Nitric Oxide Synthase Isoforms in Lung Parenchyma of Patients with Chronic Obstructive Pulmonary Disease

In patients suffering from chronic obstructive pulmonary disease (COPD), the fraction of exhaled nitric oxide (FENO), conventionally measured at single expiratory flow of 50 ml/s, is a weak diagnostic and prognostic biomarker. The levels of FENO are usually similar to or only slightly elevated above reference values in patients with COPD (1), except during exacerbations (2) or in those COPD patients with evidence of reactive airways disease (3). In recent studies, the measurement of FENO has been performed by sampling exhaled NO at different expiratory flows (4). This methodology allows the separate assessment of both peripheral and bronchial components of pulmonary inflammation. Using multiple exhalation flows, it has been shown that, whereas bronchial NO is low or normal in patients with COPD, there is an increase in NO levels generated in peripheral airways and alveoli, which is related to disease severity (5). The source of peripheral NO production in patients with COPD is unknown, although induction of NO synthase would be a logical explanation. Which one of the NO synthase family—neuronal, endothelial and inducible NO synthases (nNOS, eNOS, and iNOS, respectively)—is overexpressed in COPD is still unknown. In this issue of the Journal (pp. 21–30), Brindicci and colleagues (6) show that mRNA of both constitutive NOS (cNOS) and iNOS proteins is overexpressed in peripheral lung tissues of patients with COPD. In particular, whereas the expression of eNOS and iNOS was reduced in COPD stage 4, nNOS increased with COPD severity and negatively correlated with FEV1 and FEV1/FVC values. Furthermore, the authors show that nNOS activity in an epithelial cell line (A549) under nitrative stress is high. The work by Brindicci and coworkers is a landmark study for two reasons: (1) the enhanced expression of nNOS in peripheral lung tissues may, at least in part, explain NO production in distal airways and alveoli in patients with severe COPD; (2) the increased expression of nNOS in relation to COPD severity and its induction by nitrative stress indicates that even a constitutive enzyme can be up-regulated. The data extend previous observations from the same group (7) showing that nebulized aminoguanidine, which is a poorly selective iNOS inhibitor, reduced NO from central airways, whereas it was much less effective on distal airway NO. This suggests that in COPD, NOS isoforms other than iNOS may be involved in peripheral NO production. The hypothesis that cNOS is the key enzyme for the increased NO levels observed in the lung periphery of patients with COPD is fascinating, and may stimulate additional work. However, despite these important findings, questions remain.