Antiangiogenic treatment with sunitinib ameliorates inflammatory infiltrate, fibrosis, and portal pressure in cirrhotic rats.
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, alpha-smooth muscle actin (alpha-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, alpha-SMA abundance, LX-2 viability, collagen expression, and portal pressure.


CONCLUSIONS
These results suggest that multitargeted therapies against angiogenesis, inflammation, and fibrosis merit consideration in the treatment of cirrhosis.
Tugues
Sònia
S
Department of Biochemistry and Molecular Genetics, University of Barcelona, Barcelona, Spain.
Fernandez-Varo
Guillermo
G
Muñoz-Luque
Javier
J
Ros
Josefa
J
Arroyo
Vicente
V
Rodés
Juan
J
Friedman
Scott L
SL
Carmeliet
Peter
P
Jiménez
Wladimiro
W
Morales-Ruiz
Manuel
M
D020533:Angiogenesis Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006975:Hypertension, Portal / Q000188:drug therapy; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use; D007249:Inflammation / Q000188:drug therapy*; D008103:Liver Cirrhosis / Q000188:drug therapy*; D008297:Male; D017082:Portal Pressure / Q000187:drug effects*; D011758:Pyrroles / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D000077210:Sunitinib
D020533:Angiogenesis Inhibitors; D007211:Indoles; D011758:Pyrroles; D000077210:Sunitinib