Doctoral Thesis
Pathophysiological responses in chronic liver injury induced by thioacetamide
Doctor of Philosophy (PhD), Murdoch University
2021
Abstract
During chronic liver disease (CLD), myofibroblastic hepatic stellate cells (HSCs) activate from quiescent HSCs and generate fibrotic scarring in the liver. Perpetuation of fibrosis can lead to cirrhosis, portal hypertension and tumorigenesis, resulting in diminished liver functionality and over 1 million deaths per year. Removal of the underlying disease stimulus can lead to resolution of fibrosis. There are profound distinctions within the hepatic microenvironment during ‘profibrotic’ and subsequent ‘anti-fibrotic’ phases, and there is emerging interest in potential novel responses during re-induction of disease.
Hepatotoxic thioacetamide (TAA) was administered to TAA- ‘naïve’ or TAA- ‘pre-treated’ mice to investigate the pathophysiological distinctions occurring in response to one or two inductions of CLD. Serum and tissue samples from both groups at day 0, 1, 2, 3, 7 and 6w of TAA treatment were subjected to empirical and quantitative assessment with histological, biochemical and transcriptional examination. In addition, dynamic populations of inflammatory and liver progenitor cells (LPCs), and sub-phenotypes of HSCs were identified and characterised in both groups throughout the time course. Ex vivo precision-cut liver slice culture was also evaluated as a model of spontaneous fibrosis through analysis of viability, fibrotic gene expression and histology. Primary HSCs isolated from healthy, fibrotic and recovering mice were characterised by analysis of key fibrotic genes expression following isolation, culture activation or co-culture with the well characterised LPC line BMOL.
Compared to initial exposure to TAA, hepatotoxicity and liver fibrogenesis was suppressed during second treatment. Significant LPC expansion was detected following recovery from TAA-insult, prior to re-exposure (d0), and co-culture of LPCs was found to regulate profibrogenic gene expression of HSCs resulted. This study further defines novel underlying pathological and cellular mechanisms of recurrent hepatic injury. Furthermore, these findings highlight a key role for LPCs as regulatory cells during CLD.
Details
- Title
- Pathophysiological responses in chronic liver injury induced by thioacetamide
- Authors/Creators
- Francis David Gratte
- Contributors
- Garth Maker (Supervisor)John Olynyk (Supervisor)Nina Tirnitz-Parker (Supervisor)Robert Trengove (Supervisor)
- Awarding Institution
- Murdoch University; Doctor of Philosophy (PhD)
- Identifiers
- 991005541544907891
- Murdoch Affiliation
- College of Science, Health, Engineering and Education
- Language
- English
- Resource Type
- Doctoral Thesis
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