Cerebral ischemia induces microvascular pro-inflammatory cytokine expression via the MEK/ERK pathway.
Cerebral ischemia induces microvascular pro-inflammatory cytokine expression via the MEK/ERK pathway.
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DOI：
10.1186/1742-2094-7-14
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发表时间：
2010-02-26
影响因子：
9.3
通讯作者：
Edvinsson L
中科院分区：
文献类型：
--
作者：
Maddahi A;Edvinsson L
大脑中动脉壁（MCA）闭塞引起的脑缺血导致脑血管内皮素和血管紧张素受体表达增加，丝裂原活化蛋白激酶（MAPK）通路活化，以及梗死区域局部脑血流量减少和促炎介质水平升高。在这项研究中，我们假设用特异性MEK 1/2抑制剂（U 0126）阻断转录或联合受体阻断剂抑制脑血管炎症反应将减少梗死面积并改善神经评分。大鼠大脑中动脉闭塞（MCAO）2小时，然后再灌注48小时。研究了两组治疗动物;（i）一组在闭塞后0、6或12小时开始接受特异性MEK 12抑制剂（U 0126）的腹膜内施用，和（ii）第二组接受两种特异性受体拮抗剂（血管紧张素AT 1受体抑制剂坎地沙坦和内皮素ETA受体拮抗剂ZD 1611的组合），在闭塞后立即给药。取大脑中动脉、微血管及脑组织，采用免疫组织化学方法检测肿瘤坏死因子-α（TNF-α）、白细胞介素-1 β（IL-1 β）、白细胞介素-6（IL-6）、诱导型一氧化氮合酶（iNOS）及磷酸化ERK 1/2、p38和JNK的表达。我们观察到脑梗死体积为总脑体积的25 ± 2%，MCAO后2天神经功能下降，随后再循环48小时。免疫组化显示缺血MCA平滑肌细胞和相关脑内微血管中TNF-α、IL-1 β、IL-6和iNOS表达增强，磷酸化ERK 1/2水平升高。U 0126在缺血后0或6 h腹腔内给药，而不是在1/2 h，可减少梗死体积（分别为11.7 ± 2%和15 ± 3%），使pERK 1/2恢复正常，并阻止TNF-α、IL-1 β、IL-6和iNOS表达的升高。联合抑制血管紧张素AT_1和内皮素ETA受体可减少脑损伤体积（12.3 ± 3; P < 0.05），但仅轻微降低MCAO诱导的iNOS和细胞因子的表达。本研究表明，局灶性脑缺血后微血管TNF-α、IL-1 β、IL-6和iNOS的表达增加，并表明这种表达通过MEK/ERK途径进行转录调节。
Cerebral ischemia from middle cerebral artery wall (MCA) occlusion results in increased expression of cerebrovascular endothelin and angiotensin receptors and activation of the mitogen-activated protein kinase (MAPK) pathway, as well as reduced local cerebral blood flow and increased levels of pro-inflammatory mediators in the infarct region. In this study, we hypothesised that inhibition of the cerebrovascular inflammatory reaction with a specific MEK1/2 inhibitor (U0126) to block transcription or a combined receptor blockade would reduce infarct size and improve neurological score. Rats were subjected to a 2-hours middle cerebral artery occlusion (MCAO) followed by reperfusion for 48 hours. Two groups of treated animals were studied; (i) one group received intraperitoneal administration of a specific MEK1/2 inhibitor (U0126) starting at 0, 6, or 12 hours after the occlusion, and (ii) a second group received two specific receptor antagonists (a combination of the angiotensin AT1 receptor inhibitor Candesartan and the endothelin ETA receptor antagonist ZD1611), given immediately after occlusion. The middle cerebral arteries, microvessels and brain tissue were harvested; and the expressions of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), interleukin-6 (IL-6), inducible nitric oxide synthase (iNOS) and phosphorylated ERK1/2, p38 and JNK were analysed using immunohistochemistry. We observed an infarct volume of 25 ± 2% of total brain volume, and reduced neurological function 2 days after MCAO followed by 48 hours of recirculation. Immunohistochemistry revealed enhanced expression of TNF-α, IL-1ß, IL-6 and iNOS, as well as elevated levels of phosphorylated ERK1/2 in smooth muscle cells of ischemic MCA and in associated intracerebral microvessels. U0126, given intraperitoneal at zero or 6 hours after the ischemic event, but not at 12 hours, reduced the infarct volume (11.7 ± 2% and 15 ± 3%, respectively), normalized pERK1/2, and prevented elevation of the expressions of TNF-α IL-1ß, IL-6 and iNOS. Combined inhibition of angiotensin AT1 and endothelin ETA receptors decreased the volume of brain damaged (12.3 ± 3; P < 0.05) but only slightly reduced MCAO-induced enhanced expression of iNOS and cytokines The present study shows elevated microvascular expression of TNF-α, IL-1ß, IL-6 and iNOS following focal ischemia, and shows that this expression is transcriptionally regulated via the MEK/ERK pathway.
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影响因子：
4.8
作者：
MENZIES, SA;SMITH, RR;BETZ, AL
通讯作者：
BETZ, AL
DOI：
10.1152/ajpheart.00857.2007
发表时间：
2007-12-01
影响因子：
4.8
作者：
Ansar, Saema;Vikman, Petter;Edvinsson, Lars
通讯作者：
Edvinsson, Lars
影响因子：
8.3
作者：
BEDERSON, JB;PITTS, LH;BARTKOWSKI, H
通讯作者：
BARTKOWSKI, H
影响因子：
2
作者：
Henriksson, Marie;Stenman, Emelie;Edvinsson, Lars
通讯作者：
Edvinsson, Lars
影响因子：
2.4
作者：
Maddahi, Aida;Edvinsson, Lars
通讯作者：
Edvinsson, Lars