Differential remodeling in small and large murine airways revealed by novel whole lung airway analysis

Abstract

Airway remodeling occurs in chronic asthma leading to increased airway smooth muscle (ASM) mass and extracellular matrix (ECM) deposition. Although extensively studied in murine airways, studies report only selected larger airways at one time-point meaning the spatial distribution and resolution of remodeling are poorly understood. Here we use a new method allowing comprehensive assessment of the spatial and temporal changes in ASM, ECM, and epithelium in large numbers of murine airways after allergen challenge. Using image processing to analyze 20–50 airways per mouse from a whole lung section revealed increases in ASM and ECM after allergen challenge were greater in small and large rather than intermediate airways. ASM predominantly accumulated adjacent to the basement membrane, whereas ECM was distributed across the airway wall. Epithelial hyperplasia was most marked in small and intermediate airways. After challenge, ASM changes resolved over 7 days, whereas ECM and epithelial changes persisted. The new method suggests large and small airways remodel differently, and the long-term consequences of airway inflammation may depend more on ECM and epithelial changes than ASM. The improved quantity and quality of unbiased data provided by the method reveals important spatial differences in remodeling and could set new analysis standards for murine asthma models.