Chemokines are inflammatory mediators that are classically known for their elicitation of inflammatory cells out of the vasculature. However, more contemporary studies show that these ubiquitous factors impinge on many facets of biology, including hematopoiesis, angiogenesis, and mitogenesis. The elucidation of mechanisms involved in the immunopathogenesis of liver disease has magnified the importance of chemokines in this organ. This dissertation examines several families of chemokines in liver pathology, namely the CXC and CX3C families, which are named according to the location of their cysteine residues. Stem Cell Factor, a hematopoietic cytokine, increased survival in a model of multi-organ failure associated with an increase in systemic MIP-2 and hepatic integrity. To further examine this association, a more direct model of liver toxicity was employed, namely acetaminophen overdose. MIP-2 had therapeutic benefits due to its direct effect on hepatocyte regeneration. Furthermore, another member of the CXC family, IP-10, had therapeutic value that was dependent on the upregulation of CXCR2, the receptor for MIP-2. Finally, we examined the role of the CX3C family and found that in the absence of its receptor, there was a dramatic increase in hepatocyte proliferation associated with maintenance of Kupffer cells within the liver. Thus, the regulation of chemokines may provide novel therapeutic options during liver pathology.
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