Conclusions and perspectives
Immunotherapy with mAbs targeting IgE, several cytokines or their receptors has revolutionized the treatment landscape for patients with severe asthma. mAbs that block IgE (omalizumab), the IL-5/IL-5Rα axis (mepolizumab, reslizumab, benralizumab), IL-4Rα (dupilumab), or TSLP (tezepelumab) can produce durable responses in the majority of patients with severe asthma.
Airway remodeling is a cardinal feature of bronchial asthma and is responsible for structural alterations of the airways and lung parenchyma determining airway hyperresponsiveness and the development of fixed airflow obstruction 15. Damaged epithelial barrier 208, 209, subepithelial matrix proteins and collagen deposition 22,23, 27, infiltration and activation of inflammatory cells 57, 66,193, goblet cell hyperplasia 44, overexpression of inflammatory angiogenesis 16,17 and hyperplasia and hypertrophy of ASM cells18, 31 are major features of airway remodeling in asthma 111, 210.
At present, we have incomplete knowledge on the short- and long-term effects of biological therapies on airway remodeling in asthma. However, biological therapies targeting IgE, IL-5/IL-5Rα, IL-4Rα, TSLP and IL-33/ST2 can improve not only clinical symptoms but also certain features (e.g., FEV1, FeNO) of airway remodeling in asthma 173, 183,211-214. These findings allow us to speculate that biologics could promote the resolution of allergic inflammation. Late phases of airway remodeling are associated with infiltration/activation of both pro-fibrotic immune cells (e.g., mast cells, eosinophils and macrophages) and structural cells (e.g., fibroblasts, myofibroblasts, ASM cells and endothelial cells). Biologics may have late effects on immune and structural cells in addition to early effects on airway inflammation. The effects of each biologic on specific features of airway remodeling are summarized in Table 1.
Biologics are presently used for the treatment of patients with severe asthma who are likely to have a prolonged history of persistent and/or repetitive immunological insults. Repetitive or prolonged injury can lead to a pathological state of fibrosis associated with reduced lung function. Experimental studies indicate that there is a limited-time window in which stopping inflammation avoids fibrosis. Beyond this time-window, tissue remodeling inevitably occurs even if inflammation is resolved. In this circuit, macrophages, the most abundant immune cells in the human lung, can transition between different states, including pro-inflammatory, anti-inflammatory, and pro-fibrotic states. Although there are no clinical and experimental data, we would like to hypothesize that perhaps early treatment of mild/moderate asthma with biologics might represent an innovative strategy to limit the irreversible airway remodeling of severe asthma.
There are several limitations in studying in vivo the effects of biological therapies on airway tissue remodeling in asthmatic patients. Bronchial asthma is a highly heterogeneous disorder and different forms of airway remodeling could likely underlie several asthma pheno-/endotypes 3. The quantitative identification of immune cells in the airway epithelium and submucosa should also take in consideration the functional heterogeneity of eosinophils215, macrophages 60,193, 216, mast cells41, 217-220, neutrophils221, 222, and basophils40, 223. Potential airway remodeling biomarkers (e.g., galectin 3 and YKL40) are under investigation. Blood detection of these molecules, compared to invasive methods, could be useful in the future to evaluate bronchial remodeling224.
In conclusion, a deeper understanding of the immunological mechanisms of the formation of different forms of airway tissue remodeling in various asthma phenotypes is needed. The use of single-cell transcriptomics will be of paramount importance to chart the cellular landscape and specific signaling networks of upper and lower airways in healthy and asthmatic subjects 193. The results emerging from these studies could help in the generation of new reliable diagnostic biomarkers and targeted therapeutic approaches to improve asthma treatment.