Cooperation of the Inducible Nitric Oxide Synthase and Cytochrome P450 1A1 inMediating Lung Inflammation and Mutagenicity Induced by DieselExhaust 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.

Particle-bound PAHs and Particle-extract-induced Cytotoxicity of Emission from a Diesel-generator Fuelled with Soy-biodiesel

“…6). This phenomenon is associated with the fact that the DEP organic solvent extract contained no DEP particles, making the particle aerodynamic diameter irrelevant to the bio-toxicity (Zhao et al, 2006). However, when the cytotoxicity was converted into unit mass cytotoxicity (cell death rate per unit DEP mass), as displayed in Fig.…”

Reactive Oxygen Species- and Nitric Oxide-Mediated Lung Inflammation and Mitochondrial Dysfunction in Wild-Type and iNOS-Deficient Mice Exposed to Diesel Exhaust Particles

“…This is of interest because the in vivo action of DEP may vary if there exist counterbalancing pathways for the DEP-induced immune/inflammatory responses, and thus may show dose and time sensitivity regulated by the relative production of reactive oxygen/nitrogen species. In a previous study, it was shown that exposure of rats to DEPE for 24 h produced severe cytotoxicity, ROS generation, and altered cytokine production by AM (Zhao et al, 2006). These DEPE-mediated responses were NO dependent, as they were significantly reduced in animals treated with aminoguanadine (AG), a selective iNOS inhibitor (Zhao et al, 2006), suggesting that ROS and NO may exhibit cooperative and/or opposite effects on given cellular responses.…”

“…In a previous study, it was shown that exposure of rats to DEPE for 24 h produced severe cytotoxicity, ROS generation, and altered cytokine production by AM (Zhao et al, 2006). These DEPE-mediated responses were NO dependent, as they were significantly reduced in animals treated with aminoguanadine (AG), a selective iNOS inhibitor (Zhao et al, 2006), suggesting that ROS and NO may exhibit cooperative and/or opposite effects on given cellular responses.…”

“…Alveolar macrophages (AM) are the principal cell type in the lung that mediates the immune/inflammatory responses against inhaled particles, chemicals, or microorganisms through phagocytosis, reactive oxygen species (ROS), and nitric oxide (NO) generation, and liberation of chemokines and cytokines to protect the lung's susceptibility to infection. The in vivo action of DEP is marked by increased expression of inducible nitric oxide synthase (iNOS) in AM, which produces NO and peroxynitrite that play an important role in host defense against intracellular pathogens Takano et al, 1999;Zhao et al, 2006). The intracellular ROS, superoxide anion, is generated mainly through mitochondria, and is accompanied by controlled antioxidant defenses.…”

Ultrafine Particles of Diesel Exhaust Induces Cytochrome P450 1A1 Mediated Oxidative Stress and DNA Damage in Cultured Blood and Lung Cells

“…DEP has been shown to induce ROS generation via metabolic activation of organic compounds such as PAHs adsorbed on DEP through CYP1A1, microsomal P450 reductase and quinine reductases 41,46 . The enrichment of PAH metabolising CYP1A1 by MC may further increase the formation of ROS in these blood cells when co-exposed to DEPs 6,47 .…”