title: Regression of fibrosis and reversal of cirrhosis in rats by galectin inhibitors in thioacetamide-induced liver disease.
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.
authors.affiliation: Galectin Therapeutics Inc, Norcross, Georgia, United States of America ; Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Peter G
authors.initials: PG
authors.lastname: Traber
authors.forename: Hsin
authors.initials: H
authors.lastname: Chou
authors.forename: Eliezer
authors.initials: E
authors.lastname: Zomer
authors.forename: Feng
authors.initials: F
authors.lastname: Hong
authors.forename: Anatole
authors.initials: A
authors.lastname: Klyosov
authors.forename: Maria-Isabel
authors.initials: MI
authors.lastname: Fiel
authors.forename: Scott L
authors.initials: SL
authors.lastname: Friedman
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D005355:Fibrosis / Q000188:drug therapy*; D005685:Galactans / Q000627:therapeutic use*; D005690:Galactose / Q000031:analogs & derivatives; D037161:Galectins / Q000037:antagonists & inhibitors*; D006801:Humans; D008103:Liver Cirrhosis / Q000188:drug therapy*; D008107:Liver Diseases / Q000188:drug therapy*; D008297:Male; D008351:Mannans / Q000627:therapeutic use*; D010368:Pectins / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013853:Thioacetamide / Q000633:toxicity*
chemical_list: D005685:Galactans; D037161:Galectins; D008351:Mannans; D013853:Thioacetamide; C012990:galactomannan; D010368:Pectins; C000613472:belapectin; D005690:Galactose