Unveiling Asthma Pathways

Unveiling Asthma Pathways: Mechanical Transformations in Airway Tissues

British, American, and Spanish researchers conducted a series of experiments on mouse models of bronchial asthma and found that the pathogenesis of this disease is based on mechanical extrusion (contraction and squeezing) of the bronchial epithelium during attacks, leading to irreversible damage to the airways. Inhibiting this process effectively prevented the characteristic inflammation and increased mucus production associated with the disease. The study report was published in the journal Science.

Currently, bronchial asthma is considered an inflammatory disease characterized by variable airflow obstruction. Typical asthma maintenance therapy includes the prescription of β2-adrenergic agonists, which have bronchodilator effects, and inhaled glucocorticoids, which reduce local inflammation. These drugs provide optimal symptom control for not all patients, necessitating the prescription of other targeted medications. Despite the high effectiveness of gene-engineered immunobiological therapy in bronchial asthma, drugs in this group are not universal and have some limitations, indicating the need to explore other pathogenetic mechanisms as targets for potential treatment methods.

The bronchial epithelium serves as the primary barrier protecting the lungs from pathogens and pollutants in inhaled air. Normal functioning requires maintaining a constant density of epithelial cells. Previously, Jody Rosenblatt, working at the University of Utah, and colleagues showed that this process is regulated by the mechanical extrusion of excess cells from the epithelial layer and their death, which helps maintain a balance between epithelial cell division and apoptosis.

After joining the London Royal College, Rosenblatt, along with colleagues from the UK, Spain, and the USA, began studying the potential role of this mechanism in the pathogenesis of asthma. To do this, they applied methacholine to ex vivo slices of mouse bronchi, which were either exposed or not exposed to initial contact with allergens. Within 15 minutes of such exposure, pronounced epithelial extrusion was observed in the small and medium bronchioles – the height of the cellular layer increased on average by 196 percent, which positively correlated with the drug dose and the degree of bronchoconstriction. Further experiments showed that the β2-agonist albuterol relaxes the bronchi after 15 minutes of constriction, but does not prevent extrusion and destruction of epithelial cells. Moreover, with rapid bronchial dilation under the drug’s effect, the epithelium often detached from the smooth muscle layer, exacerbating the damage.

Earlier, researchers found that the extrusion of epitheliocytes is regulated by the stretch-activated ion channel Piezo1, which triggers the production of sphingosine-1-phosphate (S1P) – it binds to the S1P2 receptor and activates Rho-mediated actomyosin contraction. Also involved in this process are transient receptor potential (TRP) channels TRPA1, TRPV1, and TRPM8. Therefore, they used Piezo1 inhibitor and TRP hexahydrate gadolinium chloride (Gd3+), sphingosine kinase 1 (SKI-II) and 2 (K-145) blockers, as well as S1P2 receptor antagonist JTE-013 during methacholine action and found that they all significantly reduce extrusion, but only gadolinium and sphingosine kinase inhibitors prevent epithelial detachment from smooth muscles (denudation). Gadolinium, like GsMTx4 (a peptide inhibitor of Piezo1, TRPC1, and TRPC6), effectively prevented extrusion and denudation after 15 minutes of bronchoconstriction, while albuterol had no effect on this.

In subsequent experiments on mouse models of asthma, it was found that regular intranasal administration of gadolinium or sphingosine kinase inhibitors with albuterol not only prevents extrusion and denudation of the epithelium but also inflammatory changes in it, including immune cell infiltration and lung and bronchial damage at the histological level. The overall condition of the animals also did not deteriorate. In addition, gadolinium significantly reduced pathological mucus secretion in the bronchi.

In conclusion, the researchers analyzed the biopsies of the bronchioles of two asthma patients 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, were even more pronounced in them than in mice with the disease model. Thus, this mechanism is independent of the size of the airways and has clinical significance, meaning its blockade potentially can reduce inflammation, hypersensitivity, and pathological bronchial remodeling, conclude the authors of the study.