MMP-9 in Blood-Brain Barrier Failure in Fulminant Hepatic Failure

描述(申请人提供)：暴发性肝功能衰竭(FHF)是一种危及生命的疾病，可以通过肝移植有效地治疗。不幸的是，每年有许多人在等待肝脏捐赠者的过程中死亡。估计表明，仅增加48小时就会允许更多的人接受移植。在这些人中，许多人因血脑屏障(BBB)的完整性失败而导致的脑水肿是死亡的近端原因。了解导致这些患者脑水肿的具体机制可能会产生旨在提高存活率的新方法。最近的证据表明，基质金属蛋白酶，特别是基质金属蛋白酶-9(MMP9)，在脑缺血等其他疾病的脑水肿的发生发展中起关键作用。基于这些数据，我们推测基质金属蛋白酶-9在血脑屏障衰竭中起关键作用，导致血脑屏障通透性增加和随后的FHF脑水肿。对这一假设的重要支持来自我们实验室的三个关键观察结果。首先，在FHF患者的血清中，以及在实验诱导的FHF的大鼠和小鼠中，MMP9及其前体都升高。其次，MMP9活性的增加与FHF动物脑外渗增加，即血脑屏障通透性增加有关。第三，用基质金属蛋白酶-9抑制剂(GM6001)或基质金属蛋白酶-9单抗治疗可显著减少动物实验性FHF后的脑外渗。我们最近的初步结果表明，抑制基质金属蛋白酶-9可提高FHF小鼠的存活率。在这一应用中，我们建议进一步检验我们的假设，并扩展我们的研究如下。具体目的1：确定将含有基质金属蛋白酶-9的FHF血清直接注入脑循环是否会导致血脑屏障衰竭和脑水肿。具体目的2：确定抑制基质金属蛋白酶-9是否能增加实验性FHF的存活率。

DESCRIPTION (provided by applicant): 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.