title: Cooperation of the inducible nitric oxide synthase and cytochrome P450 1A1 in mediating lung inflammation and mutagenicity induced by diesel exhaust particles.
abstract: Diesel exhaust particles (DEPs) have been shown to activate oxidant generation by alveolar macrophages (AMs), alter xenobiotic metabolic pathways, and modify the balance of pro-antiinflammatory 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.
authors.affiliation: Institute of Respiratory Diseases, First Affiliated Hospital, China Medical University, Shenyang, People's Republic of China.
authors.forename: Hongwen
authors.initials: H
authors.lastname: Zhao
authors.forename: Mark W
authors.initials: MW
authors.lastname: Barger
authors.forename: Joseph K H
authors.initials: JK
authors.lastname: Ma
authors.forename: Vincent
authors.initials: V
authors.lastname: Castranova
authors.forename: Jane Y C
authors.initials: JY
authors.lastname: Ma
mesh_terms: D000393:Air Pollutants / Q000633:toxicity*; D000818:Animals; D002478:Cells, Cultured; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D016207:Cytokines / Q000032:analysis; D005742:Gasoline / Q000633:toxicity*; D066298:In Vitro Techniques; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D049449:Luminescence; D008297:Male; D008861:Microsomes / Q000201:enzymology / Q000378:metabolism; D009152:Mutagenicity Tests; D009153:Mutagens; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D009573:Nitrites / Q000378:metabolism; D030421:Peroxynitrous Acid / Q000378:metabolism; D011014:Pneumonia / Q000201:enzymology* / Q000209:etiology*; D011506:Proteins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012486:Salmonella typhimurium / Q000235:genetics; D013347:Subcellular Fractions / Q000201:enzymology / Q000378:metabolism; D001335:Vehicle Emissions / Q000633:toxicity*
chemical_list: D000393:Air Pollutants; D016207:Cytokines; D005742:Gasoline; D009153:Mutagens; D009573:Nitrites; D011506:Proteins; D001335:Vehicle Emissions; D030421:Peroxynitrous Acid; D007770:L-Lactate Dehydrogenase; D052247:Nitric Oxide Synthase Type II; D019363:Cytochrome P-450 CYP1A1