Abstract
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.
Highlights
Liver fibrosis results from a range of chronic inflammatory diseases including viral hepatitis, alcoholic and non-alcoholic steatohepatitis, immune injury, primary biliary cirrhosis, and others [1]
Our findings indicate that the two agents, Group 2 (GR)-MD-02 and GMCT-01 have a marked therapeutic effect on the histology of liver fibrosis induced by thioacetamide treatment in rats
The vehicle-treated cirrhotic rats had a doubling of the portal pressure compared to normal rats, whereas those in the treated groups, with GR-MD-02, had a significant reduction in portal pressure
Summary
Liver fibrosis results from a range of chronic inflammatory diseases including viral hepatitis, alcoholic and non-alcoholic steatohepatitis, immune injury, primary biliary cirrhosis, and others [1]. The accumulation of collagen following chronic inflammation is driven by a cascade of events that involves cytokines produced by both liver resident cells and circulating immune cells. As a result of these inflammatory stimuli, quiescent stellate cells in the space of Disse are activated to myofibroblastlike cells to secrete collagen. The accumulation of collagen and other extracellular matrix molecules far exceeds their degradation by metalloproteases released from resident and infiltrating macrophages. Fibrosis develops initially around either portal tracts or central veins, eventually forming bridging fibrosis with nodule formation surrounded by thick bands of fibrous tissue, culminating in cirrhosis. The distorted architecture of the cirrhotic liver leads to complications of portal hypertension, reduced hepatocellular function, and a risk of hepatocellular carcinoma
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