Chemokine receptors as therapeutic targets in liver disease

Parker, Richard (2015). Chemokine receptors as therapeutic targets in liver disease. University of Birmingham. Ph.D.

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Abstract

There is an urgent need for new insights into the pathology of liver disease to underpin new therapeutic approaches. Chemokines and their receptors are central to the development of liver inflammation. I investigated liver disease using ex-vivo human tissue to analyse gene and protein expression in liver and the nature of inflammation. Animal models of liver disease were used to investigate the effects of manipulating the chemokine system.
In Non-Alcoholic Fatty Liver Disease (NAFLD) expression of CCL2 is increased. A subset of monocytes expressed CD11c and CD206, and maintained CCR2 expression in NAFLD. The frequency of this subset was associated with insulin resistance. In animal models of NAFLD, antagonism of CCR2 improved liver disease. In mouse models of acute liver failure (ALF), expression of CCL25 was an early response after injury, a phenomenon also seen in human ALF. Influx of CCR9\(^+\) monocytes was a corresponding early event in murine liver. Prophylactic administration of a CCR9 antagonist reduced liver injury and macrophage infiltration. CXCR6 has contrasting effects in murine liver injury: damaging in acute injury but protective in chronic injury. In human liver CXCR6 promotes infiltration Natural Killer cells, particularly in primary biliary cirrhosis, but may also promote regeneration of hepatocytes.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):