Understanding how tissue remodeling affects airway responsiveness is of key importance, but experimental data bearing on this issue remain scant. We used lung explants to investigate the effects of enzymatic digestion on the rate and magnitude of airway narrowing induced by acetylcholine. To link the observed changes in narrowing dynamics to the degree of alteration in tissue mechanics, we compared our experimental results with predictions made by a computational model of a dynamically contracting elastic airway embedded in elastic parenchyma. We found that treatment of explanted airways with two different proteases (elastase and collagenase) resulted in differential effects on the dynamics of airway narrowing following application of ACh. Histological corroboration of these different effects is manifest in different patterns of elimination of collagen and elastin from within the airway wall and the surrounding parenchyma. Simulations with a computational model of a dynamically contracting airway embedded in elastic parenchyma suggest that elastase exerts its functional effects predominately through a reduction in parenchymal tethering, while the effects of collagenase are more related to a reduction in airway wall stiffness. We conclude that airway and parenchymal remodeling as a result of protease activity can have varied effects on the loads opposing ASM shortening, with corresponding consequences for airway responsiveness.