Fibrosis of liver, pancreas and intestine: common mechanisms and clear targets?
Chronic diseases of the liver, pancreas, intestine, kidneys, skin and lungs are usually accompanied by scarring. Loss of organ function is often progressive despite the use of immunosuppressive, antiviral or antiinflammatory agents. Therefore, well tolerated antifibrotic therapies are urgently needed. The targets for such therapies are activated mesenchymal cells that synthesize an excess of matrix proteins and resemble the myofibroblasts of healing wounds. These cells derive from normally quiescent fibroblasts or smooth muscle cells and from stellate cells of liver and pancreas. Their activation is triggered and maintained by mechanical stress and several fibrogenic modulators and cytokines. Some agents inhibit myofibroblast proliferation and collagen synthesis in vitro, but only few of them are effective in vivo. Potential antifibrotic drugs have been tested mainly in models of liver fibrosis. In the suitable rat model of biliary fibrosis, an antifibrotic effect was demonstrated for silymarin, a defined mixture of flavonoids, and to a lesser degree for pentoxifylline. A spin-off of the large multicenter trials for hepatitis C is the finding that interferon-alpha given for 6-12 months may halt or reverse fibrosis, even in virological non-responders. This has to be proven in prospective randomized trials. Specific inhibitors of the endothelin-A-receptor which are orally available can suppress liver collagen accumulation by 40-60%. Other strategies aim at inhibition of the profibrogenic cytokines TGF-beta or connective tissue growth factor. Effective drug targeting to the fibrogenic liver cells is now possible by use of cyclic peptides that bind to receptors which are specifically upregulated on activated stellate cells. Blockade of such activation receptors can induce stress-relaxation which reverts the fibrogenic cells to a fibrolytic, collagen degrading phenotype. Fibrosis has been discovered as a novel target for the pharmaceutical industry. This implies the use of combinatorial chemistry and an automatized screening machinery, greatly speeding up the design and selection of specific antifibrotic agents. Combined with the rapidly evolving validation of serological markers of fibrogenesis and fibrolysis unforeseen progress in the treatment of organ fibrosis can be expected.
Schuppan
D
D
Medizinische Klinik I, Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany.
Koda
M
M
Bauer
M
M
Hahn
E G
EG
D005355:Fibrosis; D006801:Humans; D007410:Intestinal Diseases / Q000188:drug therapy / Q000473:pathology*; D007422:Intestines / Q000473:pathology; D008099:Liver / Q000473:pathology; D008103:Liver Cirrhosis / Q000188:drug therapy / Q000473:pathology*; D010179:Pancreas / Q000473:pathology; D010182:Pancreatic Diseases / Q000188:drug therapy / Q000473:pathology*