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Title: Understanding the mechanisms regulating liver fibrosis (including the use of imaging techniques in its study and diagnosis)
Author: Hill, Stephen John
Awarding Body: University of Newcastle Upon Tyne
Current Institution: University of Newcastle upon Tyne
Date of Award: 2012
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Fibrosis is characterised by the excessive accumulation of extracellular matrix (ECM) proteins, resulting in a loss of tissue architecture and function. Central in liver fibrosis development is the transdifferentiation of hepatic stellate cells (HSCs) to a myofibroblast phenotype, responsible for increased deposition of ECM. Presently there are no treatments available for fibrosis. Critical to the discovery of novel anti-fibrotics is the development of a non-invasive imaging modality to accurately diagnose fibrosis severity. The hepatic myofibroblast specific single chain antibody (scAb) C1-3 was conjugated with a fluorophore and administered to mice with liver fibrosis prior to IVIS imaging to diagnose fibrosis severity. The expression of C1-3’s target antigen (synaptophysin) was confirmed by quantitative real-time PCR (qRT-PCR) and immunocytochemistry (ICC) in both quiescent and activated HSCs. The anti-inflammatory effects of PXR agonists were investigated utilising an in vivo model of liver fibrosis. Finally the pro-inflammatory properties of hepatic myofibroblasts were studied in vitro and in vivo. There was a statistically significant increase in fluorescence detected ex vivo in fibrotic livers versus the controls. qRT-PCR confirmed that quiescent HSCs (qHSCs) and hepatic myofibroblasts express similar levels of synaptophysin. The PXR agonist PCN significantly reduced the level of liver inflammation (NF-κB activity) following liver injury in vivo, 24 hours after its administration. The data presented indicates hepatic myofibroblasts release a pro-inflammatory soluble factor and induce NF-κB activity when injected in vivo. These findings suggest that hepatic myofibroblast number is an indicator of fibrosis severity. Hepatic myofibroblasts possess pro-inflammatory characteristics, which may contribute to fibrosis development. Finally PXR agonists exhibited anti-inflammatory properties that may be beneficial in the treatment of liver fibrosis.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available