Bronchial epithelial cells: The key effector cells in the pathogenesis of chronic obstructive pulmonary disease? WEI GAO,1* LINGLING LI,1* YUJIE WANG,1 SINI ZHANG,1 IAN M ADCOCK,2 PETER J. BARNES,2 MAO HUANG1 AND XIN YAO1 1
Department of Respiratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China, and 2 Airway Disease Section, National Heart and Lung Institute, Imperial College, London, UK
ABSTRACT The primary function of the bronchial epithelium is to act as a defensive barrier aiding the maintenance of normal airway function. Bronchial epithelial cells (BEC) form the interface between the external environment and the internal milieu, making it a major target of inhaled insults. However, BEC can also serve as effectors to initiate and orchestrate immune and inflammatory responses by releasing chemokines and cytokines, which recruit and activate inflammatory cells. They also produce excess reactive oxygen species as a result of an oxidant/antioxidant imbalance that contributes to chronic pulmonary inflammation and lung tissue damage. Accumulated mucus from hyperplastic BEC obstructs the lumen of small airways, whereas impaired cell repair, squamous metaplasia and increased extracellular matrix deposition underlying the epithelium is associated with airway remodelling particularly fibrosis and thickening of the airway wall. These alterations in small airway structure lead to airflow limitation, which is critical in the clinical diagnosis of chronic obstructive pulmonary disease (COPD). In this review, we discuss the abnormal function of BEC within a disturbed immune homeostatic environment consisting of ongoing inflammation, oxidative stress and small airway obstruction. We provide an overview of recent insights into the function of the bronchial epithelium in the pathogenesis of COPD and how this may provide novel therapeutic approaches for a number of chronic lung diseases. Key words: chronic obstructive pulmonary disease, epithelial cell, immunity, inflammation, oxidative stress. Abbreviations: BEC, bronchial epithelial cell; CB, chronic bronchitis; COPD, chronic obstructive pulmonary disease; CS, cigarette smoke; DAMP, damage-associated molecular pattern; Correspondence: Xin Yao, Department of Respiratory Medicine, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, China. Email: [email protected]
njmu.edu.cn *These authors have contributed equally to the study. Received 24 September 2014; invited to revise 18 November 2014, 12 February and 25 February 2015; revised 15 December 2014, 17 February and 26 February 2015; accepted 27 February 2015 (Associate Editor: Paul Thomas). Article first published online: 13 April 2015 © 2015 Asian Pacific Society of Respirology
DNMT, DNA methyltransferase; ECM, extracellular matrix; EGFR, epidermal growth factor receptor; EMT, epithelial–mesenchymal transition; GM-CSF, granulocyte-monocyte colony-stimulating factor; GSH, glutathione; LT, leukotriene; MAPK, mitogenactivated protein kinase; MMP, matrix metalloproteinase; NF-κB, nuclear factor-κB; PAF, platelet-activating factor; PAMP, pathogen-associated molecular pattern; PCL, periciliary liquid layer; PG, prostaglandin; PRR, pattern recognition receptor; ROS, reactive oxygen species; TNF-α, tumour necrosis factor-α; TGF-β, transforming growth factor-β.
INTRODUCTION Chronic obstructive pulmonary disease (COPD) represents a syndrome comprising chronic bronchitis (CB) and emphysema characterized by largely irreversible and progressive airflow limitation.1 More than 200 million people worldwide are currently affected by the disease, which will be the third leading cause of death worldwide by the year 2020 according to estimates of the World Health Organization. At the pathological level, COPD is associated with chronic pulmonary inflammation in response to environmental insults. This is, in turn, inextricably linked to disturbed tissue repair, increased mucus secretion and epithelial cell hyperplasia with airway wall thickening in the small conducting airways.2 Bronchial epithelial cells (BEC), which line the airway lumen, are among the first sites of contact for environmental stimuli (microorganisms, gases and allergens) and perform a crucial role in maintaining normal airway function. Studies on human bronchial biopsies in COPD have demonstrated increased inflammatory gene and protein expression and structural alterations in BEC, suggesting the important role of the cells in COPD pathogenesis.
BRONCHIAL EPITHELIAL CELLS BEC are composed of various cell types and may be classified into three categories based on ultrastructural, functional and biochemical criteria: basal, ciliated and secretory cells. Basal cells are ubiquitous in the large (50%) and small airways (81%),3 but the absolute cell count decreases with Respirology (2015) 20, 722–729 doi: 10.1111/resp.12542
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airway size. Basal epithelial cells show an important role in cell adhesion and are thought to be progenitor or stem cells because of their ability to self-renew and differentiate in response to epithelial injury.4 In addition, these cells produce various bioactive molecules, such as cytokines.5 Ciliated epithelial cells are the major cell type within the airways, accounting for over 50% of all epithelial cells.3 They possess up to 300 cilia per cell and have numerous energy-producing mitochondria adjacent to their apical surface, highlighting the critical function of the cells in clearing mucus out from the airways via directional ciliary beating. Mucus (goblet) cells secrete mucus in order to trap foreign objects in the airway lumen. A balance between the correct amount of mucus production and clearance provides a critical defensive barrier and prevents airway surface desiccation.6 Mucus cells are also capable of self-renewal and differentiation into ciliated epithelial cells. In humans, non-ciliated secretory cells called club cells exist in the small airways and trachea. These are morphologically identified by their distinctive domeshaped apical protrusions and molecularly identified by their expression of club cell secretory protein.6 They regulate bronchiolar epithelial integrity and immunity by producing bronchiolar surfactants and specific antiproteases; they metabolize xenobiotic compounds by the action of p450 mono-oxygenases and also have an important stem cell function as progenitors for both ciliated and mucus-secreting cells. Considering the critical functions of BEC in maintaining the normal structure and function of the airways, it is not surprising that dysregulated BEC may contribute to the pathogenesis of many lung diseases such as COPD. In this review, we address the evidence for a critical role of dysfunctional BEC in the pathogenesis of COPD.
BEC INITIATE AND REGULATE IMMUNE RESPONSES The lungs are persistently exposed to environmental insults, but rarely show signs of infection, implying the existence of effective host defence mechanisms. The host is protected against various stimuli by a multilayered defence system consisting of a combination of physical barriers, as well as innate and adaptive immune mechanisms.7 Vareille et al. recently summarized that BEC may act in several ways fighting against respiratory viruses.8 Firstly, BEC form an efficient physical barrier function against viral invasion. Ciliated and mucus cells together enable the formation of a mucus barrier that traps and clears approximately 90% of inhaled particles.9 Secondly, BEC rapidly recognize molecules that are exclusive to microbes, namely pathogen-associated molecular patterns (PAMP), via expression of pattern recognition receptors (PRR) such as Toll-like receptors. This recognition enables BEC to subsequently interact with, guide, activate and modulate other immune cells.10 Thirdly, BEC produce various antiviral substances and release chemokines and cytokines that © 2015 Asian Pacific Society of Respirology
723 are important in both innate and adaptive immune processes upon viral recognition. Cigarette smoke (CS) is the main aetiological factor for COPD. CS induces dramatic alterations in the airway epithelial architecture and impairs barrier functions of BEC by increasing the permeability of the airway epithelium, weakening cilia beat ability and reducing mucociliary clearance. This barrier dysfunction, which is often found in COPD,11 can increase viral binding and entry into cells, further impairing barrier function.12 CS also inhibits interferon production by BEC upon stimulation with a viral doublestranded RNA mimic, polyI:C,13 indicating an injured immune defence induced by smoking. In addition to the compromised immune barrier function following chronic CS exposure, altered BEC also show disproportionate immune responses to other environmental hazards. Inhaled toxic agents cause direct damage to BEC, leading to the release of endogenous molecules called damage-associated molecular patterns (DAMP).14 Concentrations of high-mobility group box 1,15 uric acid and extracellular ATP,16 which are important DAMP, are shown to be increased in bronchoalveolar lavage fluid of patients with COPD compared with smokers without COPD. Similar to PAMP, these signals are identified by PRR on BEC17 and can subsequently trigger a non-specific inflammatory response.18 Release of early cytokines and chemokines (such as tumour necrosis factor-α (TNF-α) and interleukin (IL)-1 and IL-8/(C-X-C motif) ligand 8 (CXCL8)) by BEC elicits the recruitment of inflammatory cells to the site of inflammation.19 Additionally, the augmented activity of proteolytic enzymes and reactive oxygen species (ROS) from BEC affects surfactant, which is produced and secreted by alveolar epithelial cells. The surfactant dysfunction contributes to increased airway resistance, damaged extracellular matrix (ECM) components and rupture of alveolar walls, leading to the development of emphysema.20 Dendritic cells (DC) are specialized antigenpresenting cells that possess a central role in the initiation of innate and adaptive immune responses. By integrating multiple signals from the local microenvironment, DC promote CD4+ T-helper cell differentiation and CD8+ cytotoxicity,14 which are both associated with more advanced stages of airflow limitation and emphysema in COPD. Considering the close proximity of BEC and DC, DC are likely to be receptive to local signals derived from epithelial cells. Several studies have demonstrated that DC migration, maturation and activation are regulated by BEC-secreted chemokines.21 For example, macrophage inflammatory protein (MIP)-3α/(C-C motif) ligand 20 (CCL20), the unique ligand for CCR6 released by BEC in response to CS exposure, can facilitate the recruitment of DC subsets to the airway epithelium.22 BEC not only help promoting terminal differentiation of B-cells oriented towards polymeric immunoglobulin-A (IgA) by producing different cytokines, such as transforming growth factor (TGF)-β, IL-5 or IL-10,23 but also mediate its transportation.24 Thus, we suggest that BEC can both initiate and regulate the innate and adaptive immune systems involved in COPD pathogenesis (Fig. 1). Respirology (2015) 20, 722–729
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DAMP (ATP, HSP72, HMGB1) PRR Impaired BEC Barrier
Release of Early Cytokines and Chemokines Recruitment of Macrophages, Neutrophils and DC
Secretion of Proteolytic Enzymes
Production of ROS
Initiation of Innate and Adaptive Immunity
Destruction of Lung Tissue
BEC ACT AS BOTH TARGETS AND POTENT EFFECTOR CELLS IN CHRONIC PULMONARY INFLAMMATION Chronic inflammation contributes to airflow limitation in COPD.25 Chronic inflammation in COPD is mainly characterized by the accumulation of neutrophils, macrophages, B cells and CD8+ T cells, especially in small airways.26 Various inflammatory mediators also have important effects in the pathogenesis of the disease. BEC serve as a barrier to noxious stimuli and produce mediators and enzymes to maintain normal airway homeostasis. Respiratory viruses rapidly stimulate epithelial cells to secrete a wide range of proinflammatory mediators, such as IL-6, IL-8 and granulocyte-monocyte colony-stimulating factor (GMCSF). These early activated cells cause changes in endothelial cell physiology and further induce migration and infiltration of inflammatory cells to the airways. Normally, inflammatory cells in airways kill and eliminate foreign matter by secreting cytotoxic mediators and proteases, employing phagocytosis and a respiratory burst. However, sustained deleterious environmental stimuli may cause injury and alterations in defence mechanisms in BEC. The bronchial epithelium not only serves as a target of environmental stresses, but also works as a major effector to propagate the inflammatory process. BEC produce primary inflammatory mediators and then trigger the release of secondary mediators by themselves, including various cytokines, lipid mediators, growth factors, proteases and ROS.14 A summary profile of the mediators produced by BEC potentially involved in COPD is shown in Table 1, with further details on major mediators provided in the following section. Lipid mediators, including prostaglandins (PG), leukotrienes (LT) and platelet-activating factor (PAF), Respirology (2015) 20, 722–729
Figure 1 Bronchial epithelial cells (BEC) initiate and control immune and inflammatory responses in chronic obstructive pulmonary disease (COPD) pathogenesis. Cigarette smoke activates BEC by triggering pattern recognition receptors (PRR) such as Toll-like receptors (TLRs) either directly by cigarette components or indirectly via the release of damageassociated molecular patterns (DAMP). On activation, BEC release proinflammatory cytokines and chemokines, which recruit infiltrating inflammatory cells including macrophages, neutrophils and dendritic cells (DC). Activated immune cells, in turn, secrete additional inflammatory mediators, reactive oxygen species (ROS) and proteolytic enzymes (neutrophil elastase (NE) and matrix metalloproteinases (MMPs)). These mediators contribute to the airway remodelling and destruction of lung tissue that is involved in the pathogenesis of COPD. HMGB1, high-mobility group box 1; HSP, heat shock protein.
are produced in response to various stimuli27–29 and act in an autocrine or paracrine manner to increase their production. These mediators are chemotactic for neutrophils and macrophages and can alter vascular and epithelial permeability. PAF and LT can induce airway mucin secretion and cause bronchoconstriction.30,31 When oxidant exposure (e.g. chronic CS exposure) is continuous, oxidant species are especially important in the lung epithelium. The oxidants released by BEC32 either directly injure the airway epithelium or alter the expression and activation of redox-sensitive pro-inflammatory signalling pathways including nuclear factor-κB (NF-κB) and activation protein-1, thereby amplifying inflammatory cell influx. Primary pro-inflammatory mediators are produced rapidly by BEC upon stimulation and can feedback on the same cells to upregulate the expression and secretion of secondary cytokines.14 In addition, BEC are a major source of numerous chemokines such as CXCL1, CXCL5, CXCL10, CCL11, CCL2 and CCL5,33 which facilitate the recruitment and activation of different inflammatory cells within the airways. These recruited inflammatory cells release various proteases, which break down connective tissue components, particularly elastin, in lung parenchyma to produce emphysema. Exposure of BEC to CS results in the activation of numerous redox-associated intracellular signalling pathways including mitogen-activated protein kinases (MAPK) and NF-κB.34 Other transcription factors, including cyclic adenosine monophosphate (cAMP) response element-binding protein, CREB binding protein (CBP),35 CCAAT/enhancer-binding protein-b36 and peroxisome proliferator-activated receptor,37 are also activated by CS exposure. These all contribute to varying degrees to the expression of inflammatory mediators in BEC. © 2015 Asian Pacific Society of Respirology
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Table 1 Mediators produced by BEC in COPD Lipid mediators Reactive oxygen species (and products) Cytokines Chemokines
Pro-inflammatory T-helper CXC CC
Growth factors Proteases
PGE2, LTs B4 and C4, PAF H2O2, superoxide anion radicals, hydroxyl radicals, nitric oxide, peroxynitrite, 8-isoprostanes, 3-nitrotyrosine IL-1β, TNF-α, IL-6, IL-8, GM-CSF IL-4, IL-9, IL-10, IL-13 (T-helper-2); IFN-γ (T-helper-1) IL-8 (CXCL8), GRO-α (CXCL1), ENA-78 (CXCL5), IP-10 (CXCL10) MCP-1 (CCL2), RANTES (CCL5), eotaxin (CCL11) TGFβ, endothelin-1, PDGF, VEGF, EGF MMP-1, -2, -7, -9, -12, cathepsins, cysteine proteinases
BEC, bronchial epithelial cell; CC, C-C motif, CXC, C-X-C motif; COPD, chronic obstructive pulmonary disease; EGF, epidermal growth factor; ENA, epithelial neutrophil-activating protein; GM-CSF, granulocyte-macrophage colony-stimulating factor; GRO, growthregulated oncogene; H2O2, hydrogen peroxide; IL, interleukin; IFN, interferon; IP, interferon gamma-induced protein; LT, leukotriene; MCP, monocyte chemotactic protein; MMP, matrix metalloproteinase; PAF, platelet-activated factor; PDGF, platelet-derived growth factor; PGE2, prostaglandin E2; RANTES, T-cell-specific RANTES protein; TNF-α, tumour necrosis factor-α; VEGF, vascular endothelial growth factor.
BEC CONTRIBUTE TO THE OXIDANT/ANTIOXIDANT IMBALANCE IN OXIDATIVE STRESS Increasing evidence showed that oxidative stress is an important feature in COPD. Genetically, 200 oxidative stress-associated genes have been identified that were expressed differentially in bronchial airways between smokers with and without COPD.38 More recently, Vucic and colleagues39 demonstrated that NF-E2related factor 2-mediated antioxidant pathway was altered at multiple levels by DNA methylation in COPD bronchial airways. BEC can produce increased amounts of ROS in response to different stimuli.40 The airways are exposed to exogenous oxidants, which summate with endogenous ROS production to elevate oxidative stress and further increase the inflammatory and destructive response in COPD. Activation of MAPK and NF-κB pathways and increased cytokine release34 has also been demonstrated in airway epithelial cells in response to oxidant stress per se, and this may be linked, at least in part, to alterations in the histone acetylation/ deacetylation balance.41 The increased expression and release of mediators, such as CXCL8/IL-8, GM-CSF, soluble ICAM-1 and TNF-α, can regulate the influx of inflammatory cells. Therefore, oxidative stress in BEC may amplify the ongoing inflammatory responses in COPD. Besides, oxidative stress can increase both airway mucus obstruction in vivo and the expression of mucin genes (MUC5AC) in vitro by activating epidermal growth factor receptors (EGFR) in BEC.42,43 The activation of EGFR additionally mediates oxidative stress-induced proliferation of BEC.44 Oxidative stress also causes direct injury of BEC. Ozone alters the distribution of β1 integrins in cultured primate BEC, resulting in damage of cells and loss of cilia.45 Exposure of BEC to oxidants increases their permeability and can result in apoptosis or necrosis.46 These injuries to BEC impair their protective capacity against inhaled oxidants and other insults, enhancing local inflammation and cell death. Numerous endogenous antioxidants are produced to maintain oxidant/antioxidant homeostasis in the airways. Glutathione (GSH) is a major antioxidant in © 2015 Asian Pacific Society of Respirology
airway epithelial cells and epithelial lining fluid, while BEC serve as the source for the increased extracellular glutathione peroxidase.47 GSH and its redox system can inactivate reactive species and are important for the detoxification of lipid peroxides or other toxic metabolites in lung tissue. Moderate oxidative stress enhances GSH levels in human BEC, which was associated with the tolerance of cells to further oxidative stress.48 However, Rusznak et al. demonstrated that exposure to CS leads to a significant decrease in intracellular GSH levels without a rebound increase in levels within primary cultures of human BEC.49 Furthermore, van der Toorn et al. showed that CS irreversibly modifies GSH, thereby depleting the total available GSH pool in airway epithelial cells.50 These findings indicated a chronic lack of protection against oxidative stress, providing a mechanism by which BEC contribute to CS-induced oxidative damage found in patients with COPD (Fig. 2).
GOBLET CELL HYPERPLASIA AND MUCOUS METAPLASIA RESULTS IN CB IN COPD CB is one of the two major diseases constituting COPD and is mainly caused by excessive luminal mucus resulting from a combination of mucus hypersecretion by goblet cells51 and decreased mucus elimination. Smokers with CB have increased numbers of goblet cells, which are associated with elevated amounts of intracellular mucin, in which MUC5AC is the predominant form, compared with non-smoking controls.52 Mucus hypersecretion with increased viscosity and decreased antibacterial products aggravates airflow limitation and leads to an increased risk of chest infection.53 Inflammation, oxidative stress and proteases involved in COPD pathology have been linked to goblet cell hyperplasia accompanied with hypersecretion of mucins. Various inflammatory mediators and signalling pathways regulate the transcription of MUC genes. IL-1β, IL-17A and TNF-α induce mucus production via the activation and nuclear translocation of NF-κB.54 IL-1β not only induces Respirology (2015) 20, 722–729
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Inhaled Oxidants CS, Ozone, Hyperoxia, H2O2
GSH H2O2, OH, O2−
Oxidant/Antioxidant Imbalance ROS
Transcription of Chemokine and Cytokine Genes
Release of Inflammatory Mediators
Impairment of Anti-Inflammatory Ability
Figure 2 Bronchial epithelial cells (BEC) contribute to oxidative stress-mediated lung inflammation. BEC are exposed to exogenous oxidants, such as cigarette smoke (CS), which induces production of reactive oxygen species (ROS) and depletion of some antioxidants. Excessive ROS production overwhelms the antioxidant defence mechanisms in the airways, resulting in elevated expression of inflammatory mediators. This, in turn, induces an influx of inflammatory cells into the airway and lung. In addition, excess oxidative stress impairs the structural integrity of BEC and the protective capacity of the bronchial epithelium against inhaled oxidants, further enhancing the inflammation.
MUC5AC expression through cyclooxygenase-2generated PGE2 and cAMP-protein kinase A (PKA)mediated signalling,55 but also increases Cl− secretion and regulates mucus volume via upregulation of chloride channels expressed in BEC.56 Oxidative stress, both exogenously from CS and endogenously from neutrophils, can activate EGFR and induce mucin synthesis. A recent study reported that human BEC express the arylhydrocarbon receptor whose activation causes excess mucin production in a ROSdependent manner.57 Furthermore, human neutrophil elastase,58 matrix metalloproteinase (MMP)-959 and MMP-1460 also increase mucin production via an EGFR-mediated mechanism. Failure to clear mucus from the airway surface is another critical event in the pathogenesis of CB, which may be attributed to two mechanisms. One is the reduced ciliary beat efficiency due to the increased viscosity of the periciliary liquid layer (PCL), which underlies the mucus layer and acts as a lubricant. The other is that the depleted PCL, flattened cilia and adhesion of the thickened mucus to the apical cell surface contribute to the failure of cough-dependent clearance.61
DISORDERED REPAIR, REGENERATION AND CONSEQUENT REMODELLING OF AIRWAYS ACTIVELY CONTRIBUTE TO AIRFLOW LIMITATION IN COPD In addition to mucus accumulation in airway lumen, thickening of airway wall tissue associated with BEC repair, squamous metaplasia and increased amounts of ECM deposition are also features of airway remodelling in COPD. Under normal conditions, acute exposure of epithelial cells to inhaled toxic insults induces Respirology (2015) 20, 722–729
repair and regeneration, which ad integrum leaves no residual trace of the previous injury. However, CS exposure not only impairs the wound repair in injured airway epithelial cells,62 but also induces imbalanced DNA methylation contributing to airway remodelling and regeneration.39 Any delay or interruption in the normal repair and regeneration process may lead to ECM deposition and airway fibrosis. Epithelial–mesenchymal transition (EMT) is a process accompanied with progressive loss of epithelial markers, gain in migratory and invasive potential and elevated ability to produce ECM components,63 which all contribute to airway wall fibrosis and thickening. Zhang et al. demonstrated that EMT occurs in human BEC stimulated by TGF-β1,64 while Sohal et al. reported that EMT may be an active process in COPD airways.65 In addition, BEC can produce various inflammatory mediators like TGF-β26 to stimulate fibroblasts to produce ECM constituents. MMPs, expressed by migrating epithelial cells, have key functions in the migration of BEC (MMP-9), the shift from an epithelial to a mesenchymal phenotype (MMP-3 and MMP-11) and degradation of ECM components during the tissue remodelling process (MMP-12).66,67 Thus dysregulated production and activation of mediators by altered epithelial cells will lead to an imbalance of ECM turnover and induce degradation in lung parenchyma and deposition in bronchi and bronchioles in COPD.
CONCLUSIONS AND FUTURE DIRECTIONS Several mechanisms have been implicated in the pathogenesis of COPD, including immune dysregulation, exaggerated chronic inflammation and oxidant/antioxidant imbalance in response to © 2015 Asian Pacific Society of Respirology
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inhaled insults. As the first line of defence against noxious insults, the human bronchial epithelium exerts a negative regulatory function in preventing the onset of COPD. Upon repeated environmental challenge, BEC serve as a switchboard to initiate and orchestrate immune responses through the release of chemokines and cytokines, which recruit and activate inflammatory cells. Impaired epithelial cells produce a disorganized immune response and heightened inflammatory processes. Besides, they not only generate excess ROS, but also impair antioxidant gene expression in BEC,50 leading to an oxidant/ antioxidant imbalance and lung injury. In addition, goblet cell hyperplasia, mucus accumulation, squamous epithelial metaplasia, airway wall fibrosis and thickening caused by ECM deposition underlying the epithelium are major characteristics of COPD and can cause small airway obstruction and airflow limitation. It is noteworthy that even after smoking cessation in COPD patients, pulmonary inflammation and oxidative stress persist, which may hamper or prevent tissue repair.14 Therefore, an effective treatment regime for COPD requires stopping exposure to toxic substrates, such as CS, as well as inhibition of excessive inflammation, oxidative stress and ideally reversal of structural changes within the small airways and parenchyma.68 Considering the ability of BEC to orchestrate the myriad of downstream responses to CS, drugs that modify the pathogenic abilities of activated BEC should be effective in COPD. A consequence of preferentially targeting BEC is that downstream effects on inflammatory cell recruitment and on airway remodelling should also be improved without the need for separate therapies. Besides, as aberrant DNA methylation is a genome-wide phenomenon in small airways of COPD patients,39 the development of novel treatment strategies or the existing epigenetic-based drugs may contribute to the treatment or prevention of COPD. For example, nucleoside analogues such as 5-azacytidine act as DNA methyltransferase (DNMT) inhibitors and substitute cytidine in the DNA strand. DNMT use them as substrate analogs, which subsequently blocks enzyme activity and results in DNA hypomethylation. As such, these inhibitors may represent a promising combination therapy for COPD in addition to existing therapy.69
Acknowledgements We wish to thank Rongbin Yu for administrative support during the initial drafting of the review; and Ji Zhou, Hui Bi and Dandan Wu for their suggestions and comments during the systemic review process. This work was supported by National Nature Science Foundation of China (No. 81470237, 81070025), the National Major Scientific and Technological Special Project for Significant New Drug Development (No. 2011ZX09302-003-02), and the Priority Academic Program Development of Jiangsu Higher Education Institutions (No. JX10231801). I.M.A. and P.J.B. are supported by grants from the Medical Research Council (MRC) (G0801266) and Wellcome Trust (093080/Z/10/Z).
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