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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, 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.)

Gene transduction of an active mutant of akt exerts cytoprotection and reduces graft injury after liver transplantation.

Akt is expected to be an effective target for the treatment of ischemia‐reperfusion injury (I/R) due to its anti‐apoptotic properties and its ability to activate the endothelial nitric oxide synthase (eNOS) enzyme. Therefore, this study was aimed to determine the efficacy of an active mutant of Akt (myr‐Akt) to decrease I/R injury in a model of orthotopic liver transplantation in pigs. In addition, we analyzed the contribution of nitric oxide in the Akt‐mediated effects by using an eNOS mutant (S1179DeNOS) that mimics the phosphorylation promoted by Akt in the eNOS sequence. Donors were treated with adenoviruses codifying for myr‐Akt, S1179DeNOS or β‐galactosidase 24 h before liver harvesting. Then, liver grafts were orthotopically transplanted into their corresponding recipients. Levels of transaminases and lactate dehydrogenase (LDH) increased in all recipients after 24 h of transplant. However, transaminases and LDH levels were significantly lower in the myr‐Akt group compared with vehicle. The percentage of apoptotic cells and the amount of activated‐caspase 3 protein were also markedly reduced in myr‐Akt‐treated grafts after 4 days of liver transplant compared with vehicle and S1179DeNOS groups. In conclusion, myr‐Akt gene therapy effectively exerts cytoprotection against hepatic I/R injury regardless of the Akt‐dependent eNOS activation.

Angiogenesis and Vascular Growth in Liver Diseases

Chronic liver disease (CLD) can be defined as a complex pathophysiological process of the liver that involves a progressive destruction and regeneration of the liver parenchyma leading to fibrosis, cirrhosis, and an increasing risk of hepatocellular carcinoma (HCC). Viral hepatitis and alcohol are considered the two most important etiologies for CLD, although nonalcoholic fatty liver disease (NAFLD) is also increasingly being recognized as a common cause.