Modulation of carbon tetrachloride-induced hepatic oxidative stress, injury and fibrosis by olmesartan and omega-3

• The effects of omega-3 and olmesartan were investigated against hepatic fibrosis.
• Omega-3 and olmesartan couteracted hepatic oxidative stress.
• Omega-3 and olmesartan prevented the activation of HSCs.
• Omega-3 and olmesartan inhibited the proliferation and chemotaxis of HSCs.
• Omega-3 and olmesartan inhibited the fibrogenesis response of HSCs.

This study was designed to investigate the potential effects of omega-3, olmesartan and their combination on established hepatic fibrosis in the carbon tetrachloride (CCl4) rat model. Male Wistar rats received subcutaneous injections of CCl4 twice weekly for 12 weeks, as well as daily oral treatments of olmesartan (1 and 3 mg/kg), omega-3 (75 and 150 mg/kg) and their combination during the last 4 weeks of intoxication. Our results indicated that omega-3 and, to a lesser extent, olmesartan dose-dependently blunted CCl4-induced necroinflammation scoring and elevation of liver injury parameters in serum. Besides, omega-3 and, to a lesser extent, olmesartan treatments in a dose dependent manner attenuated CCl4-induced liver fibrosis, as demonstrated by hepatic histopathology scoring and 4-hydroxyproline content. The mechanisms behind these beneficial effects of both omega-3 and olmesartan were also elucidated. These include (1) counteracting hepatic oxidative stress and augmenting hepatic antioxidants; (2) preventing the activation of hepatic stellate cells (HSCs), as denoted by reducing α-smooth muscle actin (α-SMA) expression in the liver; (3) inhibiting the proliferation and chemotaxis of HSCs, as evidenced by downregulating platelet-derived growth factor receptors-β (PDGFR-β) expression in the liver; and (4) inhibiting the fibrogenesis response of HSCs, as indicated by inhibiting the secretion of transforming growth factor-β1 (TGF-β1). Unexpectedly, when olmesartan was co-administered with omega-3, it interfered with the hepatoprotective and anti-fibrotic activities of omega-3. In conclusion, this study introduces the first evidence regarding the pronounced anti-fibrotic activity of omega-3 and suggests that it may be beneficial in the treatment of hepatic fibrosis in humans.

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