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

描述（由申请人提供）：暴发性肝衰竭（FHF）是一种危及生命的疾病，可以通过肝移植有效治疗。不幸的是，每年都有许多人在等待肝脏捐赠时死亡。据估计，仅增加48小时就可以使更多的人接受移植。在许多这些个体中，由血脑屏障（BBB）的完整性失败引起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生存率的新方法。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（MMP-9），在其他疾病（如脑缺血）的脑水肿发展中起关键作用。基于这些数据，我们假设MMP-9在FHF中BBB衰竭中起关键作用，导致BBB渗透性增加和随后的脑水肿。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，MMP-9及其预制体在FHF患者的血清中以及在实验诱导的FHF的大鼠和小鼠中升高。第二，MMP-9活性的增加与脑外渗增加的发生相关，即FHF动物中BBB通透性的增加。第三，用MMP-9抑制剂（GM 6001）或用MMP-9单克隆抗体治疗导致动物中实验诱导的FHF后脑外渗的显著减少。我们最近的初步结果表明，MMP-9抑制增加FHF小鼠的存活率。在本申请中，我们建议进一步测试我们的假设，并扩展我们的研究如下。具体目标1：确定将含有MMP-9的FHF血清直接输注到脑体循环中是否会导致BBB衰竭和脑水肿。具体目的2：确定MMP-9的抑制是否导致实验诱导的FHF中存活率的增加。

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.