Fulminant hepatic failure (FHF) is a life-threatening disease that can be effectively treated with a liver transplant. Unfortunately, many individuals die each year while awaiting a donor liver. Estimates indicate that an increase of only 48 hours would allow a significantly larger number of individuals to receive a transplant. In many of these individuals, cerebral edema resulting from a failure in the integrity of the blood brain barrier (BBB) is the proximal cause of death. Understanding the specific mechanisms involved in causing cerebral edema in these patients is likely to yield novel approaches aimed at increasing survival. Recent evidence has implicated the matrix metalloproteases, in particular matrix metalloproteinase-9 (MMP-9), as pivotal players in the development of cerebral edema in other diseases such as brain ischemia. Based on these data we hypothesize that MMP-9 plays a critical role in BBB failure resulting in increased BBB permeability and subsequent cerebral edema in FHF. Significant support for this hypothesis has come from three key observations made in our laboratory. First, both MMP-9 and its preform are elevated in the sera of FHF patients as well as in rats and mice with experimentally induced FHF. Second, the increased MMP-9 activities correlate to the onset of increased brain extravasations, i.e. increased BBB permeability in FHF animals. Third, treatment with a MMP-9 inhibitor (GM6001) or with MMP-9 monoclonal antibody results in substantial reduction in brain extravasations following experimentally induced FHF in animals. Our recent preliminary results suggest that MMP-9 inhibition increases survival of the FHF mice. In this application, we propose to further test our hypothesis and extend our studies as follows.
Specific Aim 1 : To determine whether direct infusion of FHF sera containing MMP-9 into the brain systemic circulation results in BBB failure and cerebral edema.
Specific Aim 2 : To determine if inhibition of MMP-9 results in an increase in survival in experimentally induced FHF. ? ? ?
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