Cyclooxygenase-1 and -2 differentially modulate lipopolysaccharide-induced blood-brain barrier disruption through matrix metalloproteinase activity.
Cyclooxygenase-1 and -2 differentially modulate lipopolysaccharide-induced blood-brain barrier disruption through matrix metalloproteinase activity.
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DOI：
10.1038/jcbfm.2009.223
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发表时间：
2010-02
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环氧合酶（考克斯）-1和-2是先天性免疫应答的关键调节因子。我们最近证明，在脂多糖（LPS）诱导的先天性免疫激活过程中，促炎细胞因子和趋化因子的表达在考克斯-1 null（−/−）小鼠中减少，而在考克斯-2−/−小鼠中增加。由于趋化因子参与白细胞向炎症脑的募集，我们假设考克斯-1和考克斯-2缺失将响应于LPS而不同地调节血脑屏障（BBB）的通透性。在本研究中，使用定量磁共振成像，我们发现LPS诱导的BBB破坏在考克斯-2-/-与考克斯-2+/+小鼠中加剧。在LPS处理小鼠的海马和皮质中，考克斯-1−/−小鼠的基质金属蛋白酶（MMP）-3活性显著降低，而在考克斯-2−/−小鼠中，已知介导BBB破坏的MMP-9和MMP-3的活性均增加。LPS后，考克斯-2−/−与考克斯-2+/+小鼠的白细胞吸引趋化因子Cxcl 10、细胞间相互作用分子Icam-1、泛白细胞标记物Cd 45的脑mRNA表达增加，而考克斯-1−/−与考克斯-1+/+小鼠的Cxcl 10和Cd 45 mRNA表达降低。总之，这些结果表明，考克斯-2活性调节MMP-9和MMP-3活性，并且在Toll样受体4依赖性先天免疫激活期间维持BBB完整性是必需的。
Cyclooxygenases (COX) -1 and -2 are key regulators of innate immune responses. We recently demonstrated that the expression of pro-inflammatory cytokines and chemokines is reduced in COX-1 null (−/−), and increased in COX-2−/− mice compared with their respective wild-type controls during lipopolysaccacharide (LPS)-induced innate immune activation. As chemokines are involved in leukocyte recruitment into the inflamed brain, we hypothesized that COX-1 and COX-2 deletion will differentially modulate blood-brain barrier (BBB) permeability in response to LPS. In the present study, using quantitative magnetic resonance imaging, we found that LPS-induced BBB disruption was exacerbated in COX-2−/− versus COX-2+/+ mice. In the hippocampus and cortex of LPS-treated mice, matrix metalloproteinase (MMP)-3 activity was significantly decreased in COX-1−/− mice, whereas in COX-2−/− mice the activity of both MMP-9 and MMP-3, known to mediate BBB breakdown, was increased. Brain mRNA expression of the leukocyte attracting chemokine Cxcl10, the intercellular interaction molecule Icam-1, the pan-leukocyte marker Cd45 was increased in COX-2−/− vs. COX-2+/+ mice, whereas Cxcl10 and Cd45 mRNA expression was decreased in COX-1−/− vs. COX-1+/+ mice after LPS. Altogether, these results indicate that COX-2 activity modulates MMP-9 and-3 activities and is necessary to maintain BBB integrity during toll-like receptor 4-dependent innate immune activation.
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影响因子：
9.3
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