Manipulating macrophages to enhance liver regeneration
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Date
04/07/2015Author
Stutchfield, Benjamin Mark
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Abstract
Acute liver failure confers a high risk of death, with liver transplantation offering the only
effective therapy for life-threatening cases. Hepatic macrophages are crucial for innate
immune integrity and effective hepatocyte proliferation. The macrophage may therefore
present a novel therapeutic target to enhance regeneration following acute liver injury.
In this thesis I describe the development and use of mouse models of liver injury
including partial hepatectomy, partial hepatectomy plus chronic liver injury and
paracetamol intoxication. I show the development of liver function assays in these
models including quantification of hepatic clearance of indocyanine green by fluorescent
imaging and assessment of hepatic phagocytic capacity using fluorescent microbeads. I
then describe macrophage based therapeutic interventions in mouse models of liver
injury. Firstly the direct administration of bone marrow derived macrophages in partial
hepatectomy plus chronic liver injury. I then tested the administration of macrophage
colony stimulating factor in mouse models of partial hepatectomy, partial hepatectomy
plus chronic liver injury and paracetamol intoxication, describing the phenotype and
exploring mechanisms of action.
Collaborating with others I assessed serum CSF1 levels in humans with liver injury due
to partial hepatectomy or paracetamol intoxication. I show that in acute liver failure a
high serum CSF1 level is predictive of survival, indicating a new mechanistic biomarker.