摘要目的 研究细胞外信号调节激酶1/2(extracellular signal-regulated kinase1/2,ERK1/2)通路抑制剂U0126对蛛网膜下腔出血(subarachnoid hemorrhage,SAH)大鼠脑组织基质金属蛋白酶-9(matrix metalloproteinase-9,MMP-9)表达的影响,探讨ERK1/2与MMP-9在SAH血脑屏障(blood-brain barrier,BBB)损伤和脑水肿中的作用机制.方法 72只雄性Sprague-Dawley大鼠随机分为SAH模型组、假手术组、U0126干预组和赋形剂组.自体血枕大池单次注入法制作SAH模型.干湿重法检测脑组织水含量以评价脑水肿,伊文思蓝渗出法评价BBB通透性,免疫组化法检测MMP-9和磷酸化ERK1/2表达.结果 假手术组磷酸化ERK1/2和MMP-9表达水平较低,SAH 24 h后二者表达上调,脑组织水含量和伊文思蓝含量亦增高,给予U0126可降低ERK1/2磷酸化和MMP-9表达水平,改善BBB通透性,减轻脑水肿.结论 MMP-9参与了SAH早期BBB损伤和脑水肿的病理生理学过程,ERK1/2通路可能在MMP-9表达中起着关键作用,U0126可通过抑制ERK1/2磷酸化降低MMP-9表达从而保护BBB,减轻SAH后脑水肿.

abstractsObjective To study the effect of extracellular signal-regulated kinase1/2 (ERK1/2)inhibitor U0126 on matrix metalloproteinase-9(MMP-9)in brain tissue after subarachnoid hemorrhage(SAH)in rats and to investigate the action mechanisms of ERK1/2 and M M P-9 in blood-brain barrier(BBB)injury and brain edema after SAH.Methods Seventy-two male Sprague-Dawley rats were randomly divided into four groups:SAH model,sham operation,U0126 intervention,and vehicle groups.A SAH model was induced by injection of autologous blood into cisterna magna once.The dry-wet weight method was used to detected brain tissue water content in order to evaluate cerebral edema.BBB permeability was evaluated by the Evans blue extravasation method.The immunohistochemical method was used to detect the expression of MMP-9 and phosphorylated ERK1/2.Results The expression of phosphorylated ERK1/2 and MMP-9 was lower in the sham operation group.The expression of both was up regulated at 24 hours after SAH.The brain water content and Evans blue content also increased.U0126 treatment decreased the phosphorylation of ERK1/2 and the expression of MMP-9,improved the BBB permeability,and alleviated brain edema.Conclusions MMP-9 is involved in the pathophysiological processes of early BBB injury and brain edema aft er SAH.ERK1/2 pathway may play a vital role in the expression of MMP-9.U0126 may protect BBB and reduce brain edema after SAH by inhibiting the phosphorylation of ERK1/2.