Galectin-3 regulates myofibroblast activation and hepatic fibrosis.
Central to fibrogenesis and the scarring of organs is the activation of fibroblasts into matrix-secreting myofibroblasts. We demonstrate that Galectin-3 expression is up-regulated in established human fibrotic liver disease and is temporally and spatially related to the induction and resolution of experimental hepatic fibrosis. Disruption of the Galectin-3 gene blocks myofibroblast activation and procollagen (I) expression in vitro and in vivo, markedly attenuating liver fibrosis. Addition of exogenous recombinant Galectin-3 in vitro reversed this abnormality. The reduction in hepatic fibrosis observed in the Galectin-3(-/-) mouse occurred despite equivalent liver injury and inflammation, and similar tissue expression of TGF-beta. TGF-beta failed to transactivate Galectin-3(-/-) hepatic stellate cells, in contrast with WT hepatic stellate cells; however, TGF-beta-stimulated Smad-2 and -3 activation was equivalent. These data suggest that Galectin-3 is required for TGF-beta mediated myofibroblast activation and matrix production. Finally, in vivo siRNA knockdown of Galectin-3 inhibited myofibroblast activation after hepatic injury and may therefore provide an alternative therapeutic approach to the prevention and treatment of liver fibrosis.
Henderson
Neil C
NC
Centre for Inflammation Research, Queens Medical Research Institute, University of Edinburgh, 51 Little France Crescent, EH16 4SA Edinburgh, Scotland, United Kingdom.
Mackinnon
Alison C
AC
Farnworth
Sarah L
SL
Poirier
Francoise
F
Russo
Francesco P
FP
Iredale
John P
JP
Haslett
Christopher
C
Simpson
Kenneth J
KJ
Sethi
Tariq
T
D000818:Animals; D002251:Carbon Tetrachloride / Q000494:pharmacology; D005347:Fibroblasts; D037502:Galectin 3 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000293:injuries / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D008106:Liver Cirrhosis, Experimental; D051379:Mice; D018345:Mice, Knockout; D032342:Muscle Cells / Q000378:metabolism* / Q000473:pathology*; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D015854:Up-Regulation
D037502:Galectin 3; D034741:RNA, Small Interfering; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D002251:Carbon Tetrachloride