title: Antifibrotic mechanism of deferoxamine in concanavalin A induced-liver fibrosis: Impact on interferon therapy.
abstract: Iron-overload is a well-known factor of hepatotoxicity and liver fibrosis, which found to be a common finding among hepatitis C virus patients and related to interferon resistance. We aimed to elucidate the potential antifibrotic effect of deferoxamine; the main iron chelator, and its additional usefulness to interferon-based therapy in concanavalin A-induced immunological model of liver fibrosis. Rats were treated with deferoxamine and/or pegylated interferon-α for 6 weeks. Hepatotoxicity indices, oxidative stress, inflammatory and liver fibrosis markers were assessed. Concanavalin A induced a significant increase in hepatotoxicity indices and lipid peroxidation accompanied with a significant depletion of total antioxidant capacity, glutathione level and superoxide dismutase activity. Besides, it increased CD4(+) T-cells content and the downstream inflammatory cascades, including NF-κB, TNF-α, iNOS, COX-2, IL-6 and IFN-γ. Furthermore, α-SMA, TGF-β1 and hydroxyproline were increased markedly, which confirmed by histopathology. Treatment with either deferoxamine or pegylated interferon-α alone reduced liver fibrosis markers significantly and improved liver histology. However, some of the hepatotoxicity indices and oxidative stress markers did not improve upon pegylated interferon-α treatment alone, besides the remarkable increase in IL-6. Combination therapy of deferoxamine with pegylated interferon-α further improved all previous markers, ameliorated IL-6 elevation, as well as increased hepcidin expression. In conclusion, our study provides evidences for the potent antifibrotic effects of deferoxamine and the underlying mechanisms that involved attenuating oxidative stress and subsequent inflammatory cascade, as well as the production of profibrogenic factors. Addition of deferoxamine to interferon regimen for HCV patients may offer a promising adjuvant modality to enhance therapeutic response.
authors.affiliation: Central Administration of Pharmaceutical Affairs, Cairo, Egypt.
authors.forename: Samar F
authors.initials: SF
authors.lastname: Darwish
authors.affiliation: Pharmacology & Therapeutic Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
authors.forename: Wesam M
authors.initials: WM
authors.lastname: El-Bakly
authors.affiliation: Pharmacology & Toxicology Department, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt.
authors.forename: Reem N
authors.initials: RN
authors.lastname: El-Naga
authors.affiliation: Pharmacology & Toxicology Department, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt.
authors.forename: Azza S
authors.initials: AS
authors.lastname: Awad
authors.affiliation: Pharmacology & Toxicology Department, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt. Electronic address: ebtehal_dm@yahoo.com.
authors.forename: Ebtehal
authors.initials: E
authors.lastname: El-Demerdash
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use; D003208:Concanavalin A / Q000633:toxicity*; D003676:Deferoxamine / Q000627:therapeutic use*; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000627:therapeutic use*; D007501:Iron / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008103:Liver Cirrhosis / Q000139:chemically induced* / Q000188:drug therapy*; D008934:Mitogens / Q000633:toxicity; D018384:Oxidative Stress; D011092:Polyethylene Glycols / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000627:therapeutic use; D017262:Siderophores / Q000627:therapeutic use
chemical_list: D000998:Antiviral Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D008934:Mitogens; D011994:Recombinant Proteins; D017262:Siderophores; D003208:Concanavalin A; D011092:Polyethylene Glycols; D007501:Iron; C417083:peginterferon alfa-2b; D003676:Deferoxamine
keywords: Chloramine-T (PubChem CID: 50055044); Concanavalin A (PubChem CID: 135337769); Deferoxamine; Deferoxamine mesylate (PubChem CID: 62881); Ehlrich’s reagent (PubChem CID: 49874978); Hepcidin; Interferon; Interferon α2b (PubChem CID: 71306834); Iron; Liver fibrosis