S-allyl-glutathione suppresses liver fibrosis by inhibition of excess skewing polarization of macrophages in rats

Purpose Sustained hepatic inflammation derived from parenchymal liver injury is a major driving force of fibrogenesis. We synthesized S-allyl-glutathione (SAG) which regulates macrophage (MO) polarization, and investigated whether SAG can improve liver fibrosis. Method Liver fibrosis was induced by CCl 4 injection twice a week for 9 weeks in rats. SAG was administered as a mixed diet from the starting CCl 4 . To study fibrosis regression, rats were orally administered SAG for 5 weeks after terminating CCl 4 . In vitro studies were performed effects of SAG (10 -14M~) on M1 or M2 polarization of isolated Kupffer cells (KCs) or bone marrow derived MO (BMDM), and its interactions with isolated hepatic stellate cells (HSCs). Result and Discussion SAG markedly inhibited liver fibrogenesis in a dose-dependent manner and various fibrosis markers. In the fibrolysis stage, SAG accelerated fibrolysis after development of liver chirrosis and decreased the amount of M2 MO. Both Col1A1 and HSP47 mRNA in day 6 HSCs were inhibited by the conditioned medium of SAG-treated MO with M2 inducers onto day 3 HSCs. SAG did not directly inhibit HSC activation. In the M1 MO, SAG also inhibited. These findings suggested that SAG could improve liver cirrhosis via the attenuation of excess polarization in KCs.