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捐献肝脏的过程中死亡。据估计，只要延长48小时，接受移植的人数就会大大增加。在许多这样的个体中，由于血脑屏障（BBB）完整性失败而导致的脑水肿是近端死亡原因。了解引起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)，在脑缺血等其他疾病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。首先，FHF患者以及实验诱导的FHF大鼠和小鼠血清中MMP-9及其前体均升高。其次，MMP-9活性的增加与脑外渗的增加有关，即FHF动物血脑屏障通透性的增加。第三，用MMP-9抑制剂（GM6001）或MMP-9单克隆抗体治疗可显著减少实验诱导的动物FHF后的脑外渗。我们最近的初步结果表明，抑制MMP-9可提高FHF小鼠的存活率。在本次申请中，我们建议进一步验证我们的假设，并扩展我们的研究如下。特异性目的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血脑屏障衰竭和脑水肿。特异性目的2：确定抑制MMP-9是否会导致实验诱导的FHF存活增加。

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.