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

• Published in: The FASEB journal Vol. 22; no. 8; pp. 2723 - 2733
• Main Authors: Hartz, Anika M.S, Bauer, Björn, Block, Michelle L, Hong, Jau-Shyong, Miller, David S
• Format: Journal Article
• Language: English
• Published: United States The Federation of American Societies for Experimental Biology 01.08.2008
• Subjects: Animals; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Blood-Brain Barrier - drug effects; Blood-Brain Barrier - physiology; Capillaries - drug effects; Capillaries - metabolism; Cytokines - biosynthesis; Enzyme Inhibitors - pharmacology; Free Radical Scavengers - pharmacology; In Vitro Techniques; Inflammation Mediators - metabolism; Male; Membrane Glycoproteins - antagonists & inhibitors; Membrane Glycoproteins - genetics; Mice; Mice, Inbred C57BL; Mice, Knockout; NADPH Oxidase 2; NADPH Oxidases - antagonists & inhibitors; NADPH Oxidases - genetics; Oxidative Stress - drug effects; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species - metabolism; Receptors, Tumor Necrosis Factor, Type I - deficiency; Receptors, Tumor Necrosis Factor, Type I - genetics; Signal Transduction - drug effects; Up-Regulation - drug effects; Vehicle Emissions - toxicity
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.08-106997

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 EC₅₀ was ~5 μg/ml). Up-regulation 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-α (TNF-α) 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-κB, 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.--Hartz, A. M. S., Bauer, B., Block, M. L., Hong, J.-S., Miller, D.-S. Diesel exhaust particles induce oxidative stress, proinflammatory signaling, and P-glycoprotein up-regulation at the blood-brain barrier.