TIMP-1/MMP-9 imbalance in brain edema in rats with fulminant hepatic failure.
TIMP-1/MMP-9 imbalance in brain edema in rats with fulminant hepatic failure.
复制标题
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
复制
发表时间：
2006
期刊：
影响因子：
--
通讯作者：
Nguyen,JustinH
中科院分区：
文献类型：
--
作者：
Yamamoto,Satoshi;Nguyen,JustinH
暴发性肝功能衰竭（FHF）是一种严重的疾病。当昏迷发生时，脑水肿发展，将FHF变成致命的情况。肝移植是最终的治疗方法。然而，这些患者中有三分之一在捐献者出现之前就死于脑水肿。基质金属蛋白酶组织抑制剂（MMP）或TIMP和MMP-9与缺血性脑水肿有关。因此，我们假设，TIMP-1/MMP-9的关系不平衡发挥了作用，在FHF.MATERIALS和METHODSFHF的脑外渗和水肿增加的发展与D-半乳糖胺（250毫克/公斤）的单次腹腔注射诱导。对照组大鼠接受生理盐水。GM 6001，一种合成的MMP抑制剂，从D-半乳糖胺注射后12小时开始，每12小时给药一次（30 mg/kg），共3次。采用标准明胶酶谱法测定MMP-9。脑外渗，血脑屏障通透性的测量，用伊文思蓝测定。结果：FHF昏迷组体循环中活性MMP-9含量明显高于对照组（6.5 ± 0.7，4.6 ± 0.4，2.6 ± 0.5pg/μg，P < 0.05）;相反，TIMP-1在昏迷前和昏迷FHF大鼠中分别稳定下降35%和45%。GM 6001阻断MMP-9活性可明显减轻FHF大鼠脑水肿和脑外渗。结论：FHF脑水肿的发生与TIMP-1的降低和MMP-9的升高有关。我们的研究结果提出了一种潜在的治疗方法，以有效地增加挽救生命的肝移植的机会窗口。
BACKGROUNDFulminant hepatic failure (FHF) is a devastating disease. When coma sets in, brain edema develops, changing FHF into a lethal condition. Liver transplantation is the definitive treatment. However, a third of these patients die as the result of brain edema before a donor becomes available. Tissue inhibitor of matrix metalloproteinase (MMP), or TIMP, and MMP-9 are implicated in ischemic brain edema. We thus hypothesized that an imbalance in TIMP-1/MMP-9 relationship plays a role in the development of increased brain extravasation and edema in FHF.MATERIALS AND METHODSFHF was induced with a single intraperitoneal injection of D-galactosamine (250 mg/kg). Control rats received saline. GM6001, a synthetic MMP inhibitor, was administered (30 mg/kg) every 12 h for 3 doses starting at 12 h after D-galactosamine injection. MMP-9 was assayed with standard gelatin zymography. Brain extravasation, a measurement of the blood–brain barrier permeability, was determined with Evans blue. Brain edema was determined using specific gravity method.RESULTSThe active MMP-9 in the systemic circulation was significantly increased in the comatose FHF as compared to the precoma FHF and control animals (6.5 ± 0.7 versus 4.6 ± 0.4 versus 2.6 ± 0.5 pg/μg, respectively; P < 0.05). Conversely, TIMP-1 was steadily decreased in precoma and coma FHF rats by 35% and 45%, respectively. Blocking MMP-9 activity with GM6001 significantly attenuated brain extravasation and edema in rats with FHF.CONCLUSIONSOur study strongly supports that the perturbation of decreased TIMP-1 and increased MMP-9 contributes to the pathogenesis of brain edema in FHF. Our findings present a potential therapeutic approach to effectively increase the window of opportunity for life-saving liver transplantation.