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.