title: Melatonin limits the expression of profibrogenic genes and ameliorates the progression of hepatic fibrosis in mice.
abstract: We investigated whether melatonin ameliorates fibrosis and limits the expression of fibrogenic genes in mice treated with carbon tetrachloride (CCl4). Mice in treatment groups received CCl4 5 μL/g body weight intraperitoneally twice a week for 4 or 6 weeks. Melatonin was given at 5 or 10 mg/kg/d intraperitoneally, beginning 2 weeks after the start of CCl4 administration. Treatment with CCl4 resulted in fibrosis evidenced by the staining of Van Gieson and α-smooth muscle actin (α-SMA) positive cells in the liver. At both 4 and 6 weeks, CCl4 induced an increase in the messenger RNA levels of collagens I and III, transforming growth factor (TGF)-β, platelet-derived growth factor (PDGF), connective tissue growth factor (CTGF), amphiregulin, matrix metalloproteinase (MMP)-9, and tissue inhibitor of metalloproteinase (TIMP)-1. Protein concentrations of CTGF, amphiregulin, MMP-9, TIMP-1, and phospho-Smad3 were also significantly augmented in fibrotic mice. Melatonin successfully attenuated liver injury, as shown by histopathology and decreased levels of serum transaminases. Immunohistochemical staining of α-SMA indicated an abrogation of hepatic stellate cell activation by the indol. Furthermore, melatonin treatment resulted in significant inhibition of the expression of collagens I and III, TGF-β, PDGF, CTGF, amphiregulin, and phospho-Smad3. The MMP-9 activity decreased and the expression of nuclear factor erythroid-2-related factor 2 (Nrf2) increased in mice receiving melatonin. Data obtained suggest that attenuation of multiple profibrogenic gene pathways contributes to the beneficial effects of melatonin in mice with CCl4-induced liver fibrosis.
authors.affiliation: Institute of Biomedicine (IBIOMED), University of León, León, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Spain.
authors.forename: Irene
authors.initials: I
authors.lastname: Crespo
authors.affiliation: Institute of Biomedicine (IBIOMED), University of León, León, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: San-Miguel
authors.affiliation: Institute of Biomedicine (IBIOMED), University of León, León, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Fernández
authors.affiliation: Service of Pharmacy, Hospital of León, León, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Ortiz de Urbina
authors.affiliation: Institute of Biomedicine (IBIOMED), University of León, León, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: González-Gallego
authors.affiliation: Institute of Biomedicine (IBIOMED), University of León, León, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Spain. Electronic address: mjtung@unileon.es.
authors.forename: María J
authors.initials: MJ
authors.lastname: Tuñón
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D002251:Carbon Tetrachloride / Q000633:toxicity; D003094:Collagen / Q000235:genetics; D016207:Cytokines / Q000235:genetics; D018450:Disease Progression; D015870:Gene Expression / Q000187:drug effects; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D055370:Lung Injury / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D008550:Melatonin / Q000502:physiology / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics; D057170:Translational Research, Biomedical
chemical_list: D000199:Actins; D016207:Cytokines; D012333:RNA, Messenger; C560825:Timp1 protein, mouse; D019715:Tissue Inhibitor of Metalloproteinase-1; C544013:alpha-smooth muscle actin, mouse; D003094:Collagen; D002251:Carbon Tetrachloride; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; D008550:Melatonin