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

Abstract

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.

Fig. 1.

Schematic of the multicompartment and 2-compartment models of nitric oxide (NO) exchange in the lungs. A: multicompartment model consists of a central airway compartment that branches into 2 peripheral airway compartments, each emptying into separate alveolar regions. Each airway region is trumpet-shaped, incorporates axial diffusion, and has a constant NO flux per unit volume; alveolar compartments have a steady-state NO concentration. B: 2-compartment model consists of a single trumpet-shaped airway compartment with axial diffusion and constant NO flux per unit volume that empties into a single alveolar compartment that is at constant NO concentration. C: exhaled NO concentration in a representative child with asthma plotted as a function of exhaled airway volumes [exhaled volume (Vex)/airway volume (Vaw), unitless]. Key features include mean NO concentration of phase III (∼50 ppb) and the phase III slope (approx −2 ppb). See Glossary for abbreviations.

Fig. 2.

Exhaled NO profiles and best-fit model simulations for 4 representative children with asthma. NO was collected at 3 exhalation flows (50, 100, and 200 ml/s) from 20 children with mild asthma. Exhaled NO in the phase III region of each flow is plotted as a function of the number of exhaled airway volumes (Vex/Vaw; thin trace). Multicompartment model best-fit curves are represented by a thick black line, and 2-compartment model best-fit curves are represented by dashed lines. A: subject 6 has elevated Fe_NO (>25 ppb at a flow of 50 ml/s) with an average normalized phase III slope of −1.4%. Multicompartment and 2-compartment model best fits are nearly identical. B: subject 10 has elevated Fe_NO, with an average normalized phase III slope of −2.2%. C: subject 12 has low Fe_NO, with an average normalized slope of 0.2%. Multicompartment and 2-compartment model best fits are nearly identical. D: subject 18 has low Fe_NO, with a normalized phase III slope of −2.7%.

Fig. 3.

Comparison of 2-compartment and multicompartment models. A: total airway flux as determined by least-squares fitting the 2-compartment and multicompartment models to 20 children with asthma. Average predicted total airway NO flux for the multicompartment model was the sum of all 3 airway flux terms. B: average alveolar NO concentration determined by 2-compartment and multicompartment models. Average concentration was determined by volume weighting the 2 alveolar NO concentrations in the multicompartment model. Both models predicted similar NO levels on average (horizontal bars). C: percent improvement in residual sum of squares (RSS) between the 2-compartment and the multicompartment model as a function of the phase III slope of NO. There was a statistically significant negative correlation (solid line represents best-fit linear regression). See Glossary for abbreviations.