellate cells) undergo apoptosis (in effect commit suicide). This is a very exciting observation, which may provide a new therapeutic avenue through which the process of scarring in liver fibrosis can be halted and reversed.
To determine the mechanism of hepatic stellate cell suicide we have studied these cells in culture and demonstrated that by depriving them of the growth factors present during injury, the suicide programme ensues. We have then gone on to look at the role of TIMP-1 and TIMP-2 in the degradation of the liver scar tissue. The period of recovery is associated with a rapid decrease in expression of these proteins (TIMPs –1 and –2) whereas the expression of the scar degrading enzyme (collagenase) remains at a constant level and breakdown of the abnormal scar tissue occurs. This work has defined two of the essential elements for recovery from fibrosis.
Namely, stellate cell suicide and an increase in collagenase activity. If the process of stellate cell apoptosis can be harnessed and stimulated by drug treatment, the large numbers of stellate cells producing excessive scar tissue in liver fibrosis could be greatly diminished, with consequent beneficial effects to the liver. This work has been eagerly received by a number of collaborators and one major drug company who are keen to develop the model further in order to facilitate the development of drugs active in the treatment of established liver fibrosis.