This suggests that nebulized nitrite exposure in mice with pneumonia-induced pulmonary inflammation could result in intrapulmonary NO-dependent oxidative (nitrosative) effects. However, as DETA-NO and exhausted DETA were equally antibacterial in vitro, and as NaNO2 had a minimal effect, it is likely that NO and nitrite derived from DETA-NO did not play an important role in the observed in vivo effects of DETA-NO in murine pneumonia. Canadian Family Pharmacy
The exposure of sham mice to high-dose (ie, 125 ^mol) DETA-NO was associated with a significant, albeit slight, increase in pulmonary inflammation. This proinflammatory effect may be due to NO itself or to the DETA nucleophile moiety. Indeed, the lack of attenuation of leukocyte infiltration in DETA-NO-exposed mice with pneumonia, despite the decreased pulmonary bacterial load, may be due to a coincident proinflammatory effect of NO or DETA. The proinflammatory effects of NO have been well-recognized. NO may contribute to tissue inflammation and cell injury through several mechanisms. One of the most important mechanisms is thought to be the generation of the potent oxidizing species, peroxynitrite, via interaction of NO with superoxide. The observed increase in pulmonary bacterial load in mice with pneumonia that were exposed to 40 ppm iNO may be due to oxidative modification and the resulting impairment of components of host defense, such as surfactant-associated proteins, by these high levels of exogenous NO. It is clear that the balance of beneficial and adverse effects of high doses of exogenous NO, via iNO or nebulized NONOates, must be considered and assessed before such interventions can be considered therapeutically useful in clinical settings of lung injury, In summary, the use of nebulized NONOates may be a practical method for the intermittent, intrapul-monary administration of exogenous NO. Although nebulized DETA-NO had an in vivo antibacterial effect in our murine P aeruginosa pneumonia model, this effect appeared to be NO-independent in vitro, being largely due instead to the DETA nucleophile moiety. Moreover, rather than an antibacterial effect, iNO exposure was associated with increased intrapulmonary growth, suggesting that large doses of exogenous NO may impair host defense in this murine model of acute P aeruginosa pneumonia. Although NONOates may be very useful agents in the investigation of potentially beneficial effects of exogenous NO, the importance of proper control studies assessing the effects of the respective nucleophile moieties has been demonstrated.