Quantifying proximal and distal sources of NO in asthma using a multicompartment model

Nitric oxide (NO) is detectable in exhaled breath and is thought to be a marker of lung inflammation. The multicompartment model of NO exchange in the lungs, which was previously introduced by our laboratory, considers parallel and serial heterogeneity in the proximal and distal regions and can simulate dynamic features of the NO exhalation profile, such as a sloping phase III region. Here, we present a detailed sensitivity analysis of the multicompartment model and then apply the model to a population of children with mild asthma. Latin hypercube sampling demonstrated that ventilation and structural parameters were not significant relative to NO production terms in determining the NO profile, thus reducing the number of free parameters from nine to five. Analysis of exhaled NO profiles at three flows (50, 100, and 200 ml/s) from 20 children (age 7-17 yr) with mild asthma representing a wide range of exhaled NO (4.9 ppb < fractional exhaled NO at 50 ml/s < 120 ppb) demonstrated that 90% of the children had a negative phase III slope. The multicompartment model could simulate the negative phase III slope by increasing the large airway NO flux and/or distal airway/alveolar concentration in the well-ventilated regions. In all subjects, the multicompartment model analysis improved the least-squares fit to the data relative to a single-path two-compartment model. We conclude that features of the NO exhalation profile that are commonly observed in mild asthma are more accurately simulated with the multicompartment model than with the two-compartment model. The negative phase III slope may be due to increased NO production in well-ventilated regions of the lungs.