School of Pharmacy
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.
Digital Commons Citation
Zhao, Hongwen; Barger, Mark W.; Ma, Joseph K H; Castranova, Vincent; and Ma, Jane Y C, "Cooperation of the Inducible Nitric Oxide Synthase and Cytochrome P450 1A1 in Mediating Lung Inflammation and Mutagenicity Induced by Diesel Exhaust Particles" (2006). Faculty & Staff Scholarship. 2875.
Zhao, H., Barger, M. W., Ma, J. K. H., Castranova, V., & Ma, J. Y. C. (2006). Cooperation of the Inducible Nitric Oxide Synthase and Cytochrome P450 1A1 inMediating Lung Inflammation and Mutagenicity Induced by DieselExhaust Particles. Environmental Health Perspectives, 114(8), 1253–1258. https://doi.org/10.1289/ehp.9063