INVOLVEMENT OF SUPEROXIDE AND NITRIC-OXIDE ON AIRWAY INFLAMMATION ANDHYPERRESPONSIVENESS INDUCED BY DIESEL EXHAUST PARTICLES IN MICE

We previously demonstrated that chronic intratracheal instillation of diesel exhaust particles (DEP) induces airway inflammation and hyperre sponsiveness in the mouse, and that these effects were partially rever sed by the administration of superoxide dismutase (SOD). In the presen t study, we have investigated the involvement of superoxide in DEP-ind uced airway response by analyzing the localization and activity of two enzymes: (1) a superoxide producer, NADPH cytochrome P-450 reductase (P-450 reductase), and (2) a superoxide scavenger, SOD, in the lungs o f the exposed mice and controls. P-450 reductase was detected mainly i n ciliated cells and clara cells; its activity was increased by the re peated intratracheal instillation of DEP. While CuZn-SOD and Mn-SOD we re also present in the airway epithelium, their activity was significa ntly decreased following DEP instillation. Exposure to DEP doubled the level of nitric oxide (NO) in the exhaled air. DEP exposure also incr eased the level of constitutive NO synthase (cNOS) in the airway epith elium and inducible NO synthase (iNOS) in the macrophages. Pretreatmen t with N-G-monomethyl L-arginine, a nonspecific inhibitor of NO syntha se, significantly reduced the airway hyperresponsiveness induced by DE P. These results indicate that superoxide and NO may each contribute t o the airway inflammation and hyperresponsiveness induced by the repea ted intratracheal instillation of DEP in mice. (C) 1998 Elsevier Scien ce Inc.