Bronchial epithelial extrusion has been identified as a key mechanism in the pathogenesis of asthma

British, American and Spanish researchers conducted a series of experiments on mice and found that the basis of pathological processes in asthma is mechanical extrusion (crowding and squeezing) of bronchial epithelium during attacks, which leads to irreversible damage to the airways. Inhibiting this process effectively prevented the inflammation and increased mucus production characteristic of the disease. A report of the work is published in the journal Science.

Asthma is currently considered an inflammatory disease, but its defining characteristic is the mechanical narrowing of the bronchi (bronchoconstriction). It causes characteristic expiratory dyspnea, wheezing, and hyperproduction of bronchial secretion; its detection in the methacholine provocation test is central to the diagnosis of the disease. Typical asthma therapy includes the administration of β2-adrenoreceptor agonists, which relax bronchial smooth muscle, and inhaled glucocorticoids, which reduce local inflammation. These do not provide optimal symptom control in all patients, suggesting the need to search for other pathogenetic mechanisms as targets for potential new therapies.

The bronchial epithelium represents the primary barrier that protects the lungs from pathogens and pollutants in the inhaled air. Its normal function requires the maintenance of a constant density of epithelial cells. Previously, Jody Rosenblatt (Jody Rosenblatt), working at the University of Utah, with colleagues showed that this process is regulated by mechanical extrusion of excess cells from the epithelial layer and their death, which allows to maintain a balance between division and apoptosis of epitheliocytes.

Moving to King's College London, Rosenblatt and colleagues from the UK, Spain and the USA set about investigating the possible role of this mechanism in the pathogenesis of asthma. To do this, they exposed ex vivo slices of mouse bronchi, exposed or not to primary contact with allergens, to methacholine. Within 15 minutes after such exposure, a pronounced extrusion of the epithelium was observed in small and medium-sized bronchioles - the height of the cell layer increased by 196 percent on average, and this was positively correlated with the dose of the drug and the degree of bronchoconstriction. Further experiments showed that the β2-agonist albuterol relaxes the bronchi after 15-minute constriction but does not prevent extrusion and destruction of epithelial cells. Moreover, when the bronchi dilated abruptly under the influence of the drug, the epithelium often detached from the smooth muscle layer, which aggravated the damage.

In the course of subsequent experiments on live mice with asthma model it was found out that regular intranasal administration of gadolinium or sphingosine kinase inhibitors with albuterol prevented not only extrusion and denudation of epithelium, but also inflammatory changes in it, including infiltration by immune cells and damage of lungs and bronchi at histological level. The general condition of the animals also did not deteriorate. In addition, gadolinium significantly reduced the pathologic secretion of bronchial mucus.

In conclusion, the researchers analyzed the bronchiolar biopsy specimens obtained during the operations of two patients with asthma who received long-term treatment with glucocorticoids and β2-agonists. It turned out that extrusion and denudation of the epithelium as well as mucus secretion in them were even more pronounced than in mice with the disease model. Thus, this mechanism is independent of airway size and has clinical significance, i.e. its blocking is potentially able to prevent secondary inflammation, hypersensitivity and pathological bronchial remodeling, the authors conclude.