Abstract
Liver disease ranks as the 11th leading cause of death globally. The primary causes include metabolic dysfunction (metabolic associated fatty liver disease, alcohol consumption, and viral infections (viral hepatitis). Despite the significant morbidity and mortality associated with liver disease, there are no available pharmacological treatments. This dissertation explores various disease targets and the development of novel therapeutics for liver injury.
Understanding disease mechanisms is crucial for designing new therapeutics. Liver injury causes hepatocyte damage, triggering inflammation by activating immune cells, particularly monocytes and macrophages. This inflammation activates hepatic stellate cells, leading to excessive secretion of extracellular matrix (ECM) components like collagen, which distorts liver architecture, impairs function, and can result in hepatic decompensation and hepatocellular carcinoma.
Chapter 1 demonstrates the upregulation of fibroblast growth factor 7 (FGF7) and its receptor FGFR2b in liver injury, promoting hepatocyte proliferation and survival through AKT and ERK pathways. FGF7 also reduces liver inflammation and fibrosis, highlighting its therapeutic potential.
Chapter 2 focuses on the chemokine receptor CCR8, which correlates with liver injury. We identified a CCR8 antagonizing peptide, which reduces macrophage migration and inflammation in liver injury models, showing promise as a safe and effective treatment.
Chapter 3 investigates the CCR2/CCL2 axis, with a novel CCR2 antagonizing peptide (AP2) reducing inflammation and fibrosis in liver injury models. Cyclized AP2 demonstrated similar efficacy.
Chapter 4 reviews ECM remodeling and the role of matrix metalloproteinases (MMPs) as biomarkers and therapeutic targets in liver disease.
Chapter 5 discusses the development of MMPsomes for drug delivery, showing their potential in reducing fibrosis and inflammation in liver fibrosis models.
Chapter 6 highlights the synergistic effect of CCL2 inhibition combined with MMP-driven collagen degradation, which showed superior effect over single treatments.
These findings contribute to a better understanding of liver disease and the development of effective therapies for patients.
Understanding disease mechanisms is crucial for designing new therapeutics. Liver injury causes hepatocyte damage, triggering inflammation by activating immune cells, particularly monocytes and macrophages. This inflammation activates hepatic stellate cells, leading to excessive secretion of extracellular matrix (ECM) components like collagen, which distorts liver architecture, impairs function, and can result in hepatic decompensation and hepatocellular carcinoma.
Chapter 1 demonstrates the upregulation of fibroblast growth factor 7 (FGF7) and its receptor FGFR2b in liver injury, promoting hepatocyte proliferation and survival through AKT and ERK pathways. FGF7 also reduces liver inflammation and fibrosis, highlighting its therapeutic potential.
Chapter 2 focuses on the chemokine receptor CCR8, which correlates with liver injury. We identified a CCR8 antagonizing peptide, which reduces macrophage migration and inflammation in liver injury models, showing promise as a safe and effective treatment.
Chapter 3 investigates the CCR2/CCL2 axis, with a novel CCR2 antagonizing peptide (AP2) reducing inflammation and fibrosis in liver injury models. Cyclized AP2 demonstrated similar efficacy.
Chapter 4 reviews ECM remodeling and the role of matrix metalloproteinases (MMPs) as biomarkers and therapeutic targets in liver disease.
Chapter 5 discusses the development of MMPsomes for drug delivery, showing their potential in reducing fibrosis and inflammation in liver fibrosis models.
Chapter 6 highlights the synergistic effect of CCL2 inhibition combined with MMP-driven collagen degradation, which showed superior effect over single treatments.
These findings contribute to a better understanding of liver disease and the development of effective therapies for patients.
| Original language | English |
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| Qualification | Doctor of Philosophy |
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| Supervisors/Advisors |
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| Award date | 5 Jul 2024 |
| Place of Publication | Enschede |
| Publisher | |
| Print ISBNs | 978-90-365-6136-5 |
| Electronic ISBNs | 978-90-365-6137-2 |
| DOIs | |
| Publication status | Published - Jul 2024 |