Inhaled ultrafine particulate matter affects CNS inflammatory processes and may act via MAP kinase signaling pathways
Introduction
Numerous epidemiological and toxicological studies demonstrate that exposure to ambient particulate matter (PM) is associated with increased cardiopulmonary morbidity and mortality. The brain is another potential target for adverse effects after inhalation of particulate matter. It is possible that inhaled, nanosized particles might penetrate the lungs and be deposited in extra-pulmonary tissues (Kreyling et al., 2002, Oberdorster et al., 2002). There is also evidence that inhaled particles can reach the brain, either by transport along the olfactory nerve or possibly by penetration of a blood–brain barrier that is compromised by systemic effects of PM (Oberdorster et al., 2002). The activities of signaling pathways that mediate inflammatory responses can be up-regulated in the brains of mice exposed to concentrated ambient particles (CAPs) derived from areas near primary emission sources (Campbell et al., 2005). In addition biomarkers of oxidative stress and tissue injury in brain are observed at higher concentrations in mice after exposure to CAPs for as long as 2-week post-exposure (Campbell et al., 2005).
In this study we examined the association between exposure to PM and adverse CNS effects in apolipoprotein E knockout (ApoE−/−) mice using two concentrations of ultrafine particles (UFP). This mutant develops hypercholesterolemia and has been used as a model for atherosclerosis (Coleman et al., 2006, Zadelaar et al., 2007). The cardiovascular system of the ApoE−/− has been previously found to be especially susceptible to CAPs both in the fine (Sun et al., 2005) and ultrafine size ranges (Araujo et al., 2008). Recently, Hsu et al., 2008 determined that UFP exhibited greater upregulation of inflammatory mediators than did fine particles (FP), which is why we decided to confirm and extend these studies by doing a dose-related experiment.
This model is also of utility in the study of age-related neurological disorders. ApoE can decrease microglial activity and TNF-α secretion thus attenuating inflammatory responses in the brain (Lynch et al., 2001). Impairments in cognitive performance have been observed in aged apolipoprotein E (apoE)-deficient mice, and apoE epsilon 4 allele is a human risk factor in Alzheimer's disease (AD) (Law et al., 2003). ApoE is also the major cholesterol transporter in the brain and human carriers of the e4 allele of apoE are at a higher risk of developing Alzheimer's disease (Zerbinatti and Bu, 2005).
It is also known that the brain of the apoE null mouse is more susceptible to oxidative stress than is the wild type background strain mouse. In the hippocampus, the absence of apoE has a clear impact on the oxidant/antioxidant status. Endogenous level of thiobarbituric acid-reactive substances (TBARS) was found to be markedly elevated whereas level of alpha-tocopherol was decreased in APOE-deficient mice compared to wild type mice (Ramassamy et al., 2000, Ramassamy et al., 2001). This might be mediated via activation of glial cells. Compared to wild type mice, glial cells cultured from apoE knockout mice exhibit an enhanced production of several pro-inflammatory markers in response to treatment with amyloid-beta and other activating stimuli (LaDu et al., 2001). ApoE deficiency also accelerates the age-related decline in efficacy of the blood–brain barrier (Hafezi-Moghadam et al., 2007). Thus the ApoE deficiency found in the ApoE−/− mutant may result in increased susceptibility to cerebral inflammation, especially since this mutant exhibits chronic systemic inflammation (Grainger et al., 2004).
Section snippets
Animals and exposure conditions
C57BL/6J 6-week-old male ApoE null mice were obtained from Jackson Laboratory (Bar Harbor, ME) fed a normal chow diet. Food and water were administered ad libitum. All mice were initially housed in the UCLA campus animal facility under specific pathogen-free conditions. Mice were transported to a mobile laboratory located in the downtown of Los Angeles, close to interstate freeway I-10 (∼200 m). In the mobile laboratory, mice were housed in a Hazelton chamber (Brown and Moss, 1981) provided with
Activation of NF-κB and AP-1
In cortical tissue, levels of AP-1 that had been translocated to the cell nucleus and thus were in the activated form, were increased in mice exposed to CAPs. This response was dose-dependent in that it was greater in the group receiving the more concentrated (CAP15) exposure than in the air-exposed or low concentration group (Fig. 1a). Cortical levels of activated NF-κB also were significantly increased only in the group of mice receiving the most concentrated CAP15 (Fig. 1b).
Changes in GFAP levels
Increases in the
Discussion
In an earlier report, we described an increase of levels of cytokines interleukin-1 alpha (IL-1α) and tumor necrosis factor alpha (TNF-α) in the cortex of mice exposed to airborne particulate matter (Campbell et al., 2005). These cytokines are associated with inflammatory processes. The current report describes the upstream events which are likely to underlie such increases in markers of inflammation. Both transcription factors AP-1 and NF-κB were activated in a dose-related fashion and are
Conflict of interest
None.
Acknowledgements
This work was supported in part by grants from the National Institutes of Health ES 7992 and AG 16794 to S.C.B.; US EPA STAR Awards RD83241301 to the Southern California Particle Center and RD 8319520 to M.K.; the National Institute of Environmental Health Sciences ES13432 to A.N.
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