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.