An oral endothelin-A receptor antagonist blocks collagen synthesis and deposition in advanced rat liver fibrosis

JJ Cho, B Hocher, H Herbst, JD Jia, M Ruehl, EG Hahn… - Gastroenterology, 2000 - Elsevier
JJ Cho, B Hocher, H Herbst, JD Jia, M Ruehl, EG Hahn, EO Riecken, D Schuppan
Gastroenterology, 2000Elsevier
Background & 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 …
Background & 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
Elsevier