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Research Article Free access | 10.1172/JCI118925

Endothelin antagonism in experimental hepatic fibrosis. Implications for endothelin in the pathogenesis of wound healing.

D C Rockey and J J Chung

Liver Center Laboratory, University of California, San Francisco General Hospital 94110, USA. don@itsa.ucsf.edu

Find articles by Rockey, D. in: JCI | PubMed | Google Scholar

Liver Center Laboratory, University of California, San Francisco General Hospital 94110, USA. don@itsa.ucsf.edu

Find articles by Chung, J. in: JCI | PubMed | Google Scholar

Published September 15, 1996 - More info

Published in Volume 98, Issue 6 on September 15, 1996
J Clin Invest. 1996;98(6):1381–1388. https://doi.org/10.1172/JCI118925.
© 1996 The American Society for Clinical Investigation
Published September 15, 1996 - Version history
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Abstract

The liver's response to chronic injury is fibrosis, which is analogous to wound healing in other organs. Hepatic wounding is characterized by the "activation" of resident stellate cells (lipocytes, Ito cells) to myofibroblast-like cells that produce increased amounts of smooth muscle alpha-actin and extracellular matrix. Stellate cells possess abundant endothelin (ET) receptors (ETA/B) and, therefore, are subject to the effects of ET-1 and 3. In this study, we investigated whether ETs contribute to the activation of stellate cells and consequently, fibrogenesis. In cultured stellate cells, ET-1 and sarafotoxin S6C (a potent ETB receptor agonist) stimulated stellate cell activation, as assessed by expression of smooth muscle alpha-actin. Furthermore, the mixed ETA/B receptor antagonist, bosentan, blocked this process. Next, we administered bosentan during the induction of liver injury in two mechanistically distinct forms of hepatic wounding. Bosentan reduced levels of type I collagen and cellular fibronectin mRNAs in whole-liver tissue extracts in both models. In freshly isolated stellate cells from injured livers, bosentan reduced expression of activation markers, including smooth muscle alpha-actin and extracellular matrix mRNAs. We further demonstrate that endothelin antagonism after establishment of fibrosing injury reduced stellate cell activation and matrix production. These data indicate that ET contributes to stellate cell activation and fibrogenesis. Because ET is upregulated in diverse forms of parenchymal injury, we speculate that ET may play an important role in the wound-healing response.

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