Endothelin (ET) peptides have been implicated in the pathogenesis of several biological processes within the liver. ET levels are elevated in the circulation of patients with cirrhosis, and recent data suggest that ET may be overproduced in the liver itself in this condition. The aims of the current study were to elucidate the cellular source and expression of endothelin-1 (ET-1) in normal and injured liver, and to investigate its biological effects on stellate cells, the primary target of ETs in the liver. In normal hepatic cells, preproET-1 messenger RNA (mRNA) was detected in only nonparenchymal cells, predominantly in sinusoidal endothelial cells. After biliary fibrosis and early cirrhosis induced by bile duct ligation, preproET-1 mRNA and immunoreactive ET levels increased with progressive injury in whole liver extracts, as well as in isolated stellate and endothelial cell fractions. Eight days after bile duct ligation, the relative increase in preproET-1 mRNA was 1.6-and 7.6-fold above normal in sinusoidal endothelial and stellate cells, respectively. Additionally, immunoreactive ET peptide levels increased by 60% ؎ 27% over basal values in sinusoidal endothelial cells and 98% ؎ 40% in stellate cells. Cultured stellate cells responded dramatically to exogenous ET-1 by the spreading and up-regulation of smooth muscle ␣ actin expression. Furthermore, in early culture before cellular activation, ET-1 (10 nmol/L) caused over a twofold increase in [ 3 H]thymidine incorporation, while activated cells (i.e., those cultured for G1 week) exposed to ET-1 exhibited up to a fivefold decrease in [ 3 H]thymidine incorporation. The data indicate that not only is ET-1 overproduced by both sinusoidal endothelial and stellate cells during liver injury, but that it also has potent effects on features of stellate cell activation. We conclude that autocrine and paracrine production of ET-1 is prominent and is likely to be important in the pathogenesis of hepatic diseases. (HEPATOLOGY 1998;27:472-480.)The endothelins (ETs) form a family of 21 amino acid peptides that play an important role in many biological processes. Three unique ET species have been identified and include endothelin-1 (ET-1), endothelin-2 (ET-2), and endothelin-3 (ET-3). 1 While the major function of ETs appears to be in the local control of vascular tone, 1 these compounds have other effects, including regulation of growth and mammalian neural crest development. 2,3 ETs bind to two different G protein-coupled receptors, endothelin A (ET A ) and endothelin B (ET B ) receptors. 4 ET A receptors are found predominantly on vascular smooth muscle cells and are preferentially activated by ET-1. Rank order affinities for the ET A receptor are ET-1 Ͼ ET-2 ϾϾϾ ET-3; the affinity of ET-1 for the ET A receptor is more than 100-fold that of ET-3, while the ET B receptor has equal affinity for ET-1, ET-2, and ET-3. 4 ET receptors are present on all major rat hepatic cell types, including stellate, endothelial, and Kupffer cells, as well as hepatocytes, but saturation bi...
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 ␣ -actin and extracellular matrix. Stellate cells possess abundant endothelin (ET) receptors (ET A/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 ET B receptor agonist) stimulated stellate cell activation, as assessed by expression of smooth muscle ␣ -actin. Furthermore, the mixed ET A/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 ␣ -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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