Plasminogen activator inhibitor-1 mitigates brain injury in a rat model of infection-sensitized neonatal hypoxia-ischemia.
Plasminogen activator inhibitor-1 mitigates brain injury in a rat model of infection-sensitized neonatal hypoxia-ischemia.
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DOI：
10.1093/cercor/bhs115
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发表时间：
2013-05
期刊：
影响因子：
3.7
通讯作者：
Dianer Yang;Yu-Yo Sun;Niza Nemkul;Jessica M. Baumann;A. Shereen;R. Dunn;M. Wills-Karp;D. Lawrence;D. Lindquist;C. Kuan
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文献类型：
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作者：
Dianer Yang;Yu-Yo Sun;Niza Nemkul;Jessica M. Baumann;A. Shereen;R. Dunn;M. Wills-Karp;D. Lawrence;D. Lindquist;C. Kuan
宫内感染可加重新生儿缺氧缺血性脑损伤，损害大脑皮质发育。本研究采用低剂量脂多糖（LPS）预暴露，然后单侧脑HI损伤7日龄大鼠，以研究致病机制。我们发现，LPS预暴露阻断HI诱导的组织型纤溶酶原激活剂（tPA）的蛋白水解活性，但显著增强NF-κB信号转导，小胶质细胞活化，并在新生儿脑中产生促炎细胞因子。值得注意的是，这些致病反应都被阻断了脑室内注射的纤溶酶原激活蛋白-1称为CPAI的稳定突变形式。同样，LPS预暴露放大，而CPAI治疗减轻HI诱导的血脑屏障损伤和脑组织损失，治疗窗口在LPS/HI损伤后4 h。CPAI还阻断脑内注射LPS后的小胶质细胞活化，这需要tPA的贡献，但不需要尿型纤溶酶原激活剂（uPA），如tPA缺失和uPA缺失小鼠中的实验所示。这些结果暗示非蛋白水解tPA活性在LPS/HI诱导的脑损伤和小胶质细胞活化。最后，尽管新生儿LPS/HI损伤，CPAI治疗仍保护接近正常的运动和白色物质发育。总之，由于CPAI阻断蛋白水解和非蛋白水解tPA神经毒性，因此它是有感染或无感染的新生儿HI损伤的有希望的治疗剂。
Intrauterine infection exacerbates neonatal hypoxic-ischemic (HI) brain injury and impairs the development of cerebral cortex. Here we used low-dose lipopolysaccharide (LPS) pre-exposure followed by unilateral cerebral HI insult in 7-day-old rats to study the pathogenic mechanisms. We found that LPS pre-exposure blocked the HI-induced proteolytic activity of tissue-type plasminogen activator (tPA), but significantly enhanced NF-κB signaling, microglia activation, and the production of pro-inflammatory cytokines in newborn brains. Remarkably, these pathogenic responses were all blocked by intracerebroventricular injection of a stable-mutant form of plasminogen activator protein-1 called CPAI. Similarly, LPS pre-exposure amplified, while CPAI therapy mitigated HI-induced blood-brain-barrier damage and the brain tissue loss with a therapeutic window at 4 h after the LPS/HI insult. The CPAI also blocks microglia activation following a brain injection of LPS, which requires the contribution by tPA, but not the urinary-type plasminogen activator (uPA), as shown by experiments in tPA-null and uPA-null mice. These results implicate the nonproteolytic tPA activity in LPS/HI-induced brain damage and microglia activation. Finally, the CPAI treatment protects near-normal motor and white matter development despite neonatal LPS/HI insult. Together, because CPAI blocks both proteolytic and nonproteolytic tPA neurotoxicity, it is a promising therapeutics of neonatal HI injury either with or without infection.