They showed a dramatic reduction (∼35%-45%) in stellate cell chemotaxis, proliferation, and collagen production with Ccl5−/− splenocytes. This reduction in fibrogenic activity was even greater when stellate cells were pretreated with Met-CCL5 before the treatment with WT splenocyte–conditioned media (∼75%-80%). In the in vivo studies, Met-CCL5 (administered concomitantly with either
CCl4 or the MCD diet) significantly inhibited hepatic fibrosis progression (∼20%-40%) and the expression of hepatic genes associated with fibrogenesis. In both animal models of hepatic fibrosis, CD8+ T cells and CD68+ macrophages were significantly reduced by the in vivo Met-CCL5 treatment, whereas the numbers of natural killer and natural killer T cells, B220+ B cells, and CD11c+ dendritic cells were unchanged. When daily Met-CCL5 treatments were administered after the establishment of fibrosis by an 8-week selleck screening library CCl4 injection regimen (3 days after the final CCl4 injection), they augmented the regression of hepatic fibrosis (∼50%) after 7 days. These histological changes in fibrosis were preceded by the reduced expression of both procollagen α1(I) and tissue inhibitor of metalloproteinase 1 mRNA levels in the liver. These data are particularly interesting because they suggest the potential for the treatment of established fibrosis via the accelerated regression of fibrotic tissue, although further investigations
are warranted to selleck products evaluate 4��8C the mechanisms involved in this process. In a previous study, Ruddell et al.8 identified CD45+ immune cells as a source of RANTES in another murine model of hepatic fibrosis. They used the choline-deficient, ethionine-supplemented dietary model of hepatic injury, liver progenitor cell expansion, and portal fibrosis to demonstrate a role for the tumor necrosis factor family member lymphotoxin β (LTβ) in the process of wound healing and hepatic fibrosis.8 They proposed a novel mechanism for RANTES expression by hepatic stellate cells via
direct cell contact between liver progenitor and hepatic stellate cells that is induced by the interaction of cell surface–bound LTβ on liver progenitor cells with the LTβ receptor expressed on hepatic stellate cells. In the same study, significant numbers of CD45+ T cells were also demonstrated to express RANTES in choline-deficient, ethionine-supplemented mouse livers and were observed in close spatial association with liver progenitor cells. Neither Ruddell et al. nor Berres et al.3 examined the relative contributions of either T cells or hepatic stellate cells to RANTES expression in these models of hepatic fibrosis. Although it appears that immune cells are the major source of RANTES at least in the CCl4 and MCD models, the contributions of other resident and nonresident hepatic cells require further investigation.