of ECM especially collagen I in response to severe liver damage that occurs in many patients with chronic liver injury of any etiology and associated with inflammation and cell death with the tendency to progress into sclerosis. Toxic injury occurs in the liver more often than that in any other organ. When a drug is used widely, drug-induced liver injury has become a serious health problem. Thus research on the mechanism of drug- induced liver injury is very useful in therapy and prevention of drug-induced liver injury (Xin & Cai-qin, 2008). Liver cirrhosis represents the end-stage process of liver fibrotic degeneration of the most chronic liver diseases. Complex cellular and molecular mechanisms resulting from chronic activation of tissue repair mechanism following tissue injury have been characterized. The fibrosis process initiated upon liver tissue injury occurred, followed by the inflammatory reaction with activation of Kupffer cells and stellate cells, which in turn leading to increased expression of pro-inflammatory and pro-fibrotic cytokines and the recruitment and activation of fibroblast responsible for increased production of ECM proteins (Flier et al., 1993). Activation of HSC is regulated by several soluble factors, including cytokines such as TGF-β1 and IL- 6 and products of oxidative stress as well as by extensive changes in composition and organization of ECM components (Gressner, 1991; Stalnikowitz & Weissbrod, 2003). The production of ECM protein certainly represents the most typical function of activated HSC. In addition, along the progression of the fibrotic process, qualitative and quantitative changes in ECM are also favoured by the fact that HSC express MMP
109 which lead to disruption of normal matrix. As scarring progresses from bridging fibrosis to the formation of complete nodules it results in architectural distortion and ultimately liver cirrhosis.
On the other hand, many liver diseases are accompanied by unbalanced increase of ROS and related products of lipid peroxidation resulting from oxidative stress, which represent one aspect of a very complex series of events able to affect the liver cell structure and function. Moreover, in alcohol intoxication, viral hepatitis infection and metabolic disorders, ROS are now increasingly recognized to have significant role in both initiation and sustaining of liver fibrosis. During the development of fibrosis, kupffer cells and HSC are the actual key-players in such chronic disease process; exert a series of effects through the enhancement of the intracellular and extracellular levels of oxidants (Poli, 2000). Oxidative stress is essentially a consequence of a necrotic event, but not withstanding it, ROS produced by activated macrophages as well as reactive aldehydes stemming from membrane lipid peroxidation can stimulate the progression of collagen deposition in the inflamed tissue or organ. Production of ROS may be cause and consequence of cellular damage. For instance, many hepato-toxins lead to increased concentrations of ROS that cannot be handled in a normal way by the protective machinery of the cells (Marí et al., 2001). Excessive production of ROS results in lipid peroxidation leading to an increase in highly reactive aldehydic end products, altered signal transduction, modulation of gene expression, alteration of the redox state including decrease of glutathione levels, and induction of apoptosis and necrosis (Dalton et al., 1999).
Based on understanding of the cellular and molecular basis of hepatofibrogenesis, hepatoprotective agents can be categorized as follows; agents for scavenging of free radicals and reducing oxidative stress, agents for cytoprotection and reduction of
110 inflammation and cell death, agents for inhibition of HSC activation and agents for fibrolysis and promotion of matrix degradation. These strategies include the curing of primary disease to prevent injury; reducing inflammation; down-regulating stellate cell activation directly or by neutralizing proliferative, fibrogenic, contractile, and/or pro- inflammatory responses of stellate cells; stimulating apoptosis of stellate cells; or increasing the degradation of scar matrix. Reducing oxidative stress is another type of intervention and silymarin (our reference drug) are very good candidates in this area (Li & Friedman, 1999). Even traditional drugs such as pentoxifylline (Windmeier & Gressner, 1997), as well-known phosphodiesterase inhibitor, were unexpectedly found to block HSC activation by interfering with the oxidative stress cascade suggesting new mechanisms for their anti-fibrotic activity.
Popularity of herbal remedies is increasing worldwide and at least one quarter of patients with liver diseases use medicinal plants for the prevention and treatment of liver diseases. More efforts need to be directed towards methodological scientific evaluation for their safety and efficacy by subjecting to vigorous pre-clinical studies followed by clinical trials to scientifically prove their traditional uses on evidence-based findings (Stickel & Schuppan, 2007). Recently, some researches has confirmed the efficacy of several plants as hepatoprotective agents and evaluated their mechanisms of action. Silybum marianum (milk thistle) has been shown to have clinical applications in the treatment of liver cirrhosis via its antioxidative, antifibrotic, anti-inflammatory, immune-modulating, and liver regenerating effects. Picrorhiza kurroa, appears to have similar applications and mechanisms of action (Luper, 1998). In addition Curcuma
longa , Camellia sinensis (green tea), and Glycyrrhiza glabra have been approved to
exhibit hepatoprotective effects (Luper, 1999). Using different experimental models some other plant extracts were evaluated for their hepatoprotective activity such as
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arvensis, Pterocarpus santalinus, Solanum nigrum, and Wedelia calendulacea (Bhawna
& Kumar, 2009).