Bagley DC, Russell T, Ortiz-Zapater E, Stinson S, Fox K, Redd PF, Joseph M, Deering-Rice C, Reilly C, Parsons M, Brightling C, Rosenblatt J. Bronchoconstriction damages airway epithelia by crowding-induced excess cell extrusion. Science. 2024 Apr 5;384(6691):66-73. doi: 10.1126/science.adk2758.
Editor’s summary
Asthma, a very common airway disorder, is generally understood to be a condition of excessive inflammation in which environmental triggers stimulate immune responses in the lungs, resulting in bronchoconstriction. The mainstays of asthma therapy are albuterol, which is a short-acting bronchodilator for immediate relief of symptoms, and corticosteroids to treat the underlying inflammation. Unfortunately, this approach is not always effective even in combination. Bagley et al. have demonstrated that bronchoconstriction-induced mechanical damage to the airways and extrusion of epithelial cells also contribute to asthma pathology and may interfere with healing (see the Perspective by Drazen and Fredberg). By contrast, compounds that counteracted this mechanical damage showed beneficial effects in mouse models, either alone or combined with albuterol, although their safety in humans remains to be assessed. —Yevgeniya Nusinovich
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.