New asthma cause identified – and a new angle for treatment

Good news! This seems to be a breakthrough!

"... But the new study points to a different root cause, of which inflammation is itself a symptom. When the airway muscles contract – known as bronchoconstriction – the epithelial cells that line the airways are 'squeezed out' and later die. With fewer of these cells acting as a barrier, the chances for future asthma attacks increase. ...
“Without this barrier, asthma sufferers are far more likely to get long-term inflammation, wound healing, and infections that cause more attacks." ...
“Current therapies do not prevent this destruction – an inhaler such as Albuterol opens the airways, which is critical to breathing but, dishearteningly, we found it does not prevent the damage and the symptoms that follow an attack,” ... “Fortunately, we found that we can use an inexpensive compound, gadolinium which is frequently used for MRI imaging, to stop the airway damage in mice models as well as the ensuing inflammation and mucus secretion. Preventing this damage could then prevent the build-up of musculature that cause future attacks.”"

"Most current asthma treatments stem from the idea that it is an inflammatory disease. Yet, the life-threatening feature of asthma is the attack or the constriction of airways, making breathing difficult. The new study, published today in Science, shows for the first time that many features of an asthma attack—inflammation, mucus secretion, and damage to the airway barrier that prevents infections - result from this mechanical constriction in a mouse model. ..."

From the perspectives abstract:

"Reports of what were known at that time as “asthmatic fits” can be traced back millennia, but a mechanistic understanding of the basis for what are now called asthma exacerbations remains incomplete. Over the past 100 years, multiple mechanisms have been proposed, including constriction of the smooth muscle that encircles the airways (bronchoconstriction), persistent airway inflammation, and disruption of the epithelial layer that lines the airways. Yet how these processes interconnect and contribute to asthma exacerbations has been debated.  ... show that bronchoconstriction results in pathological overcrowding of cells in the airway epithelium, squeezing out (extruding) epithelial cells and thus damaging the epithelial layer enough to trigger inflammation. They also show that drugs that block the extrusion pathway, and thereby prevent mechanical damage to the epithelium during acute airway narrowing, may have the capacity to break the inflammatory cycle and potentially revolutionize how asthma is treated."

From the editor's summary and abstract:

"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. ... 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 ... 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. ...

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."

New asthma cause identified – and a new angle for treatment

Discovery of how limiting damage from an asthma attack could stop disease (original news release) Scientists at King’s have discovered a new cause for asthma that sparks hope for treatment that could prevent the life-threatening disease.

Epithelial cells crowded out in asthma (no public access) Bronchoconstriction causes epithelial cell extrusion that promotes airway inflammation

Bronchoconstriction damages airway epithelia by crowding-induced excess cell extrusion (no public access)