Endothelin stimulates transforming growth factor-β1 and collagen synthesis in stellate cells from control but not cirrhotic rat liver
Introduction
Physiologically, perisinusoidal stellate cells maintain the architecture of the liver by synthesizing components of extracellular matrix and the sinusoidal blood flow by contractile activity. During chronic liver injury, stellate cells lose their storage of retinoids, express α-smooth muscle actin, and transform into proliferating myofibroblast-like cells that are highly contractile and excessively fibrogenic. Thus, stellate cells play an important role in fibrogenesis during the development of liver cirrhosis Blomhoff and Wake, 1991, Geerts et al., 1994, Nakata and Shibayama, 1987.
Hepatic concentrations of endothelin-1, a powerful constrictor of the hepatic vasculature Gandhi et al., 1990, Tran-Thi et al., 1993, and its receptors increase progressively during the development of experimental cirrhosis (Gandhi et al., 1998). Furthermore, hepatic concentrations of endothelin-1 and its receptors increase in human cirrhosis Gandhi et al., 1996a, Pinzani et al., 1996 and there is a direct relationship between endothelin-1 receptor gene expression and portal pressure in cirrhotic patients (Leivas et al., 1998). Endothelin-1 causes contraction of quiescent, (Zhang et al., 1995) as well as transformed stellate cells Housset et al., 1993, Pinzani et al., 1996. Antagonism of endothelin-1 receptors has been reported to reduce the concentration of type I collagen and its mRNA in rat models of liver fibrosis (Rockey and Chung, 1996). However, whether endothelin-1 exerts this effect by direct actions on stellate cells is not known. Therefore, we investigated endothelin-1, its receptors and its effects on the fibrogenic activity of stellate cells isolated from the livers of carbon tetrachloride (CCl4)-induced cirrhotic rats.
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Materials and methods
The following chemicals and reagents were purchased from the indicated sources: protease type XIV, 5-[N-2,3-dihydroxypropylacetamido-2,4,6-troiodo-N,N′-bis(2,3-dihydroxypropyl)isophthalamide] (Nycodenz), CCl4 (99.9% purity) and BQ-788 (N-cis-2,6-dimethylpiperidinecarbonyl-l-γMeLeu-d-Trp(COOMe)-d-Nle-ONa) (Sigma, St. Louis, MO); collagenase type IV (Worthington Biochemical, Freehold, NJ); transforming growth factor β1 (TGF-β1) (Life Technologies, Grand Island, NY); endothelin-1, sarafotoxin S6c
Results
We use phenobarbital to enhance the toxicity of CCl4 and establishment of uniform cirrhosis Gandhi et al., 1996b, Gandhi et al., 1998. However, considering the effects of phenobarbital alone on the liver tissue, we compared various parameters described in this paper between the cells isolated from untreated rats (these cells are routinely used in our laboratory) and rats treated with phenobarbital. No difference was observed in the morphological and immunohistochemical characteristics, as well
Discussion
The present investigation was performed considering the evidence that interactions between endothelin-1 and stellate cells can be of significant importance in physiology and pathology of the liver. Although all of the hepatic cell types synthesize endothelin-1 Gandhi et al., 1996b, Housset et al., 1993, Kuddus et al., 2000, Laura et al., 1998, Pinzani et al., 1996 and react to its agonistic activities in cell culture Caligiuri et al., 1998, Gandhi et al., 1992a, Gandhi et al., 1992b, Housset et
Acknowledgements
This work was supported by VA merit award and NIH grant DK 54411.
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