title: Modulation of carbon tetrachloride-induced hepatic oxidative stress, injury and fibrosis by olmesartan and omega-3.
abstract: 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 12weeks, as well as daily oral treatments of olmesartan (1 and 3mg/kg), omega-3 (75 and 150mg/kg) and their combination during the last 4weeks 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.
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
authors.forename: Ahmed A
authors.initials: AA
authors.lastname: Shaaban
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt. Electronic address: mshaker2222@yahoo.com.
authors.forename: Mohamed E
authors.initials: ME
authors.lastname: Shaker
authors.affiliation: Department of Pathology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt.
authors.forename: Khaled R
authors.initials: KR
authors.lastname: Zalata
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
authors.forename: Hassan A
authors.initials: HA
authors.lastname: El-kashef
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
authors.forename: Tarek M
authors.initials: TM
authors.lastname: Ibrahim
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002251:Carbon Tetrachloride; D004359:Drug Therapy, Combination; D015525:Fatty Acids, Omega-3 / Q000494:pharmacology / Q000627:therapeutic use*; D006909:Hydroxyproline / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008106:Liver Cirrhosis, Experimental / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology / Q000627:therapeutic use*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D000199:Actins; D015415:Biomarkers; D002251:Carbon Tetrachloride; D015525:Fatty Acids, Omega-3; D006909:Hydroxyproline; D007093:Imidazoles; D020797:Receptor, Platelet-Derived Growth Factor beta; D013777:Tetrazoles; D053773:Transforming Growth Factor beta1; C498862:Acta2 protein, rat; C437965:olmesartan
keywords: Carbon tetrachloride; Hepatic fibrosis; Olmesartan; Omega-3; Silymarin