BrazJOtorhinolaryngol.2017;83(1):1---2
www.bjorl.org
Brazilian
Journal
of
OTORHINOLARYNGOLOGY
EDITORIAL
Is
there
a
role
for
regenerative
medicine
in
chronic
rhinosinusitis
with
nasal
polyps?
夽
Existe
um
papel
para
a
medicina
regenerativa
na
rinossinusite
crônica
com
pólipos
nasais?
Duringthepastfiveyears,overthan1600articleshavebeen publishedonthesubjectofChronicRhinosinusitiswithNasal Polyps(CRSwNP).Despitethis,itsphysiopathologyremains incompletelyunderstood.CRSwNPisanovertand reverber-antinflammatory disease,which leads totherecruitment of several inflammatory cells, characterized by the pres-enceofeosinophils,neutrophils,andmastcells.1Althougha
Th2-drivenresponsewasinitiallythoughttobetheprincipal inflammatorymechanismspresentinCRSwNP,itisnow rec-ognizedthatboth Th1andTh2responses canbeobserved inpatientswithCRSwNP,dependingonethnicityoron asso-ciateddiseases.1Asexample,Asianpatientsandthosewith
cysticfibrosistendtopresentmoreofaTh1-skewed inflam-matory profile as compared to European nasal polyps. It shouldbenotedthatthereasonforsuchanintense inflam-matoryprocess,andthedifferentinflammatorypatternsis stillpoorlyunderstood.
An increasedappreciation of the potential roleof the nasal epithelium and its associated barrier and defensive functions may help improve our insights into CRS patho-genesis.Emergingevidence1---3increasingly documentsthat
nasalepithelialcellsarenotsimplypassivebarriersbetween hostinteriorandexteriorenvironments,butinsteadplayan activeroleinmodulatingandcoordinatinghostresponsesto theexternalenvironment.Theyarecapableofmonitoring theenvironmentforthreatsviapathogendetection,andcan mountdefensiveresponsesbyinducingsignalingpathways, with generation of subsequent inflammation and cellular recruitment.
The integrityofthe epithelialbarrier isdeterminedby tight junctions (located more apically, and composed of
夽 Please citethis article as:Valera FC, EndamLM, IbrahimB,
BrochieroE,DesrosiersMY.Istherearoleforregenerativemedicine inchronicrhinosinusitiswithnasalpolyps?BrazJOtorhinolaryngol. 2017;83:1---2.
occluding,junctionaladhesionmoleculeAandtheclaudin family),adherensjunctions (composed by E-cadherin and catenins)anddesmosomes(composedmostlybydesmoglein anddesmocollin).2Allthesemoleculesregulatecell-to-cell
permeability,andareassociated withdifferentpathways, withdistinctrolesinhomeostasis.
Animpairedepithelialbarriercouldbearationalcause for a reverberant processsince increasedpermeability to allergens,pollutants, bacteria,viruses, fungi, andothers4
wouldfacilitatetheirpenetrationthroughintothe superfi-ciallayer.Inaddition,thiscouldcontributetodysregulated ion and fluid transport through epithelial cells as well asaltered cellular function. In support of this, disrupted epitheliahavenowbeenproventopromoteaTh2signaling atlowerairways,4 andasthma, chronicrhinosinusitisand,
more recently allergic rhinitis2 have recently been
asso-ciated with lower expression of tight junction proteins. Intriguingly,these disordersarealso sharesimilar genetic underpinnings.5
However,littleis knownaboutthepotentialcauses for this barrier defects and its real impact on CRSwNP. Do epithelialdefectsleadtoinflammation,oristhecontrary, with environmental agents contributing to dysfunctional epithelium?
Ourgroup6,7 haspreviouslyperformed pooled
Genome-WideAssociationStudy(GWAS)toevaluatepossiblegenetic polymorphismsassociated with CRS. Among the potential 400 genes identified, the most importantly related ones
wereLAMA2(laminin-␣2)andLAMB1(laminin-1).Laminins
areessentialproteinsatbasallamina,thusthisresult sug-geststhatgeneticdisturbance(s)incellularcomponentsmay leadtoepithelialdysfunctioninCRS.
Conversely, other studies have demonstrated that the epithelial barrier couldbe compromised by extrinsic fac-tors.In particular, the observedinflammation in CRS may contribute to epithelial dysfunction.Wise et al.3 showed
that primary nasal epithelial cells, when exposed to IL-4
http://dx.doi.org/10.1016/j.bjorl.2016.10.002
2 EDITORIAL
andIL-13,presentedlowerexpressionofJAM-A(junctional adhesion molecule A) and E-cadherin, with consequent diminishedtransepithelialresistance.Asimilarpatternwas observedbyRamezanpouretal.8afterprimarynasal
epithe-lialcellswereexposedtoTh17cytokines(IL-17,IL-22,and IL-26).
Bacterial factors may also play a role. Our group has demonstrated that primary nasal epithelial cells, when exposed to Pseudomonas aeruginosa diffuse mate-rial(PsaDM),exhibitedalowercapabilitytorepairwounds following injury, and also manifest a significant reduc-tionincysticfibrosistransmembraneconductanceregulator (CFTR)expressionandfunction,evenin non-cysticfibrosis patients.9,10 This finding is especially important after the
description,alsobyourgroup,11thatinhibitingCFTRin
non-CFnasalpolypssignificantlyinhibitedwoundclosure. Theseinflammatoryandinfectiouscomponentsmaynot onlyaffectmature,differentiatedcellsbutmayalsoimpact epithelial progenitor cells, thus interfering with epithe-lial regeneration and reparative processes in response to injury.Yuetal.12 demonstratedthat epithelial basalcells
fromnasalpolypsgrowandproliferateslowerthancontrol mucosa,whenbotharesubmittedtothesame experimen-tal conditions. Moreover, in our own work, we observed thatundifferentiatedbasalcellculturesraisedfrompatients withCRSwNP (without CF)exhibitedlower wound healing ratesthancontrols(unpublisheddata).
All those findings suggest that epithelial repair is impaired in patients with CRSwNP and that regenerative medicine in this disease has been poorly explored until now. Enhanced epithelial repair could interfere with the reverberantinflammatorypatternpresent inpatientswith chronicrhinosinusitis,thusallowingdiseaseresolution.This suggestsitmayrepresentan interestingnoveltherapeutic target,whichcouldbeaddressedirrespectivelyofwhether the cause was genetic or induced by external agents. Whilemostresearchesonregenerativemedicinetodayhave focused on the use of stem cells,13,14 other therapeutic
approachesaimedatimprovingepithelialregenerationand repair may offer a benefit in treating CRSwNP, either as an isolated therapy, or concomitantly with current anti-bacterialandimmunomodulatorystrategies.
Continuedeffortstobetterunderstandthemechanisms of wound healing and epithelial repair/regeneration in CRSwNP may thus yield novel therapeutic approaches for CRSwNP.BytargetingthisnovelelementofCRS pathogene-siswhichhasuntilnownotbeenaddressed,wemayusher inanewerainCRStreatment,thusimprovingoutcomesfor ourCRSpatients.
Conflicts
of
interest
Theauthorsdeclarenoconflictsofinterest.
References
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2.SteelantB,FarréR,WawrzyniakP,BelmansJ,DekimpeE, Van-heelH,etal.Impairedbarrierfunctioninpatientswithhouse dustmite-inducedallergicrhinitisisaccompaniedbydecreased
occluding and zoluna occludens-1 expression. J Allergy Clin Immunol.2016;137:1043---53.
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9.TrinhNTN,BilodeauC,MailléE,RuffinM,QuintalMC,Desrosiers MY,etal. Deleteriousimpactof Pseudomonasaeruginosa on cystic fibrosis transmembrane conductance regulator func-tion and rescue in airways epithelial cells. Eur Respir J. 2015;45:1590---602.
10.RuffinM,VilodeauC,MailléÉ,LaFayetteSL,McKayGA,Trinh NT,etal.Quorum-sensinginhibitionabrogatesthedeleterious impactofPseudomonasaeruginosaonairwayepithelialrepair. FASEBJ.2016;30:3011---25.
11.Trinh NTN, Bardou O, Privé A, Maillé E, Adam D, Lingée S, et al. Improvement of defective cystic fibrosis airways epithelial wound repair after CFTR rescue. Eur Respir J. 2012;40:1390---400.
12.Yu XM, Li CW, Chao SS, Li YY, Yan Y, Zhao XN, et al. Reduced growth and proliferation dynamics of nasal epithe-lial stem/progenitor cells in nasal polyps in vitro. Sci Rep. 2014;4:4619.
13.RosenthalN,BadylakS.Regenerativemedicine:today’s discov-eriesinformingthefutureofmedicalpractice.NPJRegenMed. 2016;1:16007.
14.Pezato R, Gregorio LC, Voegels RL, Kosugi EM, Pinna F, Perez-NovoC, etal. Hypothesesabout thepotentialrole of mesenchymalstemcellonnasalpolyposis:asoftinflamed tis-sue suffering from mechanical dysfunction. Austin Immunol. 2016;1:1004.
FabianaC.P.Valeraa,b,LeandraM.Endama,c,
BadrIbrahima,EmmanuelleBrochieroa,d,
MartinY.Desrosiersa,c,∗
aCentredeRechercheduCentreHospitalierde
l’UniversitédeMontréal(CRCHUM),Montréal,Québec,
Canada
bUniversidadedeSãoPaulo,FaculdadedeMedicinade
RibeirãoPreto(FMRP-USP),Divisãode
Otorrinolaringologia,RibeirãoPreto,SP,Brazil
cCentredeRechercheduCentreHospitalierde
l’UniversitédeMontréal(CRCHUM),Departmentof
Otolaryngology,Montréal,Québec,Canada
dUniversitédeMontréal,DepartmentofMedicine,
Montréal,Québec,Canada
∗Correspondingauthor.
