Tang Jiping, Liu Jun, Zhou Changman, Alexander J Steven, Nanda Anil, Granger D Neil, Zhang John H
Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport 33932, USA.
J Cereb Blood Flow Metab. 2004 Oct;24(10):1133-45. doi: 10.1097/01.WCB.0000135593.05952.DE.
Matrix metalloproteinase-9 (MMP-9) participates in the disregulation of blood-brain barrier during hemorrhagic transformation, and exacerbates brain injury after cerebral ischemia. However, the consequences of long-term inhibition or deficiency of MMP-9 activity (which might affect normal collagen or matrix homeostasis) remains to be determined. The authors investigated how MMP-9 gene deficiency enhances hemorrhage and increases mortality and neurologic deficits in a collagenase-induced intracerebral hemorrhage (ICH) model in MMP-9-knockout mice. MMP-9-knockout and corresponding wild-type mice at 20 to 35 weeks were used to model an aged population (because advanced age is a significant risk factor in human ICH). Collagenase VII-S (0.5 microL, 0.075 U) was injected into the right basal ganglia in mice and mortality, neurologic deficits, brain edema, and hemorrhage size measured. In addition, MMP-9 activity, brain collagen content, blood coagulation, cerebral arterial structure, and expressions of several MMPs were examined. Increased hemorrhage and brain edema that correlated with higher mortality and neurologic deficits were found in MMP-9-knockout mice. No apparent structural changes were observed in cerebral arteries, even though brain collagen content was reduced in MMP-9-knockout mice. MMP-9-knockout mice did exhibit an enhanced expression of MMP-2 and MMP-3 in response to ICH. The results indicate that a deficiency of MMP-9 gene in mutant mice increases collagenase-induced hemorrhage and the resulting brain injury. The intriguing relationship between MMP-9 deficiency and collagenase-induced ICH may reflect the reduction in collagen content and an enhanced expression of MMP-2 and MMP-3.
基质金属蛋白酶-9（MMP-9）在出血性转化过程中参与血脑屏障的失调，并加重脑缺血后的脑损伤。然而，MMP-9活性长期抑制或缺乏的后果（这可能会影响正常的胶原蛋白或基质稳态）仍有待确定。作者在MMP-9基因敲除小鼠的胶原酶诱导脑出血（ICH）模型中研究了MMP-9基因缺陷如何加重出血、增加死亡率和神经功能缺损。使用20至35周龄的MMP-9基因敲除小鼠和相应的野生型小鼠来模拟老年人群（因为高龄是人类ICH的一个重要危险因素）。将胶原酶VII-S（0.5微升，0.075单位）注射到小鼠右侧基底神经节，测量死亡率、神经功能缺损、脑水肿和出血大小。此外，检测了MMP-9活性、脑胶原蛋白含量、凝血、脑动脉结构以及几种MMP的表达。在MMP-9基因敲除小鼠中发现出血和脑水肿增加，这与更高的死亡率和神经功能缺损相关。尽管MMP-9基因敲除小鼠的脑胶原蛋白含量降低，但在脑动脉中未观察到明显的结构变化。MMP-9基因敲除小鼠在ICH后确实表现出MMP-2和MMP-3表达增强。结果表明，突变小鼠中MMP-9基因的缺乏增加了胶原酶诱导的出血和由此导致的脑损伤。MMP-9缺乏与胶原酶诱导的ICH之间的有趣关系可能反映了胶原蛋白含量的减少以及MMP-2和MMP-3表达的增强。
