Reactive Oxygen Species- and Nitric Oxide-Mediated Lung Inflammation and Mitochondrial Dysfunction in Wild-Type and iNOS-Deficient Mice Exposed to Diesel Exhaust Particles

• Published in: Journal of Toxicology and Environmental Health, Part A Vol. 72; no. 8; pp. 560 - 570
• Main Authors: Zhao, Hongwen, Ma, Joseph K., Barger, Mark W., Mercer, Robert R., Millecchia, Lyndell, Schwegler-Berry, Diane, Castranova, Vince, Ma, Jane Y.
• Format: Journal Article
• Language: English
• Published: England Taylor & Francis Group 01.01.2009; Taylor & Francis Ltd
• Subjects: Albumin; Alveoli; Animals; Biological Availability; black carbon; Bronchoalveolar Lavage Fluid - cytology; Bronchus; Carbon; Cells, Cultured; Comet Assay; Comparative analysis; Cytokines; Cytokines - metabolism; Diesel; Diesel engines; DNA; DNA Damage; Exhaust emissions; Exhausts; Infiltration; Inflammation; Injuries; Interleukin 10; Interleukin 12; L-Lactate dehydrogenase; L-Lactate Dehydrogenase - metabolism; Leukocytes (neutrophilic); Lipopolysaccharides; Lung; Macrophages; Mice; Mice, Knockout; Microscopy, Confocal; Microscopy, Electron, Transmission; Mitochondria; Mitochondrial Diseases - chemically induced; Mitochondrial Diseases - pathology; Nitric oxide; Nitric Oxide - toxicity; Nitric Oxide Synthase Type II - genetics; Nitric Oxide Synthase Type II - physiology; Nitric-oxide synthase; Oxygen; Particulate Matter - pharmacokinetics; Particulate Matter - toxicity; Particulates; Pharynx; Pneumonia - chemically induced; Pneumonia - pathology; Pulmonary Alveoli - pathology; Reactive oxygen species; Reactive Oxygen Species - toxicity; Rodents; Stress; Studies; Vehicle Emissions - toxicity
• ISSN: 1528-7394; 1087-2620; 2381-3504
• DOI: 10.1080/15287390802706330

Pulmonary responses to diesel exhaust particles (DEP) exposure are mediated through enhanced production of reactive oxygen species (ROS) and nitric oxide (NO) by alveolar macrophages (AM). The current study examined the differential roles of ROS and NO in DEP-induced lung injury using C57B/6J wild-type (WT) and inducible NO synthase knockout (iNOS KO) mice. Mice exposed by pharyngeal aspiration to DEP or carbon black particles (CB) (35 mg/kg) showed an inflammatory profile that included neutrophil infiltration, increased lactate dehydrogenase (LDH) activity, and elevated albumin content in bronchoalveolar lavage fluid (BALF) at 1, 3, and 7 d postexposure. The organic extract of DEP (DEPE) did not induce an inflammatory response. Comparing WT to iNOS KO mice, the results show that NO enhanced DEP-induced neutrophils infiltration and plasma albumin content in BALF and upregulated the production of the pro-inflammatory cytokine interleukin 12 (IL-12) by AM. DEP-exposed AM from iNOS KO mice displayed diminished production of IL-12 and, in response to ex vivo lipopolysaccharide (LPS) challenge, decreased production of IL-12 but increased production of IL-10 when compared to cells from WT mice. DEP, CB, but not DEPE, induced DNA damage and mitochondria dysfunction in AM, however, that is independent of cellular production of NO. These results demonstrate that DEP-induced immune/inflammatory responses in mice are regulated by both ROS- and NO-mediated pathways. NO did not affect ROS-mediated mitochondrial dysfunction and DNA damage but upregulated IL-12 and provided a counterbalance to the ROS-mediated adaptive stress response that downregulates IL-12 and upregulates IL-10.