title: Hepatic and systemic effects of rosuvastatin on an experimental model of bile duct ligation in rats.
abstract: In the early stages of cholestasis, a plethora of mechanisms are considered to contribute to the liver injury: oxidative stress, inflammation, cholangiocytes proliferation and fibrosis. Our study aims to investigate the effects of different doses of rosuvastatin (Ro) on experimental bile duct ligation-induced cholestasis. 40 female Wistar rats were randomly divided into 4 groups (n=10): Sham group (laparotomy); BDL group (subjected to bile duct ligation); BDL group treated with Ro (5 mg/bw daily); BDL group treated with Ro (10 mg/bw daily). After 6 days of treatment, in the day 7 after BDL, the animals were sacrificed and we explored hepato-cytolysis, the seric parameters for cholestasis and oxidative stress in plasma, liver, brain and kidneys. Proliferation was investigated by expression of proliferating cell nuclear antigen (PCNA), while inflammation by liver histology, TNFR2 expression and NF-κB induction and activation. To assess fibrosis, we performed Tricrom-Masson staining, transforming growth factor beta-1 (TGF-β1) expression, and for myofibroblast activation, we analyzed α-SMA expression. The administration of Ro in early stages of cholestasis proved to have a beneficial effect by decreasing α-SMA. Ro didn't exert systemic oxidative stress effects, but increased hepatocytolysis, oxidative stress and inflammation in the liver and sustained increased levels of pro-fibrotic cytokine TGF-β1 as well as the number of proliferating cells in ducts and parenchyma. Ro inhibited the induction and the activation of NF-κB, which could be considered a beneficial effect. Further studies must be carried out in order to clearly investigate the balance between risks and benefits for Ro administration in early stages of cholestasis.
authors.affiliation: Department of Physiology, "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania.
authors.forename: D
authors.initials: D
authors.lastname: Olteanu
authors.forename: A
authors.initials: A
authors.lastname: Nagy
authors.forename: M
authors.initials: M
authors.lastname: Dudea
authors.forename: A
authors.initials: A
authors.lastname: Filip
authors.forename: A
authors.initials: A
authors.lastname: Muresan
authors.forename: C
authors.initials: C
authors.lastname: Catoi
authors.forename: P A
authors.initials: PA
authors.lastname: Mircea
authors.forename: S
authors.initials: S
authors.lastname: Clichici
mesh_terms: D000199:Actins / Q000378:metabolism; D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D001219:Aspartate Aminotransferases / Q000378:metabolism; D001652:Bile Ducts; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002779:Cholestasis / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D005464:Fluorobenzenes / Q000494:pharmacology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008026:Ligation; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008315:Malondialdehyde / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D018384:Oxidative Stress; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D050050:Protein Carbonylation / Q000187:drug effects; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000378:metabolism; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D005723:gamma-Glutamyltransferase / Q000378:metabolism
chemical_list: D000199:Actins; D000410:Alanine Transaminase; D001219:Aspartate Aminotransferases; D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008315:Malondialdehyde; D016328:NF-kappa B; D018809:Proliferating Cell Nuclear Antigen; D011743:Pyrimidines; D047889:Receptors, Tumor Necrosis Factor, Type II; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides; D053773:Transforming Growth Factor beta1; D005723:gamma-Glutamyltransferase; C498862:Acta2 protein, rat