Amidst a plethora of available therapies to manage chronic asthma symptoms, the respiratory condition remains incurable. Unveiling an unexpected asthma trigger could revolutionize treatment prospects.
In an April 5 report in Science, researchers suggest a mechanical glitch in the normal turnover process of lung epithelial cells might be culpable. A deeper comprehension of this underlying physical force driving chronic asthma attacks could pave the way for novel therapeutic approaches.
The mechanical mechanism responsible for epithelial lung cell turnover, known as cell extrusion, operates as follows: Lung lining epithelial cells replicate, causing congestion and heightened pressure between cells. Sensing this crowding, cells initiate a process ejecting weaker ones from the layer, ensuring tissue health in the airways.
Though hints of this process's involvement in asthma have surfaced previously, research efforts have primarily focused on other triggers. Early discoveries in the 1900s pointed towards epinephrine's ability to reverse breathlessness, suggesting lung muscle constriction as the primary cause. Subsequent revisions incorporated persistent airway inflammation.
Upon examining lung images afflicted with chronic asthma damage, cell biologist Jody Rosenblatt had an insight. Her previous research in 2015 revealed that overcrowding pressure in the epithelium could induce cell death and extrusion. She speculated whether a single asthma attack's pressure could initiate a cycle of cell death, lung damage, and subsequent attacks.
To validate the hypothesis, Rosenblatt and colleagues simulated asthma attacks in living mouse lung cells using methacholine, a bronchiole-narrowing drug. Constricted airways caused severe epithelial cell overcrowding and increased cell ejection, correlating with constriction severity and cell sloughing.
To assess human relevance, they examined airway samples from moderate to severe asthma patients undergoing lung cancer surgery. Samples exhibited severe extrusion, mucus buildup, immune cell accumulation, and airway damage.
Albuterol treatment, which relaxes airways, mitigated constriction but failed to reverse damage. As airways relaxed and opened, epithelial lining gaps increased, potentially exacerbating asthma symptoms over time.
Physicist Lisa Manning lauds the study as an exemplary illustration of tissue mechanics' role in disease. She emphasizes the significance of physical forces in human health, often underestimated.
In subsequent experiments, Rosenblatt's team explored blocking cell receptors sensing mechanical force in mouse cells to mitigate damage from excessive cell extrusion. Inhibiting piezo1, a protein sensing epithelial cell crowding, significantly reduced cell ejection, inflammation, and mucus production.
While promising, these findings necessitate further validation in animal models and humans for potential clinical translation.
