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Diesel exhaust particles (DEP), an environmental pollutant, are known to induce lung cancer in experimental animals. To clarify whether reactive oxygen species (ROS) are involved in its carcinogenic mechanism, we examined the levels of 8-hydroxyguanine (8-OH-Gua), its total repair and the repair enzyme OGG1 mRNA in female Fischer 344 rat lungs, as markers of the response to ROS, after DEP was intratracheally instilled. The 8-OH-Gua levels in both DEP-treated groups (2 and 4 mg) were increased during the 2-8 h following exposure to DEP. The 8-OH-Gua repair activities in the DEP-treated groups decreased during the period from 2 h to 2 days following DEP exposure and then recovered to the level of the control group at 5 days after exposure. OGG1 mRNA was induced in rats treated with 4 mg DEP for 5-7 days after administration. In conclusion, the 8-OH-Gua level in rat lung DNA increases markedly at an early phase after DEP exposure, by the generation of ROS and the inhibition of 8-OH-Gua repair activity, and induction of OGG1 mRNA is also a good marker of cellular oxidative stress during carcinogenesis.

Objective-Three-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are known to enhance vascular expression of endothelial (eNOS) and inducible nitric oxide synthase (iNOS). In this study, we examined whether statins also upregulate vascular expression of neuronal NOS (nNOS). Methods and Results-In cultured rat aortic smooth muscle cells, treatment with atorvastatin significantly increased nNOS expression, associated with activation of Akt and NF-B. Inhibition of Akt by dominant-negative Akt suppressed atorvastatin-induced nNOS expression as well as Akt and NF-B activation. Inhibition of NF-B by dominant-negative IB also attenuated atorvastatin-induced nNOS expression and NF-B activation, but not Akt activation. We further examined whether atorvastatin also enhances nNOS expression in isolated mouse aorta, and if so, how much nNOS-derived NO accounts for atorvastatin-induced NOx production. In isolated aortas of wild-type mice, atorvastatin significantly increased all three NOS isoform expression and NOx production. In isolated aortas of doubly i/eNOS Ϫ/Ϫ , n/eNOS Ϫ/Ϫ , and n/iNOS Ϫ/Ϫ mice, which express only nNOS, iNOS, and eNOS, respectively, atorvastatin-induced NOx production was approximately 25%, 25%, and 50% to that of wild-type mice, respectively, suggesting that nNOS accounts for 25% of the atorvastatin-mediated NOx production. Conclusions-These

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