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Diesel exhaust particles induce oxidative stress, proinflammatory signaling, and P‐glycoprotein up‐regulation at the blood‐brain barrier
Author(s) -
Hartz Anika M. S.,
Bauer Björn,
Block Michelle L.,
Hong Jau-Shyong,
Miller David S.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.08-106997
Subject(s) - proinflammatory cytokine , oxidative stress , tumor necrosis factor alpha , blood–brain barrier , chemistry , reactive oxygen species , nadph oxidase , microbiology and biotechnology , cytokine , p glycoprotein , signal transduction , pharmacology , biochemistry , inflammation , biology , immunology , endocrinology , central nervous system , antibiotics , multiple drug resistance
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 ~5 μg/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‐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. FASEB J. 22, 2723–2733 (2008)