Years of research on alcoholic liver disease (ALD) have clearly demonstrated the multifactorial nature of this disease and, to date, the list of factors that have been implicated as causative in the disease is still growing. This is of no surprise because alcohol (ethanol) is a cytotoxic agent and, as such, is expected to affect many facets of liver cells' function. Therefore, there is an ongoing necessity to search for novel aspects related to the mechanisms underlying ALD. This project's long-term objective is investigation into what may constitute yet another aspect of the disease mechanism(s): a potential role of matrix metalloproteinases (MMPs) in the development and progression of ALD. We postulate that MMPs play an important pathogenic role in the earlier phases of the disease by both mediating the transmigration of extrahepatic cells into the liver which, in turn, produce liver injury, and by disturbing the liver structural architecture. If confirmed by experimental work, this postulate may unravel a novel aspect of the disease mechanisms and bring into light a novel target for therapeutic interventions in ALD: the MMPs. This project has two specific aims: 1)To investigate the kinetics of expression of MMPs and their natural inhibitors, tissue inhibitors of metalloproteinases, (TIMP), in the liver of laboratory animals (mice treated with alcohol) from the onset of the disease and during its progression toward more advanced phases, and 2) To investigate the effects of several synthetic inhibitors of MMPs on the occurrence and progression of ALD. These experiments will be performed on mice chronically fed alcohol to develop alcoholic liver injury resembling the ALD in humans. The data obtained will provide an enhanced insight into the mechanisms of ALD and may provide insights into novel therapeutic approaches of ALD. ? ? ?
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