ABSTRACT
Asthma is deemed an inflammatory disease, yet the defining diagnostic feature is mechanical bronchoconstriction. We previously discovered a conserved process called cell extrusion that drives homeostatic epithelial cell death when cells become too crowded. In this work, we show that the pathological crowding of a bronchoconstrictive attack causes so much epithelial cell extrusion that it damages the airways, resulting in inflammation and mucus secretion in both mice and humans. Although relaxing the airways with the rescue treatment albuterol did not affect these responses, inhibiting live cell extrusion signaling during bronchoconstriction prevented all these features. Our findings show that bronchoconstriction causes epithelial damage and inflammation by excess crowding-induced cell extrusion and suggest that blocking epithelial extrusion, instead of the ensuing downstream inflammation, could prevent the feed-forward asthma inflammatory cycle.
Subject(s)
Asthma , Bronchi , Bronchoconstriction , Animals , Humans , Mice , Asthma/pathology , Asthma/physiopathology , Bronchoconstriction/drug effects , Inflammation/pathology , Signal Transduction , Ion Channels/antagonists & inhibitors , Lysophospholipids/antagonists & inhibitors , Sphingosine/analogs & derivatives , Sphingosine/antagonists & inhibitors , Bronchi/pathology , Bronchi/physiopathologyABSTRACT
Asthma is deemed an inflammatory disease, yet the defining diagnostic symptom is mechanical bronchoconstriction. We previously discovered a conserved process that drives homeostatic epithelial cell death in response to mechanical cell crowding called cell extrusion(1, 2). Here, we show that the pathological crowding of a bronchoconstrictive attack causes so much epithelial cell extrusion that it damages the airways, resulting in inflammation and mucus secretion. While relaxing airways with the rescue treatment albuterol did not impact these responses, inhibiting live cell extrusion signaling during bronchoconstriction prevented all these symptoms. Our findings propose a new etiology for asthma, dependent on the mechanical crowding of a bronchoconstrictive attack. Our studies suggest that blocking epithelial extrusion, instead of ensuing downstream inflammation, could prevent the feed-forward asthma inflammatory cycle.
