Title: Non-local impacts of distal airway constrictions on patterns of inhaled particle deposition

Abstract: Airway constriction and blockage in obstructive lung diseases create barriers to effective drug deposition by altering how different regions of the lungs are ventilated. Established computational particle deposition models have not accounted for these impacts of disease. We present a new particle deposition model that calculates ventilation based on the resistance of each airway, such that ventilation patterns respond to airway constriction. We incorporate distal airway constrictions representative of cystic fibrosis, and assess the resulting impact on deposition down to the single-airway scale. We demonstrate how constriction reduces deposition in the airways directly distal and proximal to the affected airways. When multiple constrictions are clustered together, deposition in the central airways proximal to the constrictions is more strongly reduced, and deposition in the other central airways is generally increased. This results in more uneven deposition in both the central and distal airways, even when constrictions affect only the distal airways. We use our model to calculate lung clearance index (LCI), a clinical measure of ventilation heterogeneity, in lungs with constrictions of various severities localised to one lobe. We find an increase in LCI coinciding with a significant drop in deposition throughout the affected lobe.