The potential of in vitro and ex vivo models to predict the efficacy of antifibrotic drugs


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    Fibrosis is involved in approximately 45% of all deaths in developed countries and available pharmacological treatments are scarce, if at all. Fibrosis is the result of a chronic pathological tissue repair process which can affect different organs of the body, leading to organ failure over time. In fibrotic diseases, healthy tissue is replaced by scar tissue mainly consisting of collagen type I, due to the imbalance between the synthesis and degradation. The increased deposition of extracellular matrix is driven by the activated fibroblast, the so-called myofibroblast.
    Only a few antifibrotic drugs are available, which is mainly due to the discordance of translation between pre-clinical studies and human clinical trials. In this thesis, we first present an optimized format of in vitro macromolecular crowding with a reduced culture time and minimal effect on myofibroblast phenotype, and tested the efficacy of four antifibrotic drugs (Imatinib, Omipalisib, Nintedanib and Galunisertib). Furthermore, we used the combination of in vitro and ex vivo models to evaluate its predictive power regarding three antifibrotic drugs (Imatinib, Pirfenidone and Galunisertib) in the context of animal models and clinical trials of kidney fibrosis. Finally, we describe the in vitro antifibrotic effect of a repurposed FDA-approved drug (Verteporfin) in Dupuytren’s disease fibroblasts, as well as a pilot study for establishing an ex vivo model for antifibrotic drug testing for the same disease.
    Originele taal-2English
    KwalificatieDoctor of Philosophy
    Toekennende instantie
    • Rijksuniversiteit Groningen
    • Olinga, Peter, Supervisor
    • Bank, Ruud, Supervisor
    Datum van toekenning19-nov.-2021
    Plaats van publicatie[Groningen]
    Gedrukte ISBN's978-94-6421-514-4
    StatusPublished - 2021

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