Cooperation of the Inducible Nitric Oxide Synthase and Cytochrome P450 1A1 in Mediating Lung Inflammation and Mutagenicity Induced by Diesel Exhaust Particles

Diesel exhaust particles (DEPs) have been shown to activate oxidant generation by alveolar macrophages (AMs), alter xenobiotic metabolic pathways, and modify the balance of proantiinflammatory cytokines. In this study we investigated the role of nitric oxide (NO) in DEP-mediated and DEP organic extr...

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Bibliographic Details
Published in:Environmental health perspectives 2006-08, Vol.114 (8), p.1253-1258
Main Authors: Zhao, Hongwen, Barger, Mark W., Joseph K. H. Ma, Castranova, Vincent, Jane Y. C. Ma
Format: Article
Language:English
Subjects:
Air Pollutants - toxicity
Animals
Cells, Cultured
Cytochrome P-450 CYP1A1 - biosynthesis
Cytochrome P-450 CYP1A1 - metabolism
Cytochrome P-450 CYP1A1 - physiology
Cytochromes
Cytokines
Cytokines - analysis
Diesel exhaust
Diesel motor exhaust gas
Enzymes
Gasoline - toxicity
In Vitro Techniques
Inflammation
L-Lactate Dehydrogenase - metabolism
Luminescence
Lungs
Macrophages
Male
Microsomes - enzymology
Microsomes - metabolism
Mutagenicity
Mutagenicity Tests
Mutagens
Nitric oxide
Nitric Oxide Synthase Type II - biosynthesis
Nitric Oxide Synthase Type II - metabolism
Nitric Oxide Synthase Type II - physiology
Nitrites - metabolism
Oxides
Peroxynitrous Acid - metabolism
Pneumonia
Pneumonia - enzymology
Pneumonia - etiology
Proteins - metabolism
Rats
Rats, Sprague-Dawley
Reactive oxygen species
Salmonella typhimurium - genetics
Subcellular Fractions - enzymology
Subcellular Fractions - metabolism
Vehicle Emissions - toxicity
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Summary:Diesel exhaust particles (DEPs) have been shown to activate oxidant generation by alveolar macrophages (AMs), alter xenobiotic metabolic pathways, and modify the balance of proantiinflammatory cytokines. In this study we investigated the role of nitric oxide (NO) in DEP-mediated and DEP organic extract (DEPE)-mediated inflammatory responses and evaluated the interaction of inducible NO synthase (iNOS) and cytochrome P450 1A1 (CYP1A1). Male Sprague-Dawley rats were intratracheally (IT) instilled with saline, DEPs (35 mg/kg), or DEPEs (equivalent to 35 mg DEP/kg), with or without further treatment with an iNOS inhibitor, aminoguanidine (AG; 100 mg/kg), by intraperitoneal injection 30 min before and 3, 6, and 9 hr after IT exposure. At 1 day postexposure, both DEPs and DEPEs induced iNOS expression and NO production by AMs. AG significantly lowered DEP- and DEPE-induced iNOS activity but not the protein level while attenuating DEPE- but not DEP-mediated pulmonary inflammation, airway damage, and oxidant generation by AMs. DEP or DEPE exposure resulted in elevated secretion of both interleukin (IL)-12 and IL-10 by AMs. AG significantly reduced DEP- and DEPE-activated AMs in IL-12 production. In comparison, AG inhibited IL-10 production by DEPE-exposed AMs but markedly increased its production by DEP-exposed AMs, suggesting that NO differentially regulates the pro- and antiinflammatory cytokine balance in the lung. Both DEPs and DEPEs induced CYP1A1 expression. AG strongly inhibited CYP1A1 activity and lung S9 activity-dependent 2-aminoanthracene mutagenicity. These studies show that NO plays a major role in DEPE-induced lung inflammation and CYP-dependent mutagen activation but a lesser role in particulate-induced inflammatory damage.
ISSN:0091-6765
1552-9924
DOI:10.1289/ehp.9063