Combination of sorafenib and gadolinium chloride (GdCl3) attenuates dimethylnitrosamine(DMN)-induced liver fibrosis in rats.

BACKGROUND/AIMS: Liver sinusoidal endothelial cells (SECs), hepatic stellate cells (HSCs) and Kupffer cells (KCs) are involved in the development of liver fibrosis and represent a potential therapeutic target. The therapeutic effects on liver fibrosis of sorafenib, a multiple tyrosine kinase inhibitor, and gadolinium chloride (GdCl3), which depletes KCs, were evaluated in rats. METHODS: Liver fibrosis was induced in rats with dimethylnitrosamine, and the effects of sorafenib and/or GdCl3 in these rats were monitored. Interactions among ECs, HSCs and KCs were assessed by laser confocal microscopy. RESULTS: The combination of sorafenib and GdCl3, but not each agent alone, attenuated liver fibrosis and significantly reduced liver function and hydroxyproline (Hyp). Sorafenib significantly inhibited the expression of angiogenesis-associated cell markers and cytokines, including CD31, von Willebrand factor (vWF), and vascular endothelial growth factor, whereas GdCl3 suppressed macrophage-related cell markers and cytokines, including CD68, tumor necrosis factor-α, interleukin-1ß, and CCL2. Laser confocal microscopy showed that sorafenib inhibited vWF expression and GdCl3 reduced CD68 staining. Sorafenib plus GdCl3 suppressed the interactions of HSCs, ECs and KCs. CONCLUSION: Sorafenib plus GdCl3 can suppress collagen accumulation, suggesting that this combination may be a potential therapeutic strategy in the treatment of liver fibrosis.