MMP-9 mediates cerebral edema in fulminant liver 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。FHF的决定性治疗是肝移植。不幸的是，35%的FHF患者和62%的非对乙酰氨基酚诱导的FHF患者在达到3级或4级昏迷后48小时内死亡，同时等待移植。增加这一狭窄的治疗窗口将为这些患者提供更多的移植机会。这些人死亡的主要原因之一是脑水肿。FHF患者脑水肿的机制尚不清楚。最近来自其他实验室的证据表明，基质金属蛋白酶-9（MMP-9）可能在其他疾病状态下脑水肿的发展中起关键作用。例如，用MMP-9合成抑制剂或抗MMP-9单克隆抗体治疗已显示导致脑梗塞大小的显著减小。此外，使用MMP-9敲除小鼠的研究显示脑缺血或创伤事件后脑水肿显著减轻。基于这些数据，我们假设MMP-9在FHF后脑水肿的发展中起关键作用。我们实验室的两个观察结果有力地支持了这一假设。首先，proMMP-9和MMP-9在FHF患者的血清和实验诱导的FHF大鼠中均升高。第二，在初步研究中，我们已经表明，用MMP-9抑制剂（GM 6001）治疗导致实验诱导的FHF大鼠脑水肿减少约30%。在本申请中，我们特别提出： 1.进一步确定MMP合成抑制剂GM 6001抑制MMP-9是否减轻实验诱导FHF大鼠的脑水肿。 2.确定实验诱导的FHF后MMP-9基因敲除小鼠的脑水肿是否减轻。

DESCRIPTION (provided by applicant): Fulminant hepatic failure (FHF) is a life-threatening disease. The definitive treatment for FHF is a liver transplant. Unfortunately, 35% of all FHF patients and 62% of nonacetaminophen-induced FHF patients die within 48 hours after reaching stage 3 or 4 coma, while awaiting a transplant. Increasing this narrow therapeutic window would provide substantially more opportunities for these patients to be transplanted. One of the primary causes of death in these individuals is cerebral edema. The mechanisms responsible for cerebral edema in these FHF patients are poorly understood. Recent evidence from other laboratories has shown that matrix metalloproteinase-9 (MMP-9) may play a pivotal role in the development of cerebral edema in other disease states. For example, treatment with either MMP-9 synthetic inhibitors or anti-MMP-9 monoclonal antibodies has been shown to result in a significant reduction in the size of cerebral infarcts. Further, studies using MMP-9 knockout mice have shown a significant attenuation in cerebral edema following either cerebral ischemic or traumatic events. Based on these data we hypothesize that MMP-9 plays a critical role in the development of cerebral edema following FHF. Significant support for this hypothesis has come from two observations made in our laboratory. First, both proMMP-9 and MMP-9 are elevated in the sera of FHF patients and in rats with experimentally induced FHF. Second, in a pilot study, we have shown that treatment with an MMP-9 inhibitor (GM6001) results in an approximate 30% reduction in cerebral edema in rats with experimentally induced FHF. In this application, we specifically propose to: 1. To further determine if inhibition of MMP-9 by the MMP synthetic inhibitor GM6001 attenuates cerebral edema in rats with experimentally induced FHF. 2. To determine whether cerebral edema is attenuated in MMP-9 knockout mice following experimentally induced FHF.