MMP-9 mediates cerebral edema in fulminant liver failure

MMP-9介导暴发性肝衰竭中的脑水肿

• 批准号: 6743631
• 负责人: JUSTIN H NGUYEN
• 金额: $ 15.4万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-01 至 2005-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6743631
• 关键词: blood brain barrier; brain edema; galactosamine; genetically modified animals; hepatic coma /encephalopathy; hydroxamate; inhibitor /antagonist; laboratory mouse; laboratory rat; liver failure; liver transplantation; metalloendopeptidases; monoclonal antibody

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.

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。FHF的最终治疗方法是肝脏移植。不幸的是，35%的FHF患者和62%的非对乙酰氨基酚诱导的FHF患者在等待移植时达到3或4级昏迷后48小时内死亡。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。这些人的主要死亡原因之一是脑水肿。这些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(MMP9)可能在其他疾病状态下脑水肿的发生发展中起关键作用。例如，使用基质金属蛋白酶-9合成抑制剂或抗基质金属蛋白酶-9单抗的治疗已被证明可显著缩小脑梗塞的范围。此外，使用MMP-9基因敲除小鼠的研究表明，无论是脑缺血还是创伤事件后，脑水肿都显著减轻。基于这些数据，我们推测基质金属蛋白酶-9在FHF后脑水肿的发生发展中起关键作用。对这一假设的重要支持来自我们实验室的两个观察结果。首先，在FHF患者和实验性FHF大鼠的血清中，ProMMP9和MMP9均升高。其次，在一项先导性研究中，我们已经证明，在实验诱导的FHF大鼠中，使用基质金属蛋白酶-9抑制剂(GM6001)治疗可以减少大约30%的脑水肿。在本申请中，我们特别建议： 1.进一步确定基质金属蛋白酶合成抑制剂GM6001抑制基质金属蛋白酶-9是否能减轻实验性FHF大鼠的脑水肿。 2.确定实验性FHF后MMP一9基因敲除小鼠的脑水肿是否减轻。

项目成果

Cerebrospinal fluid drainage and cranial decompression prolong survival in rats with fulminant hepatic failure.

脑脊液引流和颅脑减压可延长暴发性肝衰竭大鼠的生存期。

• DOI: 10.1111/j.1432-2277.2006.00322.x
• 发表时间: 2006
• 期刊: Transplant international : official journal of the European Society for Organ Transplantation
• 作者: Yamamoto,Satoshi;Steers,JefferyL;WharenJr,RobertE;Eckman,ChristopherB;Nguyen,JustinH
• 通讯作者: Nguyen,JustinH

TIMP-1/MMP-9 imbalance in brain edema in rats with fulminant hepatic failure.

暴发性肝衰竭大鼠脑水肿中 TIMP-1/MMP-9 失衡。

• DOI: 10.1016/j.jss.2005.11.588
• 发表时间: 2006
• 期刊: The Journal of surgical research
• 作者: Yamamoto,Satoshi;Nguyen,JustinH
• 通讯作者: Nguyen,JustinH