An oral endothelin-A receptor antagonist blocks collagen synthesis and deposition in advanced rat liver fibrosis
2000; Elsevier BV; Volume: 118; Issue: 6 Linguagem: Inglês
10.1016/s0016-5085(00)70370-2
ISSN1528-0012
AutoresJae‐Jin Cho, Berthold Hocher, H Herbst, Jidong Jia, Martin Ruehl, Eckhart G. Hahn, E. O. Riecken, Detlef Schuppan,
Tópico(s)Pediatric Hepatobiliary Diseases and Treatments
ResumoBackground & Aims: Endothelin 1 induces contraction, proliferation, and collagen synthesis of hepatic stellate cells in vitro, which may be mediated via the endothelin A receptor. It is unknown if specific blockade of the endothelin A receptor inhibits hepatic fibrosis in vivo. Methods: Groups of 10-20 rats with bile duct occlusion were treated with the nonpeptide endothelin-A receptor antagonist LU 135252 at 80 mg · kg−1 · day−1 from week 1-6 or from week 4-6, or with LU at 10 mg · kg−1 · day−1 from week 1-6. Animals with bile duct occlusion alone and sham-operated rats without or with LU at 80 mg · kg−1 · day−1 over 6 weeks served as controls. After 6 weeks, parameters of fibrogenesis were determined. Results: LU treatment led to improved histology, paralleled by a dose-dependence up to 60% reduction of liver collagen, even when administered at an advanced fibrosis stage. This was accompanied by a decreased messenger RNA of hepatic procollagen α1(I) and tissue inhibitor of metalloproteinase 1, 2 major effectors of fibrosis, and of serum procollagen type III, a surrogate marker of liver fibrogenesis. Conclusions: Selective endothelin-A receptor blockade can dramatically reduce collagen accumulation in rat secondary biliary fibrosis, a model refractory to most potential antifibrotic agents. Endothelin-A receptor antagonists are promising antifibrotic agents in chronic liver disease.GASTROENTEROLOGY 2000;118:1169-1178
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