Acute liver failure is a condition in which the liver undergoes massive loss of function and the ability to repair. ALF is hallmarked by significantly decreased serum levels of pro-inflammatory cytokines followed by markedly increased serum levels of anti-inflammatory cytokines and the inability of monocytes and macrophages to become activated. In order to further understand the pathology of ALF, a greater understanding of normal liver repair processes must be attained. The mechanisms by which macrophages may contribute to the liver injury and their role in the subsequent repair are not well characterized. The purpose of these studies was to determine the role of macrophages in acute liver injury and repair in response to carbon tetrachloride treatment. We found that compared to control mice, the ALT activity level was not significantly different in macrophage-depleted mice, suggesting that macrophages do not cause the initial injury in this model. However, an increased area of necrosis was observed in macrophage-depleted mice 72hrs following injury. Markers of hepatocyte proliferation did not differ significantly between the macrophage depleted mice and control mice. However, a decreased amount of Type I collagen staining was seen in macrophage-depleted mice while no change was seen in the mRNA levels of Type I collagen and factors related to collagen production. In the future, more studies into the activation states of various factors that affect the post-transcriptional regulation of collagen deposition will be conducted. Collectively, these studies suggest that macrophages may play a role in the clearance of necrotic cells and collagen remodeling to aid in liver repair. Macrophages are known to polarize into a pro-inflammatory phenotype termed M1 macrophages and an anti-inflammatory phenotype, M2 macrophages. Currently, the role of M1 and M2 macrophages in liver injury and repair is not clear. A number of studies indirectly suggest that M1 macrophages contribute to liver injury while M2 macrophages promote liver repair. However, the adoptive transfer of either M1 or M2 macrophages into macrophage depleted mice following the induction of an acute liver injury would enable us to characterize the role of M1 and M2 macrophages in this process. I have conducted preliminary studies that determined the validity and feasibility of the in vitro macrophage polarization and the localization of adoptively transferred macrophages to the liver.
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