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The genetic and epigenetic landscapes of the epithelium in asthma Moheimani, Fatemeh; Hsu, Alan C; Reid, Andrew T; Williams, Teresa; Kicic, Anthony; Stick, Stephen M; Hansbro, Philip M; Wark, Peter A; Knight, Darryl A Sep 22, 2016

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REVIEW Open AccessThe genetic and epigenetic landscapes ofthe epithelium in asthmaFatemeh Moheimani1,2* , Alan C-Y Hsu1,2, Andrew T Reid1,2, Teresa Williams1,2,3, Anthony Kicic4,5,6,7,Stephen M. Stick4,5,6,7, Philip M. Hansbro1,2, Peter A.B. Wark2,8 and Darryl A. Knight1,2,9AbstractAsthma is a global health problem with increasing prevalence. The airway epithelium is the initial barrier againstinhaled noxious agents or aeroallergens. In asthma, the airway epithelium suffers from structural and functionalabnormalities and as such, is more susceptible to normally innocuous environmental stimuli. The epithelial structuraland functional impairments are now recognised as a significant contributing factor to asthma pathogenesis. Bothgenetic and environmental risk factors play important roles in the development of asthma with an increasing numberof genes associated with asthma susceptibility being expressed in airway epithelium. Epigenetic factors that regulateairway epithelial structure and function are also an attractive area for assessment of susceptibility to asthma. In thisreview we provide a comprehensive discussion on genetic factors; from using linkage designs and candidate geneassociation studies to genome-wide association studies and whole genome sequencing, and epigenetic factors; DNAmethylation, histone modifications, and non-coding RNAs (especially microRNAs), in airway epithelial cells that arefunctionally associated with asthma pathogenesis. Our aims were to introduce potential predictors or therapeutictargets for asthma in airway epithelium. Overall, we found very small overlap in asthma susceptibility genes identifiedwith different technologies. Some potential biomarkers are IRAKM, PCDH1, ORMDL3/GSDMB, IL-33, CDHR3 and CST1 inairway epithelial cells. Recent studies on epigenetic regulatory factors have further provided novel insights to the field,particularly their effect on regulation of some of the asthma susceptibility genes (e.g. methylation of ADAM33).Among the epigenetic regulatory mechanisms, microRNA networks have been shown to regulate a majorportion of post-transcriptional gene regulation. Particularly, miR-19a may have some therapeutic potential.Keywords: Epithelial cells, Asthma, Genes, DNA methylation, Histone acetylation, microRNABackgroundAsthma affects people of all ethnicities and ages andthere has been a substantial increase in the prevalence ofasthma over the past few decades, with current estimatesof approximately 300 million people suffering from thedisease worldwide [1]. Asthma is characterised by cough-ing, shortness of breath, chest tightness and wheezing,often triggered by exposure to allergens and foreign patho-gens [1]. The initial response consists primarily of airwaysmooth muscle constriction and airway inflammation(oedema, inflammatory cell infiltration, increased airwaysecretions). Whereas more chronic responses such asstructural remodelling of the airway including smoothmuscle and sub-mucosal gland hyperplasia and hyper-trophy, extracellular matrix (ECM) deposition and angio-genesis are generally thought to occur in parallel withinflammatory responses [1].The airway epithelium is the interface between the res-pirable environment and the sub-mucosa and acts as thefirst defence line against inhaled noxious agents andaeroallergens [2]. The epithelium of conducting airwaysis pseudo-stratified and consists of ciliated columnar epi-thelial cells, goblet cells, intermediate columnar epithe-lial cells, side population cells, serous cells, and basalcells [3]. The epithelium of asthmatics presents severalstructural and functional abnormalities, including agreater proportion of resident stem cells and basal cells,goblet-cell hyperplasia and excessive mucus production* Correspondence: fatemeh.moheimani@newcastle.edu.au1School of Biomedical Sciences and Pharmacy, Faculty of Health andMedicine, HMRI building, The University of Newcastle, Callaghan, NSW 2308,Australia2Priority Research Centre for Healthy Lungs, Hunter Medical ResearchInstitute, The University of Newcastle, New South Wales, AustraliaFull list of author information is available at the end of the article© 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Moheimani et al. Respiratory Research  (2016) 17:119 DOI 10.1186/s12931-016-0434-4as well as fewer ciliated cells compared to healthy individ-uals, suggesting dysregulated differentiation [4, 5]. Theepithelial abnormalities are associated with increasedsusceptibility to oxidant-induced stress, aberrant cyto-kine and ECM release [6], mitotic dyssynchrony [7]and a deficient innate immune response [8–10]. Theseabnormalities also affect epithelial repair and regener-ation processes after injury, leading to defective main-tenance of the epithelial barrier and its normalfunction [2, 11, 12].Both genetic susceptibility and environmental risk factorsinfluence asthma [13]. Genetic studies have progressedfrom using linkage designs and candidate gene associationstudies to genome-wide association studies (GWAS) [14]and whole genome sequencing (WGS) [15], and detecteddifferent genes associated with asthma susceptibility. Sev-eral of the recent GWAS have shown to have a significantepithelial contribution, which also segregates away from al-lergy/atopy. Furthermore, different environmental chal-lenges (such as smoking, air pollution, and microbialexposures) can affect gene expression through epigeneticregulation. Epigenetic factors are an important regulator ofgene transcription, that do not influence gene sequence[16]. Epigenetic mechanisms include DNA methylation,histone modifications, and regulation by non-coding RNAs,especially microRNAs (miRNAs). This review will focus onidentifying genetic and epigenetic candidates in airwayepithelium, which are functionally associated with asthmaand may act as predictors or therapeutic targets.Asthma susceptibility genes in airway epitheliumEarly genetic studies relied on positional cloning in com-bination with linkage analysis leading to detection ofgenes associated with asthma expressed in airway epithe-lium including A disintegrin and metalloprotease 33(ADAM33), GPRA, protocadherin-1 (PCDH1), Serineprotease inhibitor Kazal type-5 (SPINK5), IL-1 receptorassociated kinase-M (IRAKM), Dipeptidyl-peptidase 10(DPP10) and HLA-G genes (Table 1) [17–31]. ADAM33on chromosome 20p13, was the first asthma susceptibil-ity gene discovered [17]. ADAM33 protein is expressedin many cells including the airway epithelium [18], fibro-blasts and smooth muscle cells [17, 18, 32] and is knownas a membrane-anchored metalloprotease with diversefunctions, including shedding of cell-surface proteinssuch as cytokines and cytokine receptors [17]. ADAM33has be associated with airway remodelling and bronchialhyperresponsiveness (BHR) through epithelial–mesen-chymal trophic unit (EMTU), leading to proliferation ofbiosynthetically active fibroblasts, myofibroblasts andsmooth muscle [17]. PCDH1 is located on chromosome5q31-q33 and encodes the protocadherin-1 protein[22, 23]. The expression of PCDH1 is aligned with theapical adhesion complex expression in airway epithelialTable 1 Asthma susceptibility genes identified by positional cloning and genome-wide association (GWAS) in airway epitheliumPositional cloningChromosome Gene Function Reference20p13 ADAM33 Airway remodelling and BHR [17]5q31-q33 PCDH1a Airway remodelling and BHR [22–24]2q14-32 DPP10 BHR [27–29]6p21 HLA-G BHR [30, 31]7p15-p14 GPRA/NPSR1/GPR154 Cell homeostasis [19–21]5q31-35 SPINK5/LEKTI Protective against allergen/inflammation [25]12q13-24 IRAKMb Inflammation [26]Genome-wide association (GWAS) and associated SNPChromosome SNP Gene Function References2 rs3771166 IL1RL1 andIL18R1Alarmin to alert the immune system after epithelial cell damageduring trauma or infection[45, 50]6 re9273349 HLA-DQ Recognition of non-self antigens [13]9 rs1342326 IL33+ Alarmin [13, 50]15 rs744910 SMAD3 TGF-β1 signaling and response to respiratory viral infection [50, 57–59]17 rs2305480 ORMDL3b+GSDMBb+BHREpithelial cell homeostasis[13, 64, 66–68]5 rs1837253 TSLP+ Epithelial cell homeostasis and improving wound healing-Protectiverole against asthma[42, 43, 71–74]aAdult and childrenbEarly onset+common between different ethnic groupMoheimani et al. Respiratory Research  (2016) 17:119 Page 2 of 15cells hence association of PCDH1 with asthma is proposedto be through epithelial structural defects leading to BHR[22, 23] and is IgE independent [24]. Dysregulation ofPCDH1 expression in asthma also leads to impaired differ-entiation of epithelial cells [23]. Another gene is DPP10which shown to preferentially expressed in the epitheliumof asthmatics [27]. DPP10, is located on 2q14-32 and en-codes the di-peptidyl peptidase like 10 protein, which un-like other members of DPP family is unable to cleave theterminal of dipeptides from cytokines and chemokines[27, 28]. These suggest other potential mechanisms forDPP10 association with asthma. In the nervous system,DPP10 has been shown to modulate the electrophysio-logical properties, cell-surface expression and subcellularlocalisation of voltage-gated potassium channels [33].Considering the important role of potassium ion channelsin asthma [34], DPP10 may also be involved in thisprocess although this requires further investigation. Fur-thermore, Zhou et al. reported the association of DPP10with BHR in Chinese population [29]. HLA-G on chromo-some 6p21 is also expressed highly in bronchial epithelialcells of asthmatics and is associated with BHR [30].HLA-G inhibits the effecter function of T cells and nat-ural killer (NK) cells [35]. Three miRNAs; miR-148a,miR-148b, and miR-152 have been reported to affectHLA-G expression, suggesting that miRNA mediatedmechanisms may contribute to the impact of HLA-Gon asthma risk [31].Other studies detected GPRA (also known as Neuro-peptide S Receptor 1; NPSR1, and GPR154) on chromo-some 7p15-p14 [19–21]. Both GPRA, which belongs tothe G protein-coupled receptor family, and its agonist,Neuropeptide S (NPS) are co-expressed in bronchial epi-thelium and specific activation of the GPRA-A isoformwith NPS inhibits cell growth [19, 20]. Since the balancebetween epithelial cell proliferation and regeneration isdysregulated in asthmatics [4, 36], GPRA likely plays animportant role in the pathogenesis of disease [19, 20].Further studies identified the SPINK5 gene on chromosome5q31-35 which encodes a multidomain serine proteaseinhibitor known as lympho-epithelial Kazal-type-relatedinhibitor (LEKTI). LEKTI has been shown to be a majorphysiological inhibitor of multiple serine proteinases, in-cluding the exogenous serine proteases trypsin, plasmin,subtilisin A, cathepsin G and neutrophil elastase [37].SPINK5 is essential in the epidermal barrier functionthrough regulating protease activity [38] and LEKTI playsa crucial role in skin homeostasis by selectively inhibitinghuman kallikrein-related peptidase genes including, KLK5,KLK7 and KLK14 [39]. LEKTI may therefore protect theepithelium against allergens or inflammatory related pro-teases. However, the exact function of SPINK5 in airwayepithelium remains to be elucidated. Another asthma sus-ceptibly gene is IRAKM, which is located on chromosome12q13-24. IRAK-M regulates NF-kB and inflammation viasuppressing Toll-like receptor/IL-1R pathways. WhenIRAK-M function is hampered, overproduction of inflam-matory cytokines in the lung in response to infection/aller-gens may result in a Th2-mediated allergic response and/or Th1-dependent exacerbation of asthma symptoms [26].Further technological advances led to GWAS [40], andassociated single nucleotide polymorphisms (SNPs) [13],which detected a completely different set of genes; inter-leukin (IL) 1 receptor-like 1 (IL1RL1) and IL18 receptor1 (IL18R1), IL33, HLA-DQ, SMAD3, thymic stromallymphopoietin (TSLP), ORM1-like 3 (ORMDL3) andgasdermin B (GSDMB) as asthma susceptibility genesexpressed in airway epithelium (Table 1) [13, 14, 41–43].IL1RL1 and IL18R1 contain SNP rs3771166 on chromo-some 2 [13, 44]. IL1RL1 (also known as T1, ST2, DER4,or FIT-1) belongs to the IL-1 superfamily and is the re-ceptor for IL-33 [45]. IL33 with SNP rs1342326 locatedon chromosome 9 is also associated with atopic asthma[13, 46, 47]. IL-33 possesses potent transcriptional-repressive properties and is constitutively expressed inepithelial cells [48]. It has been shown that IL-33 activatesNF-kB and mitogen-activated protein (MAP) kinases, andinduces production of T-helper (Th) 2-associated cyto-kines, including IL-4, IL-5, and IL-13 [49]. In this context,IL-33 functions as a prototypical ‘alarmin’ and an en-dogenous ‘danger’ signal to alert the immune system afterepithelial cell damage during trauma or infection [50] andplays an essential role in pro-inflammatory pathway inasthma [13]. IL18R1 encodes the receptor for IL-18 [45].IL-18 modulates innate and adaptive immune responsesby increasing interferon (IFN)-γ production by Th1 andnatural killer (NK) cells or by activating IgE productionand Th2 cell differentiation [45].Another candidate gene detected by GWAS is HLA-DQregion of the major histocompatibility (MHC) gene lo-cated on chromosome 6, which contains SNP rs9273349[51]. The airway epithelium expresses MHC class II; a het-erodimer molecule that consists of an α- and a β-chain inone of three HLA loci: DR, DP and DQ [52], on theirsurface [53]. Immune response to allergens is also re-lated to specific HLA-DR and DQ haplotypes [13], andis associated with asthma induced by house dust mite,aspirin, soybean, and occupational triggers [54]. How-ever, the exact role of HLA-DQ in airway epitheliumstill remains unclear.SMAD3, with SNP rs744910 located on chromosome15, is another asthma susceptibility gene [13]. SMAD3 isan essential signal transducer in transforming growthfactor (TGF)-β signalling, which is elevated in airwayepithelial cells of some asthmatics [55]. TGF-β1 inducesepithelial–mesenchymal transition (EMT) in airwayepithelial cells via a SMAD3-dependent transcriptionfactor snail1 (SNAI1) which transcriptionally supressesMoheimani et al. Respiratory Research  (2016) 17:119 Page 3 of 15E-cadherin [36, 56]. Furthermore, the TGF-β/SMAD3pathway play essential roles in the airway epithelial re-sponse to respiratory viral infection [57–59], includingincreasing replication of both respiratory syncytial virus[57, 58] and rhinovirus [59].Among asthma susceptibility genes, ORMDL3 andGSDMB, with SNP rs2305480 at chromosome 17q21,are associated with childhood asthma [60]. ORMDL3 isa member of a gene family that encodes transmembraneproteins anchored in the endoplasmic reticulum of airwayepithelial cells, predominantly [60, 61]. Allergens induceORMDL3 expression in airway epithelium leading to in-creased expression of asthma-associated chemokines,metalloproteases and the unfolded protein response(UPR), which may implicate the potential link betweenORMDL3 and asthma [61]. ORMDL regulates ORMprotein expression in airway epithelial cells, which isinduced in response to allergen challenge [62]. ORMproteins are important homeostatic regulators of sphingo-lipid metabolism [63], which is associated with the patho-genesis of asthma [64]. Sphingolipids are pivotal inmaintenance of cell structure and signaling pathways inphysiological and pathological processes; e.g. proliferation,apoptosis and migration [63, 65] and have been shown tocontribute to BHR in experimental models of asthma [66].Further meta-analysis has showed that SNP rs7216389 inthe ORMDL3 may play essential and independent predis-posing roles in ethnically diverse populations for bothchildhood and adult-onset asthma [41]. GSDMB is adja-cent to ORMDL3 and is a member of gasdermin familythat encodes gasdermin B protein which has roles insecretory pathways, epithelial cell differentiation, cell cyclecontrol and apoptosis [67, 68]. Furthermore, there are sev-eral response elements for interferon regulatory factorspresent in the GSDMB promoter region and epithelialinterferon-α induces GSDMB gene and protein in humannasal epithelial cells, in vitro [69]. GSDMB has beenproposed to be the causative gene associated withasthma [70].Among the candidate genes identified by GWAS, TSLPon chromosome 5 plays protective roles against the riskof asthma, atopic asthma and BHR across various ethnicgroups [42, 43, 71–73]. The rs1837253 SNP may be dir-ectly involved in the regulation of TSLP secretion inprimary nasal epithelial cells [42]. TSLP is an IL-7 likecytokine that induces myeloid dendritic cells to stimu-late the differentiation of naive CD4+ T cells to Th2cells. TSLP mRNA and protein are highly expressed inthe asthmatic airway epithelium [72–74]. TSLP hasbeen shown to induce bronchial epithelial cell prolifer-ation and increases repair responses to injury throughIL-13 production [74].Collectively these genes are important in epithelialcell damage, innate and adaptive immunity, and airwayinflammation, which are pivotal in the pathology ofasthma. Furthermore, some of the products associatedwith these genes can determine the phenotype of asthma.For instance, the level of IL-33 is highly elevated andwidely distributed in bronchial epithelial cells of moderateand severe asthmatics [48]. IL-18 may also contribute toasthma exacerbations in mild and moderate asthmaticsthrough activation of immunologic responses [51]. Giventhe relationship to asthma endotypes, these genes may in-dicate pathways for therapeutic intervention. In fact, PhaseII trials are currently proceeding using an anti-TSLP anti-body; AMG 157 from Amgen Corp., to neutralise theTSLP cytokine for the treatment of allergic diseases asasthma [75].Notably, only a few genes, such as IL33 and TSLP, areshared among all asthmatics [42, 76, 77] and may playroles as potential biomarkers. Furthermore, while theassociation of the 17q21 locus (ORMD/GSDMB) withasthma is the most consistent finding from differentstudies, there is limited evidence to validate certainSNPs [14]. Integrative genomics defined as identificationof causal genes and variants, with improved statisticalpower, is a promising new approach. By using gene ex-pression as a phenotype and examining how DNApolymorphisms contribute to both gene expression(expression quantitative trait loci; eQTLs) and diseasephenotypes, true causal relationships can be discovered[78–80]. Although GWAS have identified loci that arestrongly associated with asthma, the molecular mecha-nisms underlying these associations rely on other technol-ogy such as eQTLs [78].One eQTL study showed that chromosome 17q21,which contained strong GWAS hits, also regulates ex-pression levels of cyclin-dependent kinase 12 (CDK12),protein phosphatase 1 regulatory subunit 1B (PPP1R1B),titin-cap (TCAP) and StAR-related lipid transfer(START) domain containing 3 (STARD3) genes in theairway epithelium [78]. CDK12 is a member of thecyclin-dependent kinase (CDK) family, which areserine/threonine kinases regulating cell cycle progression[78, 81]. Airway epithelial cells from asthmatics overexpressthe CDK inhibitor; p21waf [82], which may explain the ab-normal repair responses of the airway epithelium of asth-matics after wounding [82]. However, the role of TCAP,PPP1R1B, STARD3 in asthma are still unknown [78]. Fur-thermore, epithelial eQTL detected Cystatin SN (CST1) onchromosome 20p11.21, which contains SNP rs16856186[78]. CST1 may neutralise cystatin C; a potent cathepsinB inhibitor, and increase cell proliferation [83]. CST1 isexpressed differentially in airway cells of asthmaticswith exercise-induced bronchoconstriction (EIB) comparedto asthmatics without EIB [84]. eQTL also confirmedcadherin-related family member 3 (CDHR3) gene, as anepithelial susceptibly gene for severe exacerbations inMoheimani et al. Respiratory Research  (2016) 17:119 Page 4 of 15childhood asthma [78, 85]. CDHR3 encodes a hemophiliccell adhesion molecule, which may be involved in maintain-ing cell integrity by forming cell-cell junctions. Further-more, functional disruption of CDHR3 has been reportedin human rhinovirus-induced asthma exacerbation [86].Also, epithelial eQTL supported SPINK5 as an asthma sus-ceptibility gene [86], as described earlier.It is also essential to note that in a disease as complexas asthma, it is unlikely that one or a few functional genevariants will be responsible for all pathophysiologicalevents. While GWAS have been useful and continue toidentify novel genes for allergic diseases through in-creased sample sizes and phenotype refinement, furtherapproaches to integrate analyses of rare variants, eQTLapproaches, and epigenetic mechanisms will likely leadto greater insight into the genetic basis of the disease.The advent of whole genome sequencing (WGS), whichincludes copy number variants (CNVs) and low-frequencyvariants, has been proposed to overcome the drawbacks ofthe earlier technologies [15, 76]. CNVs, which are geneticvariants including the deletion or duplication of more than50 bp of gene sequence [15], are one the most recent ad-vances to detect asthma susceptibility genes. Recently, anassociation between a 6 kbp deletion in an intron ofNEDD4L with increased risk of asthma was reported butonly in Hutterites [15]. NEDD4L is expressed in bronchialepithelial cells, and NEDD4L knockout mice showed se-vere airway inflammation and mucus accumulation [15].To adequately assess the entire genome, a large numberof genetic polymorphisms (250,000 to 1 million) is requiredand the number of polymorphisms will vary between stud-ies due to different levels of linkage disequilibrium [14].Currently, WGS is neither affordable nor feasible on thelarge number of individuals to acquire sufficient power fordetecting associations with asthma [15].Effect of environmental exposure on asthmaEnvironmental factors play essential roles in asthma aeti-ology. The increase in the prevalence of asthma world-wide during recent decades, the substantial variations inpopulations with a similar racial and ethnic backgroundbut exposed to different environmental stimuli, and thesignificant increase in the frequency of occupationalasthma are all pointing out toward the important role ofenvironmental factors [87].Environmental stimuli affecting asthma are categorisedto outdoor and indoor factors. Outdoor stimuli thattrigger or exacerbate asthma include microbial and viralpathogens, airborne particulates, ozone, diesel exhaustparticles, pollens, outdoor moulds, environmental tobaccosmoke, cold air, and humidity [87, 88]. Indoor environ-mental factors include allergens derived from dust mites,cockroaches, mice and pets which has been shown to in-duce airway inflammation; particles generated from indoorburning of tobacco, wood, and biomass; and biologicalagents such as indoor endotoxin, products from gram-positive bacteria, and 1,3-β-glucans from moulds [87, 88].In particular relation to asthma susceptibility, the ex-posure to specific environmental factors can play keyfactor in the induction or suppression of asthma-relatedgenes. The main areas of studies in regards to the impactof gene-environment interactions on asthma developmentand pathogenesis have been so far related to smoking, airpollution, and microbial exposures. Maternal smoking isone of the major risk factor for asthma in offspring. Ma-ternal smoking substantially enhances the strength of thelinkage signal on chromosome 5q31–34 to asthma in thechildren [89, 90]. Furthermore, polymorphic variationin candidate genes known to be involved in asthma, forexample TNF-308 and glutathione-S-transferase M1(GSTM1; involved in detoxification of oxidative stressand lung function growth in children), are predictors ofBHR to passive smoking [89, 91]. The most well-knowninteraction between environmental factors and gene isbetween endotoxin with Toll like receptor (TLR)-4 withfurther impact on adaptive immune response, epithelialand smooth muscle cells through NF-kB. Polymorph-ism in TLR-4 is related to asthma and it is proposedthat the other TLRs (e.g. TLR-9 and -3) present thesimilar polymorphic associations with other environ-mental stimuli, such as CpG methylation of TLR-9 anddouble-stranded RNA (dsRNA) for TLR-3 [89, 92].These reports point out to the importance of early lifeenvironmental factors, such as passive smoking, pollu-tant exposure and viral infections, as a perverse factoron the developing asthma in childhood.However little is known about the effect ofenvironmental-gene interactions in airway epitheliumof asthmatics. It has been shown that particulate matterwith a diameter of <10 μm diameter (known as PM10) in-creases HAT activity and the level of acetylated histone 4(H4) through oxidative stress. PM10 induced histoneacetylation is associated with promoter region of the IL-8resulting in increased IL-8 gene and protein release fromalveolar epithelial (A549) cells [93]. Interestingly, butyrate;a fermentation product of intestinal bacteria, also showedto enhance histone acetylation by inhibition of HDACenzymes leading to an increase in gene expression ofinflammatory cytokines in intestinal epithelial cells [94].Cigarette smoke-induced oxidative stress also reducesHDAC2 and increases cytokines expression in alveolarmacrophages [95] but the effect on airway epithelium isyet to be determined.Most importantly, many of the indoor and outdoorasthma triggers also have demonstrable reprogrammingeffects on the immature airway during early life, leadingto altered asthma risk in later life. Asthma hence is not ahomogeneous disease but a condition influenced byMoheimani et al. Respiratory Research  (2016) 17:119 Page 5 of 15interactions between genetic and environmental factorsthrough epigenetic mechanisms that influence geneexpression.Epigenetic regulatory factors in airway epitheliumEnvironmental challenges can affect gene expressionthrough epigenetic mechanisms. Epigenetics is describedas a heritable regulation of gene transcription that doesnot require alterations in gene sequence [16]. Epigeneticchanges may form stable heritable changes in gene ex-pression and in a tissue-specific fashion [96, 97]. Par-ticularly, epigenetic regulation affects gene expressionthrough three main mechanisms, including DNA modi-fications, histone modifications, and non-coding RNAs(Fig. 1 and Table 2).DNA modificationsModification of DNA occurs through addition or re-moval of small covalent molecules such as methyl oracetyl groups. DNA methylation occurs when methylgroups are added by a DNA methyltransferase (DNMT),onto cytosine nucleotides that are followed by guanineresidues (CpG sites). Gene promoters are relatively richin CpG sites which are known as CpG islands. DNAmethylation can lead to gene expression silencing throughformation of 5-methyl-cytosine (5mC) [98].Recent studies have characterised a number of DNAmethylation signatures in epithelial cells of asthmatics,including cytokeratin 5 (KRT5) [99], signal transducer andactivator of transcription 5A (STAT5A) [99], cysteine-richprotein 1 (CRIP1) [99], arginase 2 (ARG2) [100], IL-6[98], inducible nitric oxide synthase (iNOS) [98] andADAM33 [101] (Table 2).KRT5 is a marker of basal cells and its expression is in-creased in the epithelium of asthmatics [5, 36]. In asthmaticchildren, KRT5 exhibits reduced methylation resulting inincreased expression of this gene [97, 99]. Increased KRT5may hence be associated with dysregulated epithelium dif-ferentiation. The STAT5A transcription factor is activatedby different pro-Th2 cytokines (e.g. IL2, IL7, or TSLP) sug-gesting its significant role in promoting Th2 cell differenti-ation and responses [102] and epithelial cell proliferation[103]. CRIP1 has been reported to play a role in cell motil-ity, adhesion, and structure through interaction with thecytoskeletal protein actin [104] and also translocates to thenucleus to facilitate protein interactions important for tran-scriptional regulation [105]. The promoters of STAT5A andCRIP1 are hyper-methylated in epithelium of asthmaticchildren [99], resulting in decreased expression of STAT5A,contrary to increased CRIP1 expression [99]. Further stud-ies are therefore needed to understand the roles of STAT5Aand CRIP1 in epithelial function.Fig. 1 Epigenetic regulatory factors in airway epithelium. a DNA methylation; white circles represent unmethylated CpGs that induces geneexpression (e.g. KRT5) while black circles represent methylated CpGs that suppresses gene expression (e.g. STAT5A). b Histone acetylation; greencircles refer to acetylated histone tail that stimulate gene expression (e.g. ΔNp63) while red circles indicate free histone tails that suppressed geneexpression. c Noncoding RNA; miRNAs affect gene expression by either RNA degradation or translational inhibition. miRNAs hence (e.g. miR-19a)may suppress mRNA expression (e.g. TGF-β receptor 2)Moheimani et al. Respiratory Research  (2016) 17:119 Page 6 of 15ARG2, IL-6 and iNOS are three methylated genes thathave been related to fractional exhalation of nitric oxide(FeNO) in asthmatic children [98, 100, 106]. Methylationof the ARG2 promoter in asthmatic children is associ-ated with reduced FeNO [100]. However, asthmaticchildren with lower DNA methylation of the IL-6 andiNOS promoters in nasal epithelial cells had higher air-way inflammation, as measured by increased FeNO[98]. Therefore, further investigation is required to de-termine the underlying biological mechanisms drivingthe association of these DNA methylations with FeNOand whether children with different degrees of asthmaseverity and symptom management have different levelsof DNA methylation.Furthermore, hyper-methylation on ADAM33 in bron-chial epithelial cells is strongly associated with BHR,irrespective of asthma status [101]. This is in contrastto ADAM33 hypo-methylation in fibroblasts, which isspeculated to be involved in airway remodelling [107].This highlights the importance of cell specific epigeneticchanges, as well as the potential challenges in developingnovel therapeutics.Recently, DNA methylation has been shown to occurin airway epithelial cells isolated from asthmatics after asingle 24 h exposure to IL-13 [108]. Intriguingly, areasof methylation were mainly adjacent to asthma suscepti-bility genes and in particular genes related to fibroticand inflammatory pathways (e.g. neutrophil cytosolic fac-tor 2; NCF2, and MMP14) [108]. Global and gene specificmethylation status in the airway epithelium however stillrequires further investigation before potential targets canbe identified and trialled as therapies for asthma.Histone modificationsThe DNA of each cell is packaged into nucleosomeswhere its 147 base pairs wrap around an octamer of fourcore histone (H2A, H2B, H3, and H4). The covalentalterations of the amino acid residues of core histoneN-terminal tails are essential for modification of thechromatin structure and regulate gene expression. ForTable 2 Epigenetic regulatory factors associated with asthma in airway epithelial cellsDNA modification signaturesGene Status Function ReferencesKRT5a Hypo-methylation Epithelial homeostasis [97, 99]STAT5Aa Hyper-methylation Immune system, Cell proliferation [99]CRIP1a Hyper-methylation Epithelial homeostasis, transcription [99]ARG2a Hyper-methylation Reduced FeNO [100]IL-6a Hypo-methylation Increased FeNO [98]iNOSa Hypo-methylation Increased FeNO [98]ADAM33 Hyper-methylation BHR [101]Histone modification signaturesHDAC/HAT Status Function ReferencesH3K18 Acetylation Increases the expression of ΔNp63, EGFR and STAT6 affecting epithelial homeostasis [109]HDAC2a De-acetylation Anti-inflammatory [112]miRNA signaturesmiRNA Status Function Referenceslet-7fb Overexpressed unknown [121]miR-487bbmiR-181cbmiR-203b Suppressed Targeting p63 and c-Abl [121–123]miR-34/449 family Suppressed Targeting NOTCH1 mRNA and affecting cell homeostasis [125]miR-18a Suppressed activation/signalling of IL-6 and IL-8 [129]miR-27amiR-128miR-155miR-19ac Overexpressed Targeting TGF-β receptor 2 mRNA and affecting cell homeostasis [130]aChildrenbMild asthmacSevere asthmaMoheimani et al. Respiratory Research  (2016) 17:119 Page 7 of 15example, the acetylation of lysine residues on histonetails via histone acetyltransferases (HATs), generally re-sults in increased gene transcription whereas removal ofthe acetyl group via deacetylases (HDACs) leads to genesuppression. In contrast, methylation of histone tails canbe both activating and suppressing depending on the par-ticular residue. Methyl groups are added to lysine or argin-ine residues by histone methyltransferases (HMTs) andremoved by histone demethylases (HDMs) [109, 110].Increased HAT activity and reduced HDAC activity inbiopsies from mild asthmatics have been reported tolead to the increased expression of multiple inflammatorygenes [111]. Interestingly, these activities may be partiallyreversed by treatment with inhaled corticosteroids [111].Furthermore, within the adult airway epithelium, elevatedhistone H3 lysine 18 (H3K18) acetylation and histone H3lysine 9 trimethylation (H3K9me3) have been shown inasthmatics [109]. H3K18 acetylation increases the expres-sion of ΔNp63, EGFR, and STAT6, which, are known to bealtered in the epithelium of asthmatics [109]. Very fewstudies have investigated histone modifications in childrenwith asthma. In one study, passive cigarette smoke re-duced HDAC2 activity and protein expression via PI3Ksignalling in children with severe asthma. This is believedto suppress the anti-inflammatory effects of corticosteroidtreatment [112] (Table 2).Whether histone modifications in epithelial cells aremajor contributors in conferring asthma susceptibilityand/or severity remains to be determined.Non-coding RNAsA number of classes of noncoding RNAs have been dis-covered in mammalian cells including long non-codingRNAs (lncRNAs), Piwi-interacting RNAs (piRNAs), andmiRNAs.lncRNAs are non-protein coding RNA transcripts lon-ger than 200 nucleotides. There are approximately15,000 lncRNAs discovered so far although only a smallnumber of which have been shown to be biologicallyrelevant. piRNAs are small non-coding RNAs of 26–31nucleotides long, predominantly found in spermatogenicand ovarian cells [113]. Their functions have been linkedto both epigenetic and post-transcriptional gene silencing[113]. piRNAs interact with piwi protein, a RNA-bindingprotein, which degrades target mRNAs to prevent proteintranslation [113]. There have been no studies that exten-sively investigate profiles of lncRNAs and piRNAs in airwayepithelium of asthmatics. Only one study has shown thatpiR30840 directly targets and degrades IL-4 mRNAs lead-ing to inhibition of the development of Th2 T-lymphocytes.Furthermore, the level of piR30840 is significantly reducedin serum from patients with asthma [113].miRNAs are proposed to control expression of 30–60 %of human genes [114] and hence are crucial in mostbiological and pathological processes including cellproliferation, differentiation, apoptosis, carcinogenesisand immune responses [115–117]. miRNAs are 20–24nucleotides long and bind to the 3′ untranslated region(UTR) of target mRNAs resulting in their degradation ortranslational inhibition [118–120]. Currently, there are over1000 miRNAs identified in miRbase (www.mirbase.org),many of which have multiple binding partners and thusaffect multiple pathways [118]. miRNAs may modulate pro-tein synthesis at both initiation and post-initiation of trans-lation [118]. miRNAs have also been shown to up-regulatesome mRNA targets [120]. The balance between up- anddown-regulation of miRNA plays a pivotal role in cell cycleand process of cell proliferation and regeneration, a processthat is dysregulated in asthmatic epithelium. miRNAsare therefore interesting regulatory factors which maycontribute substantially to airway epithelium abnormal-ities in asthmatics.miRNA expression in epithelium of asthmaticsThere are a limited number of studies examining miRNAexpression in epithelium of asthmatics or non-asthmatics(Table 2). miRNA microarray performed on primary bron-chial epithelial cells cultured at air-liquid interface (ALI)showed higher expression of let-7f, miR-181c* and miR-487b but lower expression of miR-203 in mild asthmaticscompared with healthy controls [121]. miR-203 has beenshown to play a potent role in the (keratinocyte) self-renewal program during epidermal differentiation by target-ing p63, facilitating cell cycle exit and promoting differenti-ation [122]. Given that the epithelium of asthmaticsexpresses higher levels of p63 [36], it is intriguing to specu-late that there is a direct link between miR-203 and p63(Fig. 2). Recently, miR-203 has also been shown to inhibitairway smooth cell proliferation through targeting the non-receptor tyrosine kinase c-Abl (Abelson tyrosine kinase,Abl, ABL1) [123]. In particular, Abl kinases regulate cell-cell adhesion in epithelial cells and fibroblasts throughcadherin-mediated adhesion signals via regulating the ac-tivities of the Rac and Rho GTPases [124]. Since, c-Ab1plays important roles in regulation of the actin cytoskel-eton and hence different cellular functions such as prolif-eration, cell adhesion and migration as well as growth anddevelopment [123], the reduced level of miR-203 in epi-thelial cells of asthmatics may promote cell proliferation,increase goblet cell hyperplasia and/or decrease ciliatedcells. Genome wide profiling of bronchial epithelial brush-ings also revealed four members of the miR-34/449 family(miR-34b-5p, miR-34c-5p, miR-449a, and miR-449b-5p)were significantly suppressed in asthma [125]. Interest-ingly, no clear relationship was observed betweenthese differentially expressed miRNA and serum IgElevel in asthmatics [125], which indicates the role ofthese miRNAs at cellular and molecular levels ratherMoheimani et al. Respiratory Research  (2016) 17:119 Page 8 of 15than inflammatory and allergic responses. Furthermore,inhaled corticosteroids showed only minor effects onmiRNA expression, and failed to restore miRNA levelsto healthy control levels [125]. The miR-34/449 familyare closely associated with regulation of epithelial cellproliferation and differentiation. Specifically, miR-449is essential in regulation of airway ciliated cells by tar-geting NOTCH1 [126]. Notch signaling triggers airwaymucous metaplasia and inhibits alveolar development(ciliated cells) [127]. The low level of miR-449 in epi-thelial cells of asthmatics may therefore shift the fate ofthese cells toward more mucous production (Fig. 2).Furthermore, miR-34/449-deficient mice suffer fromprimary ciliary dyskinesia (PCD). These abnormalitieshave been shown to be mediated by Cp110, a centriolarprotein suppressing cilia assembly, that is a target ofmiR-34/449 [128]. A panel of miRNAs including miR-18a,miR-27a, miR-128 and miR-155 were also down-regulatedin the epithelium of asthmatics. These miRNAs are in-volved in activation/signaling of IL-6 and IL-8 [129].Recently, miR-19a was reported to be the only miRNAthat differentiates severe from mild asthma. miR-19a isup-regulated in severe asthmatic epithelial cells and isnot restored by corticosteroids [130]. Elevated levels ofmiR-19a further stimulate cell proliferation of epithelialcells by targeting TGF-β receptor 2 mRNA. Overexpres-sion of miR-19a results in reduction in phosphorylatedSMAD3 whereas suppression of miR-19a facilitatesSMAD3 phosphorylation through TGF-β receptor 2signaling and restore epithelial cells proliferation [130].These may suggest the potential of miR-19a as a thera-peutic target in airway epithelium of asthmatics to re-establish epithelial regeneration.There are limited numbers of investigations on miR-NAs expression in asthmatic epithelium of children,possibly due to difficulty in obtaining epithelial samples.Higher level of miR-148b; a member of miR-152 family,was reported in airway epithelial cells of adults with anasthmatic mother and correlates with sHLA-G levels inthe BAL fluid of these subjects [131]. The prenatal effectsof maternal asthma on the regulation of foetal genes inairway cells may persist well into adulthood throughmiRNA regulatory mechanisms.Other miRNAs in airway epithelium with potential role inasthma developmentAirway epithelial cells display dysregulted differentiationin asthma. It is therefore important to investigate po-tential miRNAs fundamental for lung developmentand epithelial cell homeostasis such as miR-17 family[132, 133]. miR-17 family consist of three paralog clustersof miR-17–92 (miR-17-5p, miR-18, miR-19b, miR-20a,miR-92, miR-19a and miR-17-3p), miR-106a–363 (miR-106a, miR-18b, miR-20b, miR-19b-2, miR-92–2, andmiR-363), and miR-106b–25 (miR-106b, miR-93, andmiR-25) [134]. Among the miR-17 family, the miR-17-92cluster and miR-106b have been shown to be essential inmaintaining of the structural homeostasis of developinglung epithelium [132, 134]. miR-17-5p, miR-19b and miR-20 are increased in the epithelium and mesenchyme of theembryonic lung compared with fully developed lung [132].Furthermore, miR-17, miR-20a and miR-106b modulatefibroblast growth factor (FGF)10–FGFR2b signaling byspecifically targeting STAT3 and MAPK14, and alteringE-cadherin distribution. This is vital for epithelial budmorphogenesis in response to FGF10 signaling [134].Fig. 2 Role of miRNAs in airway epithelial cells regeneration. a In healthy airway epithelial cells, miR-449 suppresses NOTCH1 mRNA and encouragesdifferentiation of ciliated cells compared with goblet cells. miR-203 may paly essential role in epithelial cell homeostasis by suppressing p63 which isexpressed in basal cells. b The level of miR-449 and miR-203 are reduced in asthmatic airway epithelial cells, which may result in increase in goblet cellsand compromising epithelial cells regeneration, respectively. Solid lines and bold fonts represent strong effect and dashed lines and normal fontrepresent weak effectMoheimani et al. Respiratory Research  (2016) 17:119 Page 9 of 15STAT3 and MAPK14 signalling play important roles inairway homeostasis. STAT3 stimulates regenerationand multiciliogenesis by inhibition of the Notch path-way and direct regulation of genes such as Mcidas andFoxj1 [135]. MAPK14 (known also as p38α) has alsobeen shown to regulate lung stem or progenitor cellproliferation and differentiation [136]. MAPK14 regu-lates C/EBP and HNF3b which are necessary for thedifferentiation of the stem cells into AT2 and Claracells, while coordinately suppressing the regulators ofstem and progenitor cells proliferation; cyclin D1 andEGFR [136]. These findings emphasise the role of thesesignalling pathways as well as their regulatory miRNAs inairway epithelial cells homeostasis, which is dysregulatedin asthma. These pathways may initiate development andprogression of asthma.ConclusionsOverall, studies on asthma susceptibility genes (Table 1)and epigenetic regulatory mechanisms (Table 2) of air-way epithelial cells provide important insights in the de-velopment and progression of asthma (Fig. 3).Among susceptibility genes detected by positionalcloning (Table 1), IRAKM may represent a potential bio-marker for early onset of asthma [26] whereas PCDH1may be a potential biomarker in both children andadults [22]. Although ADAM33 protein increases in epi-thelium of asthmatics, it is not related to severity of dis-ease [18]. None of the genes listed above can predictspecific endotypes of asthma. Some genes detected byGWAS (Table 1) have shown the potential as asthmabiomarkers in a specific age group, e.g. ORMDL3/GSDMBin children [60]. However, there is little overlap betweenasthma susceptibility genes and their products detectedwith positional cloning and GWAS. Epithelial eQTL coulddetect more specific biomarkers for different phenotype ofasthma, such as CDHR3 associated with asthma in chil-dren with severe exacerbation [78, 85], and CST1 [78],which can differentiate asthmatic with EIB from thosewith no EIB [84].Asthma is a complex disease and it is unlikely thatlimited functional genes are driving the entire patho-physiological (immunological and structural) events.Other challenges for genetic assessments are neglectingFig. 3 Overview of the key genes and epigenetic regulatory mechanisms associated with asthma in airway epithelial cells. Environmental insults(e.g. allergens or viruses) may damage the integrity of airway epithelial cells. Some of the susceptibility genes expressed in the airway epithelialcells (e.g. ADAM33) may further deteriorate this structural damage through the process of epithelial–mesenchymal trophic unit (EMTU) and henceencouraging airway remodelling and hyper-responsiveness. Whereas other asthma susceptibility genes (e.g. IRAKM) may promote (Th2)-immunityresult in activation of inflammatory responses. Some of the genes have more protective roles (e.g. SPINK5 and TSLP). Furthermore, epigeneticregulatory mechanisms may affect some of these genes (e.g. hyper-methylation of ADAM33, and HLA-G suppression by miRNAs)Moheimani et al. Respiratory Research  (2016) 17:119 Page 10 of 15information for rare variants in some populations, clin-ical heterogeneity of asthma and the effects of variousimportant environmental factors including smoking, airpollution, and microbial exposures. Recent studies onepigenetic regulatory factors (Table 2) have added newinsights to the field. Some of the DNA methylation sig-natures in epithelial cells of asthmatics may be involvedin epithelial homeostasis (KRT5 and STAT5A), BHR(ADAM33) and FeNO regulation (ARG2, IL-6 and iNOS)[98–101]. Notably, ADAM33 is also a target of methylation(Fig. 3) [101], which emphasises the importance of con-comitant assessment genetic and epigenetic regulatory fac-tors in airway epithelium of asthmatics. More profoundly,miRNA networks have been shown to regulate a major por-tion of post-transcriptional gene regulation [130].There are however some challenges in interpretationof miRNAs findings from different studies. One import-ant factor is the origin of samples; for example bronchialbiopsies [137] compared with cultured primary epithelialcells [121] or bronchial epithelial brushing that may in-clude other cells which may affect yield and type of de-tectable miRNAs [125]. Severity of disease [137] andvarying technologies and methods of analysis may alsoplay essential roles in outcomes of miRNAs quantifica-tions. The most common technology used is microarraywhich may ignore less abundant miRNAs and may notdistinguish miRNAs from other RNAs with similar se-quences, such as other members of the same miRNAfamily [125]. quantitative PCR is an alternative, whichdoes not necessarily measure all potentially biologicallyimportant miRNAs. Additionally, the method to analyseand present data; ΔΔCT [121, 129, 130] versus 2-ΔΔCT[137], can affect the outcomes. One potential way toovercome these inconsistencies is assessing miRNA ex-pression in primary airway epithelial cells at air liquidinterface culture; a mimic of pseudostratified physio-logical model, using technology such as NanoString thatcounts individual miRNA with high accuracy.Future prospects of miRNA researchWhile a number of miRNAs have been associated withabnormalities in asthmatic epithelium and disease pro-gression, current asthma treatments (e.g. corticosteroids)show no major effect on them [125, 130, 137]. Seeking anovel approach to target abnormally expressed miRNAsand hence restoring their normal functions may providea novel asthma intervention strategy. Specific targetingof miRNA clusters (e.g. miR-17-92 cluster with proposedproliferative roles) may restore normal epithelial homeo-stasis although off-target effects should to be carefullyevaluated. Further studies to identify specific miRNA-mRNA interactions and validation of target proteinsimportant in asthma pathogenesis may provide potentialsteps forward to providing important insights into thedevelopment of potential intervention to reverse the epithe-lial abnormities in asthmatics. Additionally, manipulatingepigenetic factors regulating miRNAs (e.g. re-expression ofmiRNAs using demethylating agents to inhibit DNAmethylation of the miRNA promoter) may provide anotherapproach to restore miRNA abnormalities in asthmatics. Itis also important to clarify whether these differences inmiRNAs are the major factors driving asthma or if thepathology of the disease induces these changes. Hence, add-itional studies in larger cohorts are essential to distinguishthe effects of different asthma medications on the expres-sion of miRNAs in bronchial epithelial cells.Overall, there are interactions between genetic factorsand epigenetic regulatory mechanisms and assessmentof only one factor may not provide enough information.miRNAs expression in conjunction with other epigeneticregulatory factors may be an essential contributing factorto asthma. Understanding the mechanisms that initiatethe development and progression of asthma, includingregulation of gene transcription or translation, are essen-tial to identify potential targets in airway epithelium forasthma intervention.Abbreviations5mC: 5-methyl-cytosine; ADAM33: A disintegrin and metalloprotease 33;ALI: Air-liquid interface; ARG2: Arginase 2; BHR: Bronchial hyperresponsiveness;CDHR3: Cadherin-related family member 3; CDK12: Cyclin-dependent kinase 12;CNVs: Copy number variants; CRIP1: Cysteine-rich protein 1; CST1: Cystatin SN;DNMT: DNA methyltransferase; DPP10: Dipeptidyl-peptidase 10; dsRNA: Double-stranded RNA; ECM: Extracellular matrix; EIB: Exercise-induced bronchoconstriction;EMT: Epithelial–mesenchymal transition; EMTU: Epithelial–mesenchymal trophicunit; eQTLs: Expression quantitative trait loci; FeNO: Fractional exhalation of nitricoxide; FGF: Fibroblast growth factor; GSDMB: Gasdermin B; GSTM1: Glutathione-S-transferase M1; GWAS: Genome-wide association studies; H3K18: Histone H3 lysine18; H3K9me3: Histone H3 lysine 9 trimethylation; HAT: Histone acetyltransferase;HDAC: Histone deacetylase; HDM: Histone demethylase; HMT: Histonemethyltransferase; IFN: Interferon; IL18R1: IL18 receptor 1; IL1RL1: Interleukin (IL) 1receptor-like 1; iNOS: inducible nitric oxide synthase; IRAKM: IL-1 receptorassociated kinase-M; KRT5: Cytokeratin 5; LEKTI: Lympho-epithelial Kazal-type-related inhibitor; lncRNA: Long non-coding RNA; MHC: Major histocompatibility;miRNAs: microRNAs; NK: Natural killer; NPSR1: Neuropeptide S Receptor 1;ORMDL3: ORM1-like 3; PCDH1: Protocadherin-1; piRNA: Piwi-interacting RNA;PM10: Particulate matter with a diameter of <10 μm diameter; PPP1R1B: Proteinphosphatase 1 regulatory subunit 1B; SNAI1: SMAD3-dependent transcriptionfactor snail1; SPINK5: Serine protease inhibitor Kazal type-5; STARD3: StAR-relatedlipid transfer (START) Domani containing 3; START: StAR-related lipid transfer;STAT5A: Signal transducer and activator of transcription 5A; TCAP: Titin-cap;TGF: Transforming growth factor; Th: T-helper; TLR: Toll like receptor;TSLP: Thymic stromal lymphopoietin; UPR: Unfolded protein response;WGS: Whole genome sequencingAcknowledgementsThe authors acknowledge the research funding from the Early CareerResearcher (ECR) Grant and New Staff Grant to FM, the University ofNewcastle; McDonald Jones Homes Group Philanthropy Grant - HMRI to FMand DK, and the National Health and Medical Research Council (NHMRC: APP1064405), Australia to DK.FundingThe Early Career Researcher (ECR) Grant and New Staff Grant to FM, theUniversity of Newcastle; McDonald Jones Homes Group PhilanthropyGrant - HMRI to FM and DK; and the National Health and MedicalResearch Council (NHMRC: APP 1064405), Australia to DK.Moheimani et al. Respiratory Research  (2016) 17:119 Page 11 of 15Availability of data and materialNot applicable.Authors’ contributionsFM and DK designed the concept and organized the review. FM, AH, AR andTW participated in drafting the manuscript. AK, SS, PH, PW and DK criticallyevaluated and improved the manuscript. All authors read and approved thefinal manuscript.Competing interestsThe authors declare that they have no competing interests.Consent for publicationNot applicable.Ethics approval and consent to participateNot applicable.Author details1School of Biomedical Sciences and Pharmacy, Faculty of Health andMedicine, HMRI building, The University of Newcastle, Callaghan, NSW 2308,Australia. 2Priority Research Centre for Healthy Lungs, Hunter MedicalResearch Institute, The University of Newcastle, New South Wales, Australia.3Department of Biochemistry and Microbiology, University of Victoria,Victoria, Canada. 4Telethon Kids Institute, Centre for Health Research, TheUniversity of Western Australia, Nedlands 6009, Western Australia, Australia.5Department of Respiratory Medicine, Princess Margaret Hospital forChildren, Perth 6001, Western Australia, Australia. 6School of Paediatrics andChild Health, The University of Western Australia, Nedlands 6009, WesternAustralia, Australia. 7Centre for Cell Therapy and Regenerative Medicine,School of Medicine and Pharmacology, The University of Western Australia,Nedlands 6009, Western Australia, Australia. 8Department of Respiratory andSleep Medicine, John Hunter Hospital, New South Wales, Australia.9Department of Anesthesiology, Pharmacology and Therapeutics, Universityof British Columbia, Vancouver, Canada.Received: 22 June 2016 Accepted: 17 September 2016References1. 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