Stiffening of the Extracellular Matrix is a Sufficient Condition for Airway Hyperreactivity

Abstract

AbstractThe current therapeutic approach to asthma focuses exclusively on targeting inflammation and reducing airway smooth muscle force in an effort to prevent the recurrence of symptoms. However, the treatment is not a cure and has little beneficial effect on the progression of asthma. This suggests that there are mechanisms at play that are likely triggered by inflammation and eventually become self-sustaining so that even when airway inflammation is brought back under control, these alternative mechanisms continue to drive airway hyperreactivity in asthmatics. In this study, we hypothesized that the stiffening of the airway extracellular matrix is a core pathological change sufficient to support excessive bronchoconstriction in asthmatics even when in the absence of inflammation. To test this hypothesis, we increased the stiffness of airway ECM by photo-crosslinking collagen fibers within the airway wall using riboflavin (vitamin B2) and Ultraviolet-A radiation. In our experiments, collagen crosslinking led to a three-fold increase in stiffness of the airway extracellular matrix. This change was sufficient to cause airways to constrict to a greater degree, at a faster rate when exposed to a low dose of contractile agonist. Our results highlight the need for therapeutic approaches that target matrix remodeling to develop a lasting cure for this disease.