Manipulating macrophages to enhance liver regeneration
Stutchfield, Benjamin Mark
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.