Blocking Cell Extrusion Prevents Bronchoconstriction-Induced Airway Epithelial Damage and Inflammation

Abstract

Asthma is a common disease characterized by airway constriction, excess mucus, and inflammation. We previously showed that cell crowding drives steady-state epithelial cell extrusion and cell death. Using ex vivo lung slices, we show that excessive crowding from methacholine-induced bronchoconstriction causes extensive cell extrusion leading to destruction of the airway epithelial barrier. In live mice, bronchoconstriction-induced extrusion caused airway epithelia damage and inflammation in secondary and tertiary airways. In primary airways, bronchoconstriction triggered mucus secretion by a mechanism reminiscent of extrusion. Reversing bronchoconstriction with albuterol failed to ameliorate these symptoms, whereas inhibiting the stretch-activated calcium channel, Piezo1, prevented extrusion, inflammation, and mucus secretion. Our findings propose a new etiology for asthma where the mechanical crowding from bronchoconstriction causes so much extrusion that it compromises the barrier, triggering subsequent inflammation. Furthermore, inhibiting extrusion, potentially with gadolinium, an inexpensive Piezo1 inhibitor, may prevent the asthma inflammatory cycle.