Shelley DA, Puckett JL, George SC. Quantifying proximal and distal sources of NO in asthma using a multicompartment model. J Appl Physiol 108: 821-829, 2010. First published January 21, 2010 doi:10.1152/japplphysiol.00795.2009 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 Ͻ fractional exhaled NO at 50 ml/s Ͻ 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 leastsquares 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. nitric oxide; heterogeneity; sensitivity; phase III slope NITRIC OXIDE (NO) is a free radical present in exhaled breath and is thought to be a marker of inflammation in the lungs (3, 21). Exhaled NO can be elevated in inflammatory diseases, such as asthma, and is reduced after treatment with inhaled corticosteroids (ICS) (17). These observations have generated significant interest in the clinical use of exhaled NO as a noninvasive marker to diagnose and monitor the progression of inflammatory diseases.Elevated NO in asthma has been traditionally attributed to inflammation in the proximal airways; however, recent evidence highlights the importance of peripheral regions (e.g., respiratory bronchioles) in inflammation (13,18,19). Elevated peripheral NO has been associated with increased symptoms and can be resistant to ICS (13). When NO is measured at the mouth during exhalation, the only way to distinguish between the proximal and peripheral NO sources is through a mathematical model. The two-compartment model of NO exchange is a relatively simple, yet powerful, tool to partition the NO signal into proximal (large airways) and distal (small airways and alve...