Predicting Balb/c and B6C3F1 Mouse Sensitivity to Inhaled Methacholine: Impact of Calculating Lung-Airway Dimension and Airflow Distribution

The extent of an individual's sensitivity to inhaled bronchoconstrictors has historically been attributed to biochemical sensitivities, without regarding the dose delivered to airway surfaces. Yet computational models of the lung indicate that when individuals with different lung-airway morphometry receive the same inhalation exposure, they will not receive the same delivered dose. For example, by using a typical path geometric lung model for the first 6 tracheobronchial airway generations, previous work has shown that between-subject differences in sensitivity to bronchoconstrictors could mainly be due to airway-surface dosimetry. However, such dosimetry calculations ignore both the possible impact of the complex parallel pathways formed by lung airways and the consequence of including in the models within-lung averaging of airway dimensions. The purpose of this work was to compare the impact of several dosimetry models in predicting sensitivity to bronchoconstrictors. Two commonly used strains of laboratory mice (Balb/c and B6C3F 1 ) were used, and dosimetry calculations for inhaled methacholine were based on average or individual tracheobronchial airway dimensions as well as on the assignment of airflow distribution by distal airway volume or airway cross-sectional area. For these two strains of laboratory mice, the dosimetry calculations made by using individual airway dimensions and assigning airflow by distal airway volume predicted the greatest difference in sensitivity to bronchoconstrictors. The comparison of lung dosimetry models also showed that airway-surface dosimetry and molecular bio-sensitivity may drive pulmonary hyperresponsiveness.