Nitric oxide (NO) is a key physiological mediator and disturbed regulation of NO release is associated with the pathophysiology of almost all inflammatory diseases. A multitude of inhibitors of NOSs (
nitric oxide synthases) have been developed, initially with low or even no selectivity against the constitutively expressed NOS
isoforms, eNOS (endothelial NOS) and nNOS (neuronal NOS). In the meanwhile these efforts yielded potent and highly selective iNOS (inducible NOS) inhibitors. Moreover, iNOS inhibitors have been shown to exert beneficial anti-inflammatory effects in a wide variety of acute and chronic animal models of
inflammation. In the present mini-review, we summarize some of our current knowledge of inhibitors of the iNOS
isoenzyme, their biochemical properties and efficacy in animal models of
pulmonary diseases and in human disease itself. Moreover, the potential benefit of iNOS inhibition in animal models of
COPD (
chronic obstructive pulmonary disease), such as cigarette
smoke-induced
pulmonary inflammation, has not been explicitly studied so far. In this context, we demonstrated recently that both a semi-selective
iNOS inhibitor {L-NIL [N6-(1-iminoethyl)-
L-lysine hydrochloride]} and highly selective iNOS inhibitors (
GW274150 and BYK402750) potently diminished
inflammation in a cigarette
smoke mouse model mimicking certain aspects of human
COPD. Therefore, despite the disappointing results from recent
asthma trials, iNOS inhibition could still be of therapeutic utility in
COPD, a concept which needs to be challenged and validated in human disease.