Airway remodeling
Airway remodeling can affect both large and small airways19 and is characterized
by structural changes including goblet cell hyperplasia, subepithelial
matrix protein deposition and fibrosis, overexpression of angiogenic
factors, and hyperplasia/hypertrophy of airway smooth muscle (ASM) cells15-17,
20, 21.
Increased deposition of extracellular matrix (ECM) proteins in the
reticular basement membrane (RBM), lamina propria, and submucosa is a
characteristic of asthmatic airways and contributes to the airway wall
thickening and airflow obstruction22,
23. Collagen fibers, fibronectin and
tenascin are the most abundant elements of the ECM in the asthmatic lung24-27. Aberrant
accumulation of ECM proteins leads to alterations in tissue structure
and function, contributing to airway remodeling in asthma28-30. ASM
hypertrophy/hyperplasia (e.g., increased ASM mass) are features of
asthmatic airway remodeling18,
3132,
33. ASM cells in asthmatic individuals
also produce increased amounts of collagen and fibronectin34,
35. The increase in the ASM mass is
responsible for bronchial obstruction36, loss of function20 and greater
susceptibility to external triggers37-39.
Angiogenesis is fundamental to providing the blood vessels to maintain
tissue homeostasis 40,
whereas inflammatory angiogenesis is a critical factor in the
development of a disease process41-43. Blood vessel
density and vascular area are increased in patients with asthma16,
17. Another feature of asthma is goblet
cell hyperplasia, mucin overproduction and mucus hypersecretion44. Figure 1
schematically illustrates the fundamental characteristics of the normal
bronchial airway and the main features of airway remodeling in asthma.
A plethora of cytokines [transforming growth factor β (TGF-β),
platelet-derived growth factor (PDGF), fibroblast growth factor (FGF),
epidermal growth factor (EGF)]), vascular endothelial growth factors
(VEGFs)] and chemokines (e.g., CXCL2, CXCL3, IL-8/CXCL8) contribute
directly and indirectly to airway remodeling in asthma45-47. TGF-β, produced
by macrophages and eosinophils, is a main mediator responsible for
airway remodeling by inducing epithelial-mesenchymal transition (EMT)48.
IL-4 activates ASM cells, causing an increase in actin and collagen
synthesis as well as TGF-β release by the bronchial epithelium37,
49. IL-5, on the other hand promotes
subepithelial and peri-bronchial fibrosis through the recruitment and
activation of eosinophils, a major source of TGF-β50,
51. IL-13 induces the release of TGF-β
which increases goblet cell hyperplasia and thus mucus hypersecretion37,
52-54.
Human eosinophil granules are armed with cytotoxic major basic protein
(MBP), eosinophil peroxidase (EPX), eosinophil cationic protein (ECP),
eosinophil derived neurotoxin (EDN), and galactin-10 (also known as
Charcot-Leyden protein)55. ECP and MBP induce
the release of preformed (histamine and tryptase) and de novosynthesized mediators (prostaglandin D2:
PGD2) from human mast cells56. Activated human
eosinophils secrete LTC4 and a wide array of type 2
cytokines (i.e., IL-5, IL-4, IL-13) and TGF-β45,
57. Altogether, current data indicate
that eosinophils play a globally pathogenic role in airway remodeling.
Macrophages are the predominant immune cells in human lung parenchyma58 and are involved in
immune responses as well as tissue remodeling59. Human lung
macrophages (HLMs) contribute to airway remodeling through the release
of TGF-β, matrix metalloproteinases (MMPs), angiogenic (VEGF-A, ANGPT2)
and lymphangiogenic factors (i.e., VEGF-C)60,
61. Human lung mast cells (HLMCs) are
important lung-resident immune cells involved in asthmatic airway
remodeling 62. IgE- and
non-IgE-mediated activation of HLMCs induces the release of several
pro-fibrotic cytokines (e.g., IL-13 and TNF-α), as well as inflammatory
mediators (e.g., PGD2 and tryptase)63. Tryptase induces
fibroblast, endothelial and epithelial cell proliferation, further
fueling airway remodeling in asthmatic individuals64. Neutrophils have
also been shown to produce MMP-965,
66, angiogenic factors40 and neutrophil
extracellular traps (NETs)67 and can be
associated with severe asthma67.
The airway epithelium is a key component of the innate immune system and
the initiator of airway remodeling in asthma14. A plethora of
environmental insults (e.g., allergens, cytokines, microbial proteins,
smoke extracts, chemical and physical insults) damage and/or activate
epithelial cells to release several cytokines, including TSLP13,
68, IL-3314,
69, IL-25/IL-17E12, TGF-β and
granulocyte-macrophage colony-stimulating factor (GM-CSF), which can
recruit dendritic cells (DCs), mast cells and other immune cells70.
Thymic stromal lymphopoietin (TSLP), constitutively expressed by human
bronchial epithelial cells71-74, can be rapidly
released as a result of cell injury in response to a variety of
inflammatory stimuli 71,
75-79. TSLP is also released by DCs80, mast cells81, HLMs60, and fibroblasts82,
83. There are two isoforms of TLSP: the
short (sf) and the long (lf) isoforms. The latter is expressed at a low
or undetectable level at steady state, but its expression increases
during inflammation 60,
84. For instance, house dust mites
induce lfTSLP but not sfTSLP in human bronchial epithelial cells85. TSLP immunostaining
is increased in the airway epithelium in asthmatic patients74 and its
concentrations are increased in the broncho-alveolar lavage (BAL) fluid
of asthmatics 73.
Moreover, bronchial allergen challenge of asthmatics increases the
expression of TSLP+ cells in the epithelium and
submucosa 72. TSLP is
overexpressed in the airways of severe asthma patients73 and exerts its
effects by binding to a high-affinity heterodimeric receptor complex
composed of TSLPR and IL-7Rα13.
TSLP plays a role in airway remodeling86 by promoting the
differentiation of Th2 cells and innate lymphoid cells (ILCs)13 and the induction of
epithelial-mesenchymal transition (EMT) in airway epithelial cells87. Human lung
fibroblasts are also a significant source of TSLP83,
88. Through an autocrine mechanism, TSLP
can activate human lung fibroblasts89 to release type I
collagen 90 and promote
the proliferation of ASM cells91. TSLP has also been
shown to cause goblet cell hyperplasia and mucus production92-94. TSLP activates
human eosinophils 13,
mast cells 81,
95 and HLMs60. The multiple
activating properties of TSLP on a plethora of immune and structural
cells indicate that this cytokine plays a role in T2-high and T2-low
asthma.
IL-33, an IL-1 superfamily alarmin released by airway epithelial cells
and endothelial cells96, activates the ST2
receptor on several cells of the innate and the adaptive immunity96. Epithelial
cell-derived IL-33 induces type 2 cytokines (i.e., IL-5 and IL-13) in
human mast cells 97,
collagen and fibronectin release from airway fibroblasts98,
99. Collectively, IL-33 and IL-33/ST2
signaling pathways might be involved in both airway inflammation and
asthma remodeling through the activation of several immune and
structural cells.
IL-25, also known as IL-17E, is a unique cytokine of the IL-17 family
produced by airway epithelial cells12. Airborne allergens,
ATP, and viral infections upregulate IL-25 and its receptor IL-17RB in
airway epithelial cells and submucosa100,
101. IL-25 modulates EMT of alveolar
epithelial cells and local tissue remodeling102 and upregulates
cytokine expression in lung fibroblasts103. IL-25 drives lung
fibrosis in several mouse models102,
104,
105.
Finally, IgE itself could play a role in airway remodeling by
stimulating the production of interleukins106. Several
investigators have reported that human monomeric IgE, in the absence of
cross-linking, can induce the release of cytokines (e.g., IL-4) and
chemokines (e.g., CXCL8) from mast cells107,
108. Moreover, Roth et al . have
shown that in vitro incubation of serum containing IgE obtained
from allergic asthmatics caused ASM proliferation and marked production
of type I collagen109.
A recent study in a mouse model of asthma demonstrated dynamic changes
in the respiratory microbiota at different stages of the disease. In
particular, Staphylococcus and Cupriavidus were more
abundant during airway remodeling110. Additional
studies are urgently needed to investigate whether the dysbiosis of
airway microbiota could also play a role in the progression from
allergic inflammation to airway remodeling in humans.
Airway remodeling can sometimes cause irreversible airflow limitation
with consequent poor symptom control and lack of response to treatment20,
111,
112.