Antiangiogenic treatment with Sunitinib ameliorates... : Hepatology (original) (raw)

Liver Injury/Regeneration

Antiangiogenic treatment with Sunitinib ameliorates inflammatory infiltrate, fibrosis, and portal pressure in cirrhotic rats

Tugues, Sònia1; Fernandez-Varo, Guillermo1; Muñoz-Luque, Javier1; Ros, Josefa1; Arroyo, Vicente2; Rodés, Juan2; Friedman, Scott L.3; Carmeliet, Peter4,5; Jiménez, Wladimiro1; Morales-Ruiz, Manuel1

1 Department of Biochemistry and Molecular Genetics, University of Barcelona, Barcelona, Spain

2 Liver Unit-Institut de Malalties Digestives, Hospital Clínic, IDIBAPS, University of Barcelona, Ciberehd, Spain

3 Division of Liver Diseases, Department of Medicine, Mount Sinai School of Medicine, New York, NY

4 Department for Transgene Technology and Gene Therapy, Leuven, Belgium

5 The Center for Transgene Technology and Gene Therapy, Leuven, Belgium

Address reprint requests to: Manuel Morales-Ruiz, Ph.D., Department of Biochemistry and Molecular Genetics, Hospital Clínic, Villarroel 170, Barcelona 08036, Spain

E-mail:[email protected]

Received 8 March 2007; Accepted 9 July 2007

Published online 12 October 2007 in Wiley InterScience (www.interscience.wiley.com).

Grant sponsor: Ministerio de Educación y Ciencia Plan Nacional de I+D+I; Grant Numbers: SAF2007-63069 SAF2006-07053; Grant sponsor: National Institutes of Health; Grant Number: DK56621; Grant sponsor: Ministerio de Sanidad y Consumo; Grant Numbers: PI041198 CC02/03 PI041198.

Potential conflict of interest: Nothing to report.

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Supplementary material for this article can be found on the Hepatology website (http://interscience.wiley.com/jpages/0270-9139/suppmat/index.html).

Abstract

Liver cirrhosis is a very complex disease in which several pathological processes such as inflammation, fibrosis, and pathological angiogenesis are closely integrated. We hypothesized that treatment with pharmacological agents with multiple mechanisms of action will produce superior results to those achieved by only targeting individual mechanisms. This study thus evaluates the therapeutic use of the multitargeted receptor tyrosine kinase inhibitor Sunitinib (SU11248). The in vitro effects of SU11248 were evaluated in the human hepatic stellate cell line LX-2 by measuring cell viability. The in vivo effects of SU11248 treatment were monitored in the livers of cirrhotic rats by measuring angiogenesis, inflammatory infiltrate, fibrosis, α-smooth muscle actin (α-SMA) accumulation, differential gene expression by microarrays, and portal pressure. Cirrhosis progression was associated with a significant enhancement of vascular density and expression of vascular endothelial growth factor-A, angiopoietin-1, angiopoietin-2, and placental growth factor in cirrhotic livers. The newly formed hepatic vasculature expressed vascular cellular adhesion molecule 1 and intercellular adhesion molecule 1. Interestingly, the expression of these adhesion molecules was adjacent to areas of local inflammatory infiltration. SU11248 treatment resulted in a significant decrease in hepatic vascular density, inflammatory infiltrate, α-SMA abundance, LX-2 viability, collagen expression, and portal pressure. Conclusion: These results suggest that multitargeted therapies against angiogenesis, inflammation, and fibrosis merit consideration in the treatment of cirrhosis. (Hepatology 2007.)

Abbreviations: ang-1, angiopoietin-1; ang-2, angiopoietin-2; FITC, fluorescein isothiocyanate; HSC, hepatic stellate cell; MAPK, mitogen-activated protein kinase; PDGFR, platelet-derived growth factor receptor; α-SMA, α-smooth muscle actin; SU11248, Sunitinib; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor.