Figure Legends
Figure 1 Schematic representation of normal airway (left side)
and asthmatic airway remodeling (right side). In healthy subjects,
ciliated epithelial cells function as both a physical barrier and an
immunological organ that has evolved to defend living organisms against
pathogens and physical insults, as well to maintain tissue homeostasis.
Fibroblasts and macrophages contribute to tissue homeostasis in the
submucosa. In severe asthma, several triggers (i.e., allergens,
cytokines, cigarette smoke, microbial products, and physical insults)
damage bronchial epithelial cells that rapidly release several alarmins
(i.e., TSLP, IL-33, IL-25/IL-17E) that are constitutively expressed.
These alarmin cytokines are first reactor and rapidly initiate innate
and adaptive immune responses in asthma. Asthma is associated with
chronic inflammation and remodeling of the immune and stromal
compartments of the airway wall208,
209. Analysis of the immune and stromal
cell populations in the bronchial biopsies of asthmatic patients193 revealed
structural changes including mucus cell hyperplasia with a marked
increase in goblet cell numbers, which are rare in healthy airways.
Subepithelial matrix protein (collagen, fibronectin, tenascin)
deposition and fibrosis22,
23, 27,
29-31, 44,
57, increased blood vessel density and
overexpression of angiogenic factors16,
17, and hyperplasia and hypertrophy of
airway smooth muscle (ASM) cells are features of airway remodeling in
asthma. The goblet cell transcriptional phenotype is altered in asthma,
with upregulation of proinflammatory and remodeling genes193. Mast cell numbers
expressing high levels of tryptase genes and prostaglandin D synthase
are increased in asthma. These are intraepithelial cells and tend to
accumulate in asthmatic airway epithelium225 and increase with
disease severity 226.
Luminal and tissue macrophages are increased in asthma and contribute to
airway remodeling by releasing a plethora of inflammatory and angiogenic
factors 58,
60. Eosinophilia and neutrophil numbers
are increased in different asthma phenotypes57,
65, 66,
165,
189. Pathogenic effector
CD4+ T cells are enriched in asthmatic airways193. Airway remodeling
is also characterized by complex interactions between inflammatory and
structural cells 209via direct physical interactions and secreted proteins and small
molecules. A wealth of growth factor signaling pathways including FGF,
EGFR, TGF, PDGF, and VEGFs participate in the cell-cell interactions
between structural and immune cells.
Figure 2 Here the mAbs effective in severe asthma are listed
and their known immunological mechanisms are summarized. The targets of
approved add-on biologic treatments of severe asthma include IgE
(omalizumab), IL-5 (mepolizumab and reslizumab), IL-5 receptor
(benralizumab), IL-4/IL-13 receptor complex (dupilumab) and anti-TSLP
(Tezepelumab).