Reactive oxygen species- and nitric oxide-mediated lung inflammation and mitochondrial dysfunction in wild-type and iNOS-deficient mice exposed to diesel exhaust particles.
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.
Zhao
Hongwen
H
Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, West Virginia 26505-2888, USA.
Ma
Joseph K
JK
Barger
Mark W
MW
Mercer
Robert R
RR
Millecchia
Lyndell
L
Schwegler-Berry
Diane
D
Castranova
Vince
V
Ma
Jane Y
JY
D000818:Animals; D001682:Biological Availability; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002478:Cells, Cultured; D020552:Comet Assay; D016207:Cytokines / Q000378:metabolism; D004249:DNA Damage; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D028361:Mitochondrial Diseases / Q000139:chemically induced* / Q000473:pathology; D009569:Nitric Oxide / Q000633:toxicity*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000502:physiology*; D052638:Particulate Matter / Q000493:pharmacokinetics / Q000633:toxicity*; D011014:Pneumonia / Q000139:chemically induced* / Q000473:pathology; D011650:Pulmonary Alveoli / Q000473:pathology; D017382:Reactive Oxygen Species / Q000633:toxicity*; D001335:Vehicle Emissions / Q000633:toxicity*
D016207:Cytokines; D052638:Particulate Matter; D017382:Reactive Oxygen Species; D001335:Vehicle Emissions; D009569:Nitric Oxide; D007770:L-Lactate Dehydrogenase; D052247:Nitric Oxide Synthase Type II