iNOS affects matrix production in distal lung fibroblasts from patients with mild asthma

A high level of exhaled nitric oxide (NO) is a marker for inflammation in the airways of asthmatic subjects. However, little is known about how NO and inducible nitric oxides synthase (iNOS) activity may affect remodelling in the distal lung. We hypothesized that there is a link between iNOS and ongoing remodelling processes in the distal lung of mild asthmatics.

Patients with mild asthma (n = 6) and healthy control subjects (n = 8) were included. Exhaled NO was measured at different flow rates and alveolar NO concentrations were calculated. For studies of remodelling processes in the distal lung, primary fibroblasts were grown from transbronchial biopsies and stimulated with unselective and selective NOS inhibitors or a NO donor. The mRNA expression of iNOS and synthesis of NO (indirectly as nitrite/nitrate) were measured and distal lung fibroblast synthesis of the extracellular matrix proteoglycans were analysed.

The distal lung fibroblasts expressed iNOS, and there was a tendency of higher expression in fibroblasts from patients with asthma. The selective iNOS inhibitor 1400 W inhibited iNOS expression and NO synthesis in fibroblasts from patients with asthma (p = 0.031). Treatment with 1400 W significantly increased synthesis of the proteoglycan versican (p = 0.018) in distal fibroblasts from patients with asthma whereas there were no effects in fibroblasts from control subjects.

Our data suggest that there is a link between iNOS and remodelling in the distal lung of subjects with mild asthma and that iNOS could have a modulatory role in pathological airway remodelling.