Diesel exhaust particles induce oxidative stress, proinflammatory signaling, and P-glycoprotein up-regulation at the blood-brain barrier

被引:210
作者
Hartz, Anika M. S. [1 ,2 ]
Bauer, Bjoern [1 ,3 ]
Block, Michelle L. [1 ,4 ]
Hong, Jau-Shyong [1 ]
Miller, David S. [1 ]
机构
[1] NIEHS, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA
[2] Univ Minnesota, Sch Med, Dept Biochem & Mol Biol, Duluth, MN 55812 USA
[3] Univ Minnesota, Coll Pharm, Dept Pharmaceut Sci, Duluth, MN 55812 USA
[4] Virginia Commonwealth Univ, Dept Anat & Neurobiol, Richmond, VA USA
关键词
NADPH oxidase; reactive oxygen species; TNF-alpha; TNF-receptor; 1; JNK;
D O I
10.1096/fj.08-106997
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Here, we report that diesel exhaust particles (DEPs), a major constituent of urban air pollution, affect blood-brain barrier function at the tissue, cellular, and molecular levels. Isolated rat brain capillaries exposed to DEPs showed increased expression and transport activity of the key drug efflux transporter, P-glycoprotein (6 h EC(50) was similar to 5 mu g/ml). Upregulation of P-glycoprotein was abolished by blocking transcription or protein synthesis. Inhibition of NADPH oxidase or pretreatment of capillaries with radical scavengers ameliorated DEP-induced P-glycoprotein up-regulation, indicating a role for reactive oxygen species in signaling. DEP exposure also increased brain capillary tumor necrosis factor-alpha (TNF-alpha) levels. DEP-induced P-glycoprotein up-regulation was abolished when TNF-receptor 1 (TNF-R1) was blocked and was not evident in experiments with capillaries from TNF-R1 knockout mice. Inhibition of JNK, but not NF-kappa B, blocked DEP-induced P-glycoprotein up-regulation, indicating a role for AP-1 in the signaling pathway. Consistent with this, DEPs increased phosphorylation of c-jun. Together, our results show for the first time that a component of air pollution, DEPs, alters blood-brain barrier function through oxidative stress and proinflammatory cytokine production. These experiments disclose a novel blood-brain barrier signaling pathway, with clear implications for environmental toxicology, CNS pathology, and the pharmacotherapy of CNS disorders.
引用
收藏
页码:2723 / 2733
页数:11
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