Revealed: Mechanical damage during an asthma attack

In asthma, the tightening of muscles around the bronchi causes damage to the airway by squeezing and destroying epithelial cells, which promotes the airway inflammation and mucus production often associated with an asthma attack, researchers report. The findings suggest that preventing the mechanical damage caused by an asthma attack, rather than treating only its downstream symptoms, could pave the way for therapies that stop the whole asthma inflammatory cycle. Asthma is a common airway disorder affecting more than 300 million people worldwide. Although it is primarily considered an inflammatory disease, a diagnostic feature of asthma is mechanical bronchoconstriction – the constriction of the smooth muscle that surrounds the airway – which can result in severe breathing difficulty and increased airway mucus production. Airway immune activation and inflammation are thought to drive bronchoconstriction during asthma exacerbations (acute episodes of worsening asthma symptoms). As such, the gold standard therapy for asthma exacerbations is albuterol, a short-acting bronchodilator, and inhaled corticosteroids, which treat the underlying inflammation. However, these treatments are not always effective, and a mechanistic understanding of asthma exacerbations remains incomplete. Building on previous research, Dustin Bagley and colleagues investigated the underlying root causes of asthma pathobiology. Using mouse models of asthma and human lung tissue samples, Bagley et al. discovered that bronchoconstriction causes a pathological overcrowding of cells in the airway epithelium, triggering a process called cell extrusion that leads to airway tissue damage. This mechanism resulted in inflammation and mucus secretion in both mice and humans. This damage results in a breakdown of epithelial barrier function and could provide a pathway for further bronchoconstrictive attacks and inflammation. Although the authors show that albuterol treatment does not prevent airway epithelia damage or its resultant inflammation after an asthma attack, they found that inhibitors that stopped the cell extrusion pathway counteracted mechanical damage to the airway and substantially reduced the inflammatory response. “These findings not only establish that bronchoconstriction is a pro-inflammatory stimulus but also point toward the potential for new research avenues that seek to inhibit a ‘mechano-inflammatory’ vicious cycle,” write Jeffery Drazen and Jeffery Fredberg in a related Perspective.