Antioxidant adaptations in liver fibrogenesis

Marjolein Tiebosch

    Research output: ThesisThesis fully internal (DIV)

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    Abstract

    Liver fibrosis is a severe manifestation of many chronic liver diseases. It can evolve into cirrhosis and liver cancer. Both these conditions have a high morbidity and mortality and there a very few treatment options. Chapter 1 of this thesis describes the development of fibrosis: upon damage of the liver an inflammatory response appears with scar formation. This scar tissue is mainly produced by stellate cells and myofibroblasts. It is remarkable that in the same environment, hepatocytes die, while myofibroblasts become activated and flourish. Possibly, an adaptation of cellular anti-oxidantsystems plays a role in this phenomenon. This concept is investigated in this thesis.
    In chapter 2, the role of the enzyme heme oxygenase-1 (HO-1) is investigated. HO-1 is an important anti-oxidant enzyme. Upon artificially increasing the expression of this enzyme, liver specific macrophages, the Kupffer cells, acquire an inflammatory phenotype. We hypothesize that this mechanism contributes to reducing the development of fibrosis, because macrophages with this phenotype do not promote scar formation.
    In chapter 3, we investigated anti-oxidantsystems of stellate cells and especially if and how these systems change upon stellate cell activation. We describe an increase of certain anti-oxidants (glutathione and glutathione peroxidase-1 (GPx1)) and a reduction if others, such as the enzymes catalase and MnSOD. Activated stellate cells are less sensitive to hydrogen peroxide-induced necrosis, but they are still sensitive to apoptosis (programmed cell death).
    In chapter 4, we artificially induced the expression of MnSOD in activated stellate cells to investigate whether stellate cells reverse there phenotype to a quiescent phenotype. This indeed seems to be true. In chapter 5 we investigated the role of caffeine in liver fibrosis. Adding caffeine or its metabolite 1,7-dimetyhlxanthine to stellate cells results in a reduction of stellate cell activation. Moreover, these compounds also reduce inflammation in macrophages.
    In chapter 6 the results described in this thesis are discussed.
    Original languageEnglish
    QualificationDoctor of Philosophy
    Awarding Institution
    • University of Groningen
    Supervisors/Advisors
    • Moshage, Han, Supervisor
    • Faber, Klaas Nico, Supervisor
    Award date16-Apr-2014
    Place of Publication[S.l.]
    Publisher
    Print ISBNs978-94-6108-635-8
    Electronic ISBNs978-94-6108-639-6
    Publication statusPublished - 2014

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