Prospects for Antifibrotic Therapy

Abstract

Antifibrotic therapies should preferentially be targeted to the activated hepatic mesenchymal cells. Those cells resemble wound healing myofibroblasts and synthesize an excess of extracellular matrix (ECM) proteins. They derive from quiescent hepatic stellate cells (HSC) and portal/perivascular (myo-) fibroblasts (MF). Whereas various agents have been shown to inhibit HSC/MF proliferation and collagen synthesis in vitro, only few of them are effective. Established in vivo models are rat secondary biliary fibrosis (chronic cholestatic liver disease) and reversion of fibrosis after withdrawal of a hepatotoxin like thioacetamide. The interferons (IFN-γ>α,β) have proven antiproliferative and fibrosuppressive activity on mesenchymal cells in culture. Retrospective data suggest that IFN-α therapy for hepatitis C can halt or even reverse fibrosis. This has to be confirmed by large randomized prospective studies, but an effect in biliary fibrosis is less probable. Strategies to inhibit the key profibrogenic cytokine TGF-β, e.g. by soluble decoy receptors, or molecules that are involved in TGF-β signal transduction are evolving but targeted approaches have to be used, in order to prevent unwanted side-effects. Novel agents are being developed in the form of orally available small molecule inhibitors (peptidomimetics). These include antagonists of certain integrins (ανβ3 or ανβ6) that are involved in HSC/MF migration or TGFβ-activation, respectively, or of the endothelin A receptor that causes contraction and proliferation of activated HSC/MF. Future studies will have to show if and how far drug combination is effective in man, combined with reasonable costs and no or irrelevant side-effects. Some agents are antioxidants like silymarin, a defined mixture of flavonoids, sho-saiko-to which contains related compounds like baicalein, glitazones, phosphodiesterase inhibitors like pentoxifylline, inhibitors of the renin-angiotensin system, halofuginone and some immunosuppressants like mycophenolate mofetil and rapamycin. Drug targeting to the fibrogenic liver cells is now possible by use of small molecular ligands that bind to receptors which are specifically upregulated on activated HSC/MF. These ligands can be exploited as carriers for otherwise toxic drugs, antisense DNA or siRNAs directed against profibrogenic mRNAs, such as those against procollagen I or TGFβ1. It is likely that liver fibrosis of different etiology will need different antifibrotic treatments. Quick progress in the clinical development of antifibrotic therapies can only be expected with the evolving validation of noninvasive, serological markers of fibrogenesis or fibrolysis.