Galectin-3 protein is critical to the development of
liver fibrosis because
galectin-3 null mice have attenuated
fibrosis after liver injury. Therefore, we examined the ability of novel complex
carbohydrate galectin inhibitors to treat toxin-induced
fibrosis and
cirrhosis.
Fibrosis was induced in rats by
intraperitoneal injections with
thioacetamide (TAA) and groups were treated with vehicle, GR-MD-02 (
galactoarabino-rhamnogalaturonan) or
GM-CT-01 (
galactomannan). In initial experiments, 4 weeks of treatment with GR-MD-02 following completion of 8 weeks of TAA significantly reduced
collagen content by almost 50% based on Sirius red staining. Rats were then exposed to more intense and longer TAA treatment, which included either GR-MD-02 or
GM-CT-01 during weeks 8 through 11. TAA rats treated with vehicle developed extensive
fibrosis and pathological stage 6 Ishak
fibrosis, or
cirrhosis. Treatment with either GR-MD-02 (90 mg/kg ip) or
GM-CT-01 (180 mg/kg ip) given once weekly during weeks 8-11 led to marked reduction in
fibrosis with reduction in portal and septal
galectin-3 positive macrophages and reduction in portal pressure. Vehicle-treated animals had
cirrhosis whereas in the treated animals the
fibrosis stage was significantly reduced, with evidence of resolved or resolving
cirrhosis and reduced portal
inflammation and ballooning. In this model of toxin-induced
liver fibrosis, treatment with two
galectin protein inhibitors with different chemical compositions significantly reduced
fibrosis, reversed
cirrhosis, reduced
galectin-3 expressing portal and septal macrophages, and reduced portal pressure. These findings suggest a potential role of these drugs in human
liver fibrosis and
cirrhosis.