These authors contributed equally to this work.
Liver Failure/Cirrhosis/Portal Hypertension
Article first published online: 26 JUN 2011
Copyright © 2011 American Association for the Study of Liver Diseases
Volume 54, Issue 2, pages 573–585, August 2011
How to Cite
Thabut, D., Routray, C., Lomberk, G., Shergill, U., Glaser, K., Huebert, R., Patel, L., Masyuk, T., Blechacz, B., Vercnocke, A., Ritman, E., Ehman, R., Urrutia, R. and Shah, V. (2011), Complementary vascular and matrix regulatory pathways underlie the beneficial mechanism of action of sorafenib in liver fibrosis. Hepatology, 54: 573–585. doi: 10.1002/hep.24427
Potential conflict of interest: Nothing to report.
Supported by grants DK59615-06 (to V. S.), P30DK084567 from the National Institute of Diabetes and Digestive and Kidney Diseases, and EB000305 (to E. R.) by National Institute of Biomedical Imaging and Bioengineering.
- Issue published online: 25 JUL 2011
- Article first published online: 26 JUN 2011
- Accepted manuscript online: 12 MAY 2011 01:59PM EST
- Manuscript Accepted: 5 MAY 2011
- Manuscript Received: 25 FEB 2011
Paracrine signaling between hepatic stellate cells (HSCs) and liver endothelial cells (LECs) modulates fibrogenesis, angiogenesis, and portal hypertension. However, mechanisms regulating these processes are not fully defined. Sorafenib is a receptor tyrosine kinase inhibitor that blocks growth factor signaling in tumor cells but also displays important and not yet fully characterized effects on liver nonparenchymal cells including HSCs and LECs. The aim of this study was to test the hypothesis that sorafenib influences paracrine signaling between HSCs and LECs and thereby regulates matrix and vascular changes associated with chronic liver injury. Complementary magnetic resonance elastography, micro–computed tomography, and histochemical analyses indicate that sorafenib attenuates the changes in both matrix and vascular compartments that occur in response to bile duct ligation–induced liver injury in rats. Cell biology studies demonstrate that sorafenib markedly reduces cell–cell apposition and junctional complexes, thus reducing the proximity typically observed between these sinusoidal barrier cells. At the molecular level, sorafenib down-regulates angiopoietin-1 and fibronectin, both released by HSCs in a manner dependent on the transcription factor Kruppel-like factor 6 , suggesting that this pathway underlies both matrix and vascular changes associated with chronic liver disease. Conclusion: Collectively, the results of this study demonstrate that sorafenib inhibits both matrix restructuring and vascular remodeling that accompany chronic liver diseases and characterize cell and molecular mechanisms underlying this effect. These data may help to refine future therapies for advanced gastrointestinal and liver diseases characterized by abundant fibrosis and neovascularization. (HEPATOLOGY 2011;)