Nitric oxide synthases are associated with bronchial dysplasia

Recent studies suggest that reactive oxygen (ROS) and nitrogen species (RNS) are highly associated with the pathogenesis of cigarette smoke related lung diseases but their role in the malignant conversion of bronchial epithelium is unclear. The immunohistochemical expression of inducible, endothelial and neuronal nitric oxide synthases (iNOS, eNOS and nNOS) and nitrotyrosine as a biomarker of oxidative/nitrosative stress was evaluated in 79 cases including 13 non-smokers, 20 smokers without chronic obstructive pulmonary disease (COPD), 22 with COPD and 24 with metaplasia-dysplasia-sequence of the bronchial epithelium. Normal lung of non-smokers was mainly negative for nitrotyrosine, while it was higher in the alveolar macrophages of cigarette smokers and COPD than in non-smokers (p=0.025, p<0.001), and in the alveolar epithelium of smokers and COPD than in non-smokers (p=0.049). There were no major differences in the nitrotyrosine immunoreactivity between the metaplastic/dysplastic lesions and bronchial epithelium of cigarette smokers. Inducible NOS and nNOS were mainly non-detectable or weak in the normal looking bronchial epithelium of smokers and COPD, whereas metaplasia and dysplasia showed positivity for iNOS (22/24) and nNOS (14/24) in the majority of cases. Strong immunoreactivity for iNOS and nNOS was also found more often in dysplastic than metaplastic (p=0.011 and p=0.049, respectively) specimens. Thus, smoking can cause protein nitration also in normal lung. Prominent iNOS and nNOS immunoreactivity in the metaplasia-dysplasia-lesions suggests a divergent role of NOSs in lung carcinogenesis.