PhD ceremony Ms. M.H. Tiebosch: Antioxidant adaptations in liver fibrogenesis
| When: | We 16-04-2014 at 16:15 |
| Where: | Academiegebouw, Broerstraat 5, Groningen |
PhD ceremony: Ms. M.H. Tiebosch
Dissertation: Antioxidant adaptations in liver fibrogenesis
Promotor(s): prof. A.J. Moshage, prof. K.N. Faber
Faculty: Medical Sciences
Liver fibrosis is a severe manifestation of many chronic liver diseases. It can evolve into cirrhosis and liver cancer. Both conditions have a high morbidity and mortality and very few treatment options. This thesis describes the development of fibrosis from liver damage to an inflammatory response appearing with scar formation. The 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. In this thesis we investigated whether adaptations of cellular anti-oxidantsystems play a role in this phenomenon.
We investigated the role of the enzyme heme oxygenase-1 (HO-1), 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.
We subsequently investigated anti-oxidantsystems of stellate cells and especially if and how they change upon activation. We describe an increase of certain anti-oxidants (glutathione and glutathione peroxidase-1) and a reduction of others, such as the enzymes catalase and MnSOD. Activated stellate cells are less sensitive to hydrogen peroxide-induced necrosis, but are still sensitive to apoptosis (programmed cell death).
We artificially induced the expression of MnSOD in activated stellate cells to investigate whether they reverse their phenotype to a quiescent phenotype. This seems to be the case. Finally we found that 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.