Modeling inflammation and ventilation heterogeneity in the asthmatic lung

Nitric oxide (NO) is detectable in exhaled breath and thought to be a marker of inflammation. Exhaled NO can be elevated in asthma, generating interest for the use of NO as a non-invasive method to diagnose and monitor the disease. Asthma is characterized by inflammation and bronchoconstriction; there is also evidence of acidification. All of these processes could potentially impact exhaled NO.;Current models of NO in the lungs allow for estimation of proximal and distal sources, however the single-path nature of these models does not account for dynamic features of the exhaled profile (phase III slope). In this study, we develop a multicompartment model (MCM) of NO exchange which incorporates heterogeneity in ventilation and inflammation, and is characterized with 9 parameters. This model takes into account bimodal ventilation patterns observed in asthma, as well as allows for parallel and serial heterogeneity in inflammation. A sensitivity analysis of the MCM demonstrates that ventilation parameters have little impact on the magnitude and shape of the exhaled NO profile and can be set to their central values for model fitting, leaving 5 NO parameters. NO production in the well-ventilated region correlated negatively with phase III slope, while NO production in the defect region correlated positively with phase III slope. The model was applied to 20 asthmatic children; parameters and confidence intervals were determined by numerical least-squares fitting. The model predicted 1 to 3 of the five NO parameters within statistical significance. In general, the model was able to distinguish regional inflammation and identify cases of increased alveolar NO which are missed in the previous models.;Airway acidification can potentially confound interpretation of exhaled NO. Airway pH is thought to be regulated partly by glutaminase, an enzyme which can be altered in asthma. In this study we examine the impact of glutaminase kinetics on pH in the presence of a bicarbonate buffer. Treating the cells with cytokines and glutaminase inhibitors altered glutaminase kinetics, but there was no significant impact on pH. This suggests glutaminase may not be a major contributor to airway pH homeostasis.