Abstract
Fibrosis is an integral part of the pathophysiological mechanism underlying numerous chronic diseases which account for up to 45% of deaths in the developed world. The fibrotic process is characterized by the excessive deposition of fibrous extracellular matrix in the affected organ, resulting in organ failure. Nevertheless, clinically effective anti-fibrotic drugs remain an unmet clinical need. In this thesis, Theerut Luangmonkong explored anti-fibrotic drugs for the treatment of liver fibrosis, and developed novel disease models, using precision-cut tissue slices.
The first part of Theerut’s thesis delineates the mechanism of liver fibrogenesis and the anti-fibrotic potency of several drugs affecting multiple pro-fibrogeneic mediators. Theerut showed that galunisertib, a small molecule inhibitor against transforming growth factor beta, is an extremely promising drug candidate for the treatment of liver fibrosis; however, additional (clinical) studies are required to fully unveil its therapeutic potential. In addition, Theerut demonstrated that several drugs affecting bone morphogenetic proteins, platelet-derived growth factor, p38-mitogen-activated protein kinase and reactive oxygen species also possess anti-fibrotic potency. Simultaneous inhibition of these pro-fibrogenic mediators might be clinically feasible and will greatly improve therapeutic efficacy.
Besides the successful use of precision-cut liver slices for drug discovery, Theerut also used precision-cut tissue slices to develop experimental models of other multicellular diseases, namely non-alcoholic fatty liver disease and renal fibrosis. These newly established disease models will vastly support future research efforts into fibroproliferative diseases as well as drug development.
The first part of Theerut’s thesis delineates the mechanism of liver fibrogenesis and the anti-fibrotic potency of several drugs affecting multiple pro-fibrogeneic mediators. Theerut showed that galunisertib, a small molecule inhibitor against transforming growth factor beta, is an extremely promising drug candidate for the treatment of liver fibrosis; however, additional (clinical) studies are required to fully unveil its therapeutic potential. In addition, Theerut demonstrated that several drugs affecting bone morphogenetic proteins, platelet-derived growth factor, p38-mitogen-activated protein kinase and reactive oxygen species also possess anti-fibrotic potency. Simultaneous inhibition of these pro-fibrogenic mediators might be clinically feasible and will greatly improve therapeutic efficacy.
Besides the successful use of precision-cut liver slices for drug discovery, Theerut also used precision-cut tissue slices to develop experimental models of other multicellular diseases, namely non-alcoholic fatty liver disease and renal fibrosis. These newly established disease models will vastly support future research efforts into fibroproliferative diseases as well as drug development.
| Translated title of the contribution | OP ZOEK NAAR MEDICIJNEN TEGEN OVERMATIGE LITTEKENVORMING: EEN EX VIVO-ONDERZOEKSMODEL |
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| Original language | English |
| Qualification | Doctor of Philosophy |
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| Award date | 27-Nov-2017 |
| Place of Publication | [Groningen] |
| Publisher | |
| Print ISBNs | 978-94-034-0187-4 |
| Electronic ISBNs | 978-94-034-0186-7 |
| Publication status | Published - 2017 |