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目的探讨溶血磷脂酸(LPA)对血脑屏障(BBB)通透性的影响及其可能机制。方法向SD大鼠右侧基底节区立体定向注射LPA或LPA+苏拉明(L+S),用伊文思蓝(EB)作为示踪剂定量测定不同时间点BBB通透性,免疫组织化学技术检测基质金属蛋白酶9(MMP-9)表达的变化,并应用透射电镜观察BBB超微结构的改变。结果LPA脑内注射后6 h同侧基底节区BBB对EB的通透性开始增加,24 h通透性达最大。到48 h通透性渐减,与对照组相同时间点比较差异有显著性(P＜0．01)。L+S脑内注射组各时间点与LPA组相应时间点相比通透性明显下降(P＜0．05)。MMP-9免疫阳性细胞主要为血管内皮细胞,LPA脑内注射后6 h免疫阳性血管数增多,于24 h表达最多,48 h逐渐减少,L+S组各时间点与之分别相比差异具有显著性(P＜0．01)。透射电镜观察到LPA组BBB基底膜粗糙、断裂,星形胶质细胞足突明显肿胀,血管周围间隙增宽等,然而L+S组上述改变不明显。结论LPA能诱导BBB通透性的增加,其可能机制为LPA受体介导的内皮细胞高表达MMP-9,降解基底膜。
Objective To investigate the effect of lysophosphatidic acid (LPA) on the permeability of blood-brain barrier (BBB) and its possible mechanism. Methods LPA or LPA + suramin (L + S) was stereotactically injected into the right basal ganglia of SD rats. Evans blue (EB) was used as a tracer to quantitatively determine the permeability of BBB at different time points. Immunohistochemistry The expression of matrix metalloproteinase 9 (MMP-9) was detected and the ultrastructure of BBB was observed by transmission electron microscope. Results The permeability of BBB in ipsilateral basal ganglia BBB began to increase at 6 h after intracerebral LPA injection, and reached the maximum at 24 h. The permeability decreased gradually at 48 h, which was significantly different from the control group at the same time point (P <0.01). Compared with LPA group, the permeability of L + S group was significantly decreased at each time point (P <0.05). The positive cells of MMP-9 immunoreactive cells were mainly vascular endothelial cells. The numbers of positive immunoreactive blood vessels at 6 h after intracerebral LPA injection increased at 24 h and decreased gradually at 48 h after injection of LPA Significance (P <0.01). Transmission electron microscopy showed that the basement membrane of BBB in LPA group was rough and broken, the astrocyte foot process was obviously swollen and the perivascular space was widened. However, the above changes in L + S group were not obvious. Conclusion LPA can induce the increase of BBB permeability. The possible mechanism is that LPA receptor-mediated endothelial cell expresses MMP-9 and degrades the basement membrane.