Studies have shown that diesel exhaust particle (DEP) exposure induces lung inflammation and injury, which are mediated through reactive oxygen/nitrogen species (ROS/RNS) generation by alveolar macrophages (AM). The present study examines the differential roles of DEP particle core, represented by carbon black (CB), and DEP organic extract (DEPE) in ROS generation and nitric oxide (NO) production through inducible nitric oxide synthase (iNOS)-related cellular responses using C57B/6J wild type (WT) and iNOS knockout (iNOS KO) mice. Mice (8-10 weeks old) were exposed to saline, CB (35 mg/kg), or DEPE by aspiration and sacrificed at 1, 3 and 7 days post-exposure. AM were isolated by bronchoalveolar lavage (BAL). CB, but not DEPE, significantly induced neutrophil infiltration in both WT and iNOS KO mice. CB-exposed AM also exhibited enhanced hydrogen peroxide and superoxide anion generation, peaking at 3 d post exposure. This CB-induced oxidative stress was correlated with mitochondrial damage, involving reduction of mitochondrial mass and membrane potential in AM from both WT and iNOS KO mice. These results suggest that NO did not play a major role in modifying CB-induced mitochondrial damage in AM. In contrast, the organic component of DEP, DEPE, only slightly induced ROS generation and did not significantly affect mitochondrial function in AM. Measurement of macrophage ATP content showed that CB and DEPE did not significantly affect ATP levels in either WT or iNOS KO mice. This is due to the fact that mitochondrial oxidative phosphorylation pathway is not the major energy source for AM. In summary, this study shows that CB, but not DEPE, plays a major role in DEP-induced pulmonary inflammation and AM mitochondrial dysfunction by a mechanism independent of NO.
Bronchial-asthma; Metal-compounds; Respirable-dust; Particulate-dust; Alveolar-cells; Animal-studies; Respiratory-system-disorders; Pulmonary-system-disorders; Aerosols; Cell-alteration; Cell-damage; Cell-transformation; Cell-metabolism; Cellular-reactions; Cellular-respiration; Diesel-emissions; Diesel-exhausts
The Toxicologist. Society of Toxicology 46th Annual Meeting and ToxExpo, March 25-29, 2007, Charlotte, North Carolina