Nrf2 and Snail-1 in the prevention of experimental liver fibrosis by caffeine

• Published in: World journal of gastroenterology : WJG 2013-12, Vol.19 (47), p.9020-9033
• Main Authors: Gordillo-Bastidas, Daniela, Oceguera-Contreras, Edén, Salazar-Montes, Adriana, González-Cuevas, Jaime, Hernández-Ortega, Luis Daniel, Armendáriz-Borunda, Juan
• Format: Article
• Language: English
• Subjects: Animals; Bile Ducts - surgery; Biomarkers - metabolism; Caffeine - pharmacology; Catalase - genetics; Catalase - metabolism; CD11b Antigen - metabolism; Collagen Type I - genetics; Connective Tissue Growth Factor - genetics; Cytoprotection; Gene Expression Regulation; Interleukin-1 - genetics; Interleukin-6 - genetics; Ligation; Liver - drug effects; Liver - metabolism; Liver - pathology; Liver Cirrhosis, Experimental - etiology; Liver Cirrhosis, Experimental - genetics; Liver Cirrhosis, Experimental - metabolism; Liver Cirrhosis, Experimental - pathology; Liver Cirrhosis, Experimental - prevention & control; Male; NF-E2-Related Factor 2 - metabolism; Original; Rats; Rats, Wistar; RNA, Messenger - metabolism; Signal Transduction - drug effects; Snail Family Transcription Factors; Superoxide Dismutase - genetics; Thioacetamide; Transcription Factors - metabolism; Transforming Growth Factor beta1 - genetics; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 1007-9327; 2219-2840
• DOI: 10.3748/wjg.v19.i47.9020

To determine the molecular mechanisms involved in experimental hepatic fibrosis prevention by caffeine (CFA). Liver fibrosis was induced in Wistar rats by intraperitoneal thioacetamide or bile duct ligation and they were concomitantly treated with CFA (15 mg/kg per day). Fibrosis and inflammatory cell infiltrate were evaluated and classified by Knodell index. Inflammatory infiltrate was quantified by immunohistochemistry (anti-CD11b). Gene expression was analyzed by quantitative reverse transcription-polymerase chain reaction for collagen I (Col-1), connective tissue growth factor (CTGF), transforming growth factor β1 (TGF-β1), tumor necrosis factor alpha (TNF-α), interleukin-1 (IL-1), IL-6, superoxide dismutase (SOD) and catalase (CAT). Activation of Nrf2 and Snail-1 was analyzed by Western-blot. TNF-α expression was proved by enzyme-linked immunosorbant assay, CAT activity was performed by zymography. CFA treatment diminished fibrosis index in treated animals. The Knodell index showed both lower fibrosis and necroinflammation. Expression of profibrogenic genes CTGF, Col-1 and TGF-β1 and proinflammatory genes TNF-α, IL-6 and IL-1 was substantially diminished with CFA treatment with less CD11b positive areas. Significantly lower values of transcriptional factor Snail-1 were detected in CFA treated rats compared with cirrhotic rats without treatment; in contrast Nrf2 was increased in the presence of CFA. Expression of SOD and CAT was greater in animals treated with CFA showing a strong correlation between mRNA expression and enzyme activity. Our results suggest that CFA inhibits the transcriptional factor Snail-1, down-regulating profibrogenic genes, and activates Nrf2 inducing antioxidant enzymes system, preventing inflammation and fibrosis.