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Liu and Ong
fibrosis (23). The cytokines tissue inhibitor of metalloproteinase-1 (TIMP-1)
and matrix metalloproteinase-1 (MMP-1) have been implicated in the decomposition
of collagen. TIMP-1 promotes the progression of hepatic fibrosis
by inhibiting the degradation of collagens (24), whereas MMP-1 belongs to a
class of neutral proteases and specifically degrades the native forms of
interstitial collagen type I and III (25). It was demonstrated that SM could
inhibit TIMP-1 gene expression and induce MMP-1 gene expression (14).
Through these effects, SM was able to promote the degradation of ECM in
fibrotic rat liver, and hence prevent the deposition of type I and III collagen in
the liver matrix.
Moreover, SM was reported to prevent the development of experimental
liver fibrosis by inhibiting the activation and transformation of hepatic
stellate cell (16,26). It was also demonstrated that salvianolic acid A, a watersoluble
component of SM, significantly inhibited the proliferation and collagen
production and secretion of cultured hepatic stellate cells (27). Although
the mechanism of liver fibrosis is not fully understood, activated hepatic
stellate cells play an important role in connective tissue synthesis and
deposition during fibrogenesis. Hence, the inhibitory effects on hepatic stellate
cell activation and its function of collagen synthesis are among the main
mechanisms of SM action against liver fibrosis.
In addition to the antifibrotic potential, effects of SM on cell proliferation
and function of cultured fibroblasts have been studied. Results from
flow cytometry analysis show that SM could inhibit the proliferation of
fibroblasts either by arresting cells at G0–G1 phase of the cell cycle (28) or by
inducing apoptosis (29). It was also found that the production of the ECM
components fibronectin, laminin, and collagen type I and III by cultured
fibroblasts was significantly lower in the presence of SM (30). Furthermore,
magnesium lithospermate, a component isolated from the water extract of
SM, was found to posttranslationally modify enzymes proline and lysine
hydroxylase in collagen biosynthesis in cultured human skin fibroblasts, thus
reducing collagen secretion without affecting DNA synthesis as well as
noncollagen synthesis (31).
It should be noted that oxidative stress, including reactive oxygen
species (ROS) formation and lipid peroxidation (LPO), is also implicated in
the pathogenesis of liver fibrosis (32,33). It has recently been reported that
paracrine stimuli derived from hepatocytes undergoing oxidative stress
induce hepatic stellate cell proliferation and collagen synthesis (34). Hepatic
stellate cells have also been shown to be activated by free radicals generated
from Fe 2+ /ascorbate system (35) and by LPO product MDA (36) and 4hydroxynonenal
(37). Antioxidants, on the other hand, were observed to
inhibit hepatic stellate cell activation induced by type I collagen (35). SM was
shown to inhibit CCl 4-induced LPO in rat liver (38). In addition, it was