Initiation Of Hepatic Fibrosis Research Articles

Pterostilbene exerts cytotoxicity on activated hepatic stellate cells by inhibiting excessive proliferation through the crosstalk of Sirt1 and STAT3 pathways.

Pterostilbene (PTE), a natural analogue of resveratrol, abundantly exists in blueberries and grapes and has several beneficial potentials against oxidative stress, inflammation, and cancer. In current study, we investigated the effects of PTE on hepatic fibrosis in vitro and in vivo. Activation of hepatic stellate cells (HSCs) is an initiating event in the initiation of hepatic fibrosis. MTT assay revealed that PTE (3.125-12.5 μM) displayed cytotoxicity on activated HSCs, no cytotoxicity on AML-12 and quiescent HSCs. PTE significantly inhibited the expressions of α-SMA, collagen Ⅰ and TIMP-1/MMP13 ratio; suppressed inflammatory cascade activation to reduce inflammatory cytokines release, such as Caspase-1, IL-1β and IL-6. PTE activated Sirt1 and decreased STAT3 phosphorylation, functioning as SRT1720 and Niclosamide. Sirt1 deficiency significantly elevated p-STAT3 expression, while STAT3 deficiency resulted in Sirt1 increasing and inhibited fibrosis and inflammatory cytokines expressions. In mice with hepatic fibrosis induced by thioacetamide (TAA), PTE significantly decreased ALT and AST activities, reduced fibrosis markers, STAT3 phosphorylation and activated Sirt1 expression. PTE showed cytotoxicity on activated HSCs to ameliorate hepatic fibrosis via regulating fibrogenesis, energy metabolism and inflammation and targeting the crosstalk of Sirt1 and STAT3. In conclusion, PTE could be potentially beneficial as a natural plant metabolite in preventing and treating hepatic fibrosis.

Adoptive transfer of splenic T cells restores the hepatic fibrogenic response to chronic cholestasis in severe combined immunodeficient mice

Chronic cholestasis induces significant periportal T cell accumulation and hepatic fibrosis. Given recent experimental studies demonstrating a role for T cells in the initiation of hepatic fibrosis, we hypothesized that T cells were responsible for the development of cholestasis-induced hepatic fibrosis. Male C57Bl/6 wild type (wt) mice, severe combined immunodeficient (SCID) mice which lack mature T and B cells or SCID mice reconstituted with 1x107 wt T cells were subjected to ligation of the common bile duct (BDL) or sham surgery for a period of 14 days after which serum and tissue were collected to determine liver injury and hepatic fibrosis. Wt mice subjected to BDL showed significant increases in serum aspartate aminotransferase (AST) levels (79±14 vs. 1092±426 for sham vs. BDL; p<0.05), periportal CD3+ T cell accumulation and collagen gene expression (5.64-fold increase over sham). SCID mice subjected to BDL showed similar serum AST levels but significant reductions in hepatic collagen gene expression (5.64-fold vs. 2.87-fold for wt vs. SCID respectively). T cell reconstituted SCID mice showed nearly complete restoration of the BDL-induced collagen expression (5.64-fold vs 4.26-fold for wt vs reconstituted SCID respectively) without significantly affecting liver injury. In summary, CD3+ T cells play a significant role in the development of cholestasis-induced hepatic fibrosis. Modulation of the T cell response clinically may prove useful in treating the various forms of cholestatic liver disease. This work was supported by NIAAA grants AA014243 and F32-AA015005.

Alterations in influence of granuloma-derived cytokines on fibrogenesis in the course of murine Schistosoma mansoni infection

Schistosomiasis is the main cause of hepatic fibrosis worldwide, yet its pathogenesis remains unknown. We previously reported that conditioned medium from cultures of hepatic egg granulomas (isolated from mice acutely infected with Schistosoma mansoni) can stimulate fibroblast proliferation and matrix production in vitro. We have proposed that initiation of hepatic fibrosis in this infection might be under the control of granuloma-derived cytokines. We now report that conditioned medium from cultures of schistosomal egg granulomas isolated from liver of chronically infected mice has reduced fibrogenic activity compared with medium from cultures of granulomas obtained from more acutely infected mice. In related studies, we adoptively transferred splenocytes from infected mice and examined the fibrogenic activity in culture supernatants of hepatic egg granulomas isolated from the recipients. Those prepared from recipients of splenocytes from chronically infected mice contained substantially less fibrogenic activity than did those from recipients of splenocytes of acutely infected mice. These findings suggest that the fibrogenic influence of schistosomal egg granuloma products decreases during the course of chronic murine S. mansoni infection. Furthermore, our preliminary findings suggest that immunoregulatory cells may be responsible for the down-regulation of this influence. Previous observations indicating that in murine schistosomiasis hepatic collagen and hyaluronate synthesis and deposition are elevated in acute but not chronic infection might be explained on the basis of our observations.

Alterations in influence of granuloma-derived cytokines on fibrogenesis in the course of murine Schistosoma mansoni infection

Schistosomiasis is the main cause of hepatic fibrosis worldwide, yet its pathogenesis remains unknown. We previously reported that conditioned medium from cultures of hepatic egg granulomas (isolated from mice acutely infected with Schistosoma mansoni) can stimulate fibroblast proliferation and matrix production in vitro. We have proposed that initiation of hepatic fibrosis in this infection might be under the control of granuloma-derived cytokines. We now report that conditioned medium from cultures of schistosomal egg granulomas isolated from liver of chronically infected mice has reduced fibrogenic activity compared with medium from cultures of granulomas obtained from more acutely infected mice. In related studies, we adoptively transferred splenocytes from infected mice and examined the fibrogenic activity in culture supernatants of hepatic egg granulomas isolated from the recipients. Those prepared from recipients of splenocytes from chronically infected mice contained substantially less fibrogenic activity than did those from recipients of splenocytes of acutely infected mice. These findings suggest that the fibrogenic influence of schistosomal egg granuloma products decreases during the course of chronic murine S. mansoni infection. Furthermore, our preliminary findings suggest that immunoregulatory cells may be responsible for the down-regulation of this influence. Previous observations indicating that in murine schistosomiasis hepatic collagen and hyaluronate synthesis and deposition are elevated in acute but not chronic infection might be explained on the basis of our observations.