Antifibrotic activity of Taraxacum officinale root in carbon tetrachloride-induced liver damage in mice

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Liver fibrosis represents the excessive accumulation of extracellular matrix (ECM) proteins including collagen that occurs in most types of chronic liver diseases. Advanced liver fibrosis results in cirrhosis, liver failure, and portal hypertension and often requires liver transplantation (Bataller and Brenner, 2005). Oxidative stress has been implicated in the etiology of chronic liver disease and liver fibrosis, often in association with decreased antioxidant defenses (Parola and Robino, 2001). In the present study, increased hepatic collagen deposition in the CCl₄ group has indicated the development of liver fibrosis. The DWE therapy has induced withdrawal of collagen deposits in necrotic areas and the reversion of hepatic fibrosis. The elevation in Cu/Zn SOD activity in DWE treated groups, compared to the CCl₄ group, suggest that the hepatoprotective effect of DWE could be partially attributed to its antioxidant activity. Most recent study suggests that polyphenolic chlorogenic acid, which has been identified in DWE, has inhibitory potential on CCl₄-induced liver fibrosis in rats by inactivating HSCs (Shi et al., 2009). However, medicinal plants typically contain several different chemical compounds that may act individually, additively or in synergy to improve health (Gurib-Fakim, 2006). Therefore, it is difficult to determine the contribution of individual compounds to the pharmacological effectiveness of complex therapeutics.

The accumulation of ECM observed in fibrosis and cirrhosis is considered to be a result of activation of fibrogenic cell types, such as HSCs and portal fibroblasts, which acquire a myofibroblastic phenotype (Guyot et al., 2006). During pathological conditions, activated HSC increase the production of ECM proteins and remodel the sinusoidal wall and necrotic areas (Burt 1999; Jin et al., 2002). However, the mechanisms of hepatic fibrogenesis are not yet fully understood. In particular, the role of HSCs remains unclear. The maintenance of HSC morphology might be one of the factors playing a role in the prevention or slowing down of liver fibrosis. Buniatian (2003) has observed different patterns of activation of HSC in the ellagic acid treated hepatic cell cultures, which might correspond to distinct activities of these cells, which, in turn, might lead to different outcomes of liver fibrosis. It has been shown that HSCs have ability to migrate in vitro (Marra et al., 1999) and in vivo to the fibrotic lesions and take part in the repair of injured liver tissue (Kinnman et al., 2000). In their quiescent state, HSCs express various cellular markers, such as GFAP (Neubauer et al., 1996). Upon activation, HSCs which acquire myofibroblast phenotype increase the levels of desmin and α-SMA whereas GFAP expression decreases (Campbell et al., 2005). In this study, deposition of collagen in the liver of CCl₄-intoxicated mice, associated with increased α-SMA and decreased GFAP perisinusoidal immunopositivity, indicate engagement of HSCs in development of liver fibrosis. Furthermore, the resolution of fibrotic scares was accompanied by HSCs deactivation, as indicated by decreased α-SMA immunopositivity.

Metallothioneins (MTs) constitute a family of low molecular weight, cysteine-rich metalloproteins involved in cytoprotection during pathology. Increased MT synthesis in response to oxidative stress in both the cytosol and nucleus has been reported previously (Sato and Bremner, 1993; Levadoux-Martin et al., 2001). The biological function of MT remains unsettled, however it is known that the induction of MT synthesis can protect animals from hepatotoxicity induced by heavy metals and various toxins including CCl₄, but also may play a role in cell proliferation and liver regeneration (Cherian and Kang, 2006). Previously, we have shown up-regulation of MT I/II expression and the enchantment of hepatic regenerative capability in acute and chronic CCl₄ hepatotoxicity by luteolin (Domitrović et al., 2008; Domitrović et al., 2009). The mechanisms by which MT participates in the pathology and the recovery of liver fibrosis are still largely unknown. Jiang and Kang (2004) have shown that mice which have developed a reversible liver fibrosis upon removal of CCl₄ had a high level of hepatic MTs, but mice which developed an irreversible fibrosis had low expression of MTs. Therefore, hepatic MT expression in pathological conditions could reflect the severity of chronic liver damage (Carrera et al., 2003). MT I/II protein down-regulation in the CCl₄ group, compared to controls, suggest the suppression of hepatic regenerative response and the progression toward irreversible fibrosis. On the other hand, the positive correlation between MT I/II expression and liver tissue repairment in the DWE treated groups suggest its involvement in the liver regeneration.

In conclusion, the present study provides original evidence that the Taraxacum officinale water-ethanolic root extract elicits the therapeutic effect on hepatic fibrosis. The DWE treatment has promoted the complete regression of fibrosis and the enchantment of hepatic regenerative capabilities. The results obtained from this study strongly suggest the therapeutic potential of DWE in patients with liver fibrosis.