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 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.
Zhao
Hongwen
H
Institute of Respiratory Diseases, First Affiliated Hospital, China Medical University, Shenyang, People's Republic of China.
Barger
Mark W
MW
Ma
Joseph K H
JK
Castranova
Vincent
V
Ma
Jane Y C
JY
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*
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