Inhibiting epithelial cell extrusion and inflammation synergistically reverses asthmatic airway remodelling

Abstract

Airway smooth muscle (ASM) hyperresponsiveness is the defining feature of asthma, yet neither its origins nor the processes that establish and maintain it are understood. Here, using a mouse model, we show that hyperresponsiveness arises from ASM realignment into dense, parallel bundles reinforced by excess extracellular matrix, a fundamental remodelling rather than mere amplification of existing contractile ASM. This remodelling is initiated and sustained by a mechanical feedforward cycle. Allergen treatment initiates a contraction-relaxation cycle that realigns ASM into a bronchoconstrictive state. As bronchoconstriction triggers crowding and excess airway epithelial cell extrusion 1, the wounding then locks ASM into a hypercontractile architecture that drives further constriction. Gadolinium, a mechanosensitive channel blocker that inhibits extrusion, prevents this remodelling and hyperresponsiveness--unlike the corticosteroid budesonide. Critically, in mice with fully established disease, gadolinium reverses all asthmatic features and restores normal airway function, while budesonide alone cannot. Budesonide, however, synergises with gadolinium to normalise protein and gene expression. These findings reframe asthma pathogenesis as a mechanically driven, pharmacologically reversible process -- suggesting that asthma may be curable rather than merely treatable.