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Induction of oxidative lung injury and cellular responses by diesel exhaust particles in wild type and inducible nitric oxide synthase-deficient mice.

Ma-JY; Barger M; Ma-JK; Castranova V

Toxicologist 2006 Mar; 90(1):98

https://www.toxicology.org/pubs/docs/Tox/2006Tox.pdf

20029838

Studies have shown that diesel exhaust particle (DEP)-induced lung injury and immune deficiencies stem from enhanced production of reactive oxygen/nitrogen species by alveolar macrophages (AM). The present study examines the role of nitric oxide (NO), produced through the inducible nitric oxide synthase (iNOS), in DEP-induced lung responses using C57B/6J wild type (WT) and iNOS knockout (iNOS KO) mice. Mice (8-10 weeks) were exposed to saline or DEP (35 mg/kg) by aspiration and sacrificed at 1 and 3 days post-exposure. AM were isolated by bronchoalveolar lavage (BAL). DEP induced an inflammatory profile, including neutrophil infiltration, increased lactate dehydrogenase activity, and elevated albumin content in BAL fluid in both WT and iNOS KO mice. However, there was a significantly lowered neutrophil infiltration (at 1 day post-exposure) and albumin content (at 1 and 3 days post exposure) in iNOS KO mice compared to the WT, suggesting a role of NO in DEP-induced inflammatory injury. DEP exposure elicited significant mitochondria damage, the major source of intracellular oxidant generation, in AM from WT as well as iNOS KO mice, suggesting that NO did not play a major role in DEP-induced mitochondria damage. In response to ex vivo LPS and IFN-y challenge, AM from DEP-exposed WT mice showed a time-dependent increase of IL-12 and IL-10 production compared to control. AM from the iNOS KO mice showed a lowered production of IL-12, yet increased IL-10 production at 3 days post-exposure. This suggests that NO has a sustained effect on cellular responses to DEP, increasing IL-12 while suppressing IL-10 production by AM. In summary, this study shows that NO mediates DEP-induced inflammatory lung injury and alters the balance of pro- and anti-inflammatory cytokines in the lung.

Lung-disorders; Injuries; Cellular-reactions; Diesel-exhausts; Laboratory-animals; Animals; Animal-studies; Exposure-levels; Exposure-assessment; Respiratory-system-disorders; Pulmonary-system-disorders

10102-43-9

20060301

Abstract

2006

1

1096-6080

HELD

The Toxicologist. Society of Toxicology 45th Annual Meeting and ToxExpo, March 5-9, 2006, San Diego, California

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