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ABSTRACT: Background
Air pollution is linked to central nervous system disease, but the mechanisms responsible are poorly understood.Objectives
Here, we sought to address the brain-region-specific effects of diesel exhaust (DE) and key cellular mechanisms underlying DE-induced microglia activation, neuroinflammation, and dopaminergic (DA) neurotoxicity.Methods
Rats were exposed to DE (2.0, 0.5, and 0 mg/m3) by inhalation over 4 weeks or as a single intratracheal administration of DE particles (DEP; 20 mg/kg). Primary neuron-glia cultures and the HAPI (highly aggressively proliferating immortalized) microglial cell line were used to explore cellular mechanisms.Results
Rats exposed to DE by inhalation demonstrated elevated levels of whole-brain IL-6 (interleukin-6) protein, nitrated proteins, and IBA-1 (ionized calcium-binding adaptor molecule 1) protein (microglial marker), indicating generalized neuroinflammation. Analysis by brain region revealed that DE increased TNF? (tumor necrosis factor-?), IL-1?, IL-6, MIP-1? (macrophage inflammatory protein-1?) RAGE (receptor for advanced glycation end products), fractalkine, and the IBA-1 microglial marker in most regions tested, with the midbrain showing the greatest DE response. Intratracheal administration of DEP increased microglial IBA-1 staining in the substantia nigra and elevated both serum and whole-brain TNF? at 6 hr posttreatment. Although DEP alone failed to cause the production of cytokines and chemokines, DEP (5 ?g/mL) pretreatment followed by lipopolysaccharide (2.5 ng/mL) in vitro synergistically amplified nitric oxide production, TNF? release, and DA neurotoxicity. Pretreatment with fractalkine (50 pg/mL) in vitro ameliorated DEP (50 ?g/mL)-induced microglial hydrogen peroxide production and DA neurotoxicity.Conclusions
Together, these findings reveal complex, interacting mechanisms responsible for how air pollution may cause neuroinflammation and DA neurotoxicity.
SUBMITTER: Levesque S
PROVIDER: S-EPMC3237351 | biostudies-literature | 2011 Aug
REPOSITORIES: biostudies-literature
Environmental health perspectives 20110511 8
<h4>Background</h4>Air pollution is linked to central nervous system disease, but the mechanisms responsible are poorly understood.<h4>Objectives</h4>Here, we sought to address the brain-region-specific effects of diesel exhaust (DE) and key cellular mechanisms underlying DE-induced microglia activation, neuroinflammation, and dopaminergic (DA) neurotoxicity.<h4>Methods</h4>Rats were exposed to DE (2.0, 0.5, and 0 mg/m3) by inhalation over 4 weeks or as a single intratracheal administration of D ...[more]