Biomarkers, Models and Mechanisms of Intestinal Fibrosis

    Research output: ThesisThesis fully internal (DIV)

    677 Downloads (Pure)

    Abstract

    Chronic intestinal inflammation in Crohn’s disease (CD) frequently causes complications such as fibrosis or fistulae. Intestinal fibrosis is characterized by excessive deposition of collagens and causing stenosis and finally intestinal obstruction. Fistulae on the other hand are characterized by a relative decrease in deposition of collagens due to persistent inflammation. Despite advances in treatment with anti-inflammatory drugs, the incidence of fibrosis and fistulae remains high. Repetitive endoscopic dilatation of stenosis, or surgery for fibrosis or fistulae are so far the only therapeutic options. Furthermore, currently no serological biomarkers are available to detect the presence of intestinal fibrosis or fistulae.

    The development of drugs against intestinal fibrosis/fistulae is being hampered by the lack of insight in the underlying mechanism and by the lack of translational models that can predict drug efficacy in humans. We describe a novel translational ex vivo model for intestinal fibrosis, which could bridge the gap between pre-clinical and clinical research to evaluate the efficacy of anti-fibrotic drugs in man. In addition, pH sensing receptor ovarian cancer G-protein coupled receptor-1 was confirmed to be part of the mechanism of inducing intestinal fibrosis and may be a target for CD-associated fibrosis. Furthermore, we propose targets to inhibit intestinal fibrosis and existing drugs acting on these targets, based on increased mRNA expression of enzymes involved in the post-translational collagen processing of intestinal fibrosis affected tissue. Finally, we provide evidence for the use of serological markers related to turnover of extra cellular matrix to detect the presence of penetrating CD.
    Original languageEnglish
    QualificationDoctor of Philosophy
    Awarding Institution
    • University of Groningen
    Supervisors/Advisors
    • Olinga, Peter, Supervisor
    • Dijkstra, Gerard, Supervisor
    • Boersema, Miriam, Co-supervisor
    Award date11-Sep-2019
    Place of Publication[Groningen]
    Publisher
    Print ISBNs978-94-034-1885-8
    Electronic ISBNs978-94-034-1884-1
    DOIs
    Publication statusPublished - 2019

    Cite this