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Whenthe causeofacomplaintis anaccess problem, olfactoryability cansometimesberestoredeven
afteraconsiderableperiodoftime.Forexample,when,aftermanyyears,patientswhohadundergone
larynectomywereabletomoveairthroughtheirnosesbyconnectingatubefromthestomatothemouth,
olfactoryabilitywasrestoredtonormallevelsformostpatients.
7
Asawordofcaution,inratswithconductionproblemslikethoseaccompanyingallergicrhinitis,an
increaseinthesizeandnumberofBowmanglandsandtheinfiltrationofseveralkindsofwhitebloodcell
havebeenobservedinadditiontotheblockednasalpassages.Ifobservationsfromanimalmodelscanbe
appliedtohumans,restoring nasal airflowmaynot immediatelyresolve the olfactorycomplaint asthe
increaseinglandactivitycouldcontributetoolfactoryproblems.
8
The degreeofopennessofthe nasal cavity atsome level contributes tothefeelingof“comfortable
breathing.”Inaddition,thestimulationofcoldreceptorsandothertrigeminalreceptorsandthepresence
of a dry mucosa can all contribute to the sensation of stuffiness. Total nasal resistance may also
contribute, althoughtherearesomedatatosupportthe hypothesis thattheobstructiononthemore open
sideofthenoseisprimarilyresponsibleforthepresenceorabsenceofnasalcomplaints.
9,10
Toaddtothecomplexityoftherelationshipbetweennasalanatomyandolfactoryability,apatternhas
beenobserved in most humannoses inwhich congestion on one side of the nose is accompanied by
decongestionontheother(Fig.2.4).Thispatterniscalledthenasalcycle.Theperiodicityofthecycleis
between50minutesand7hours.Therehasevenbeenacorrelationreportedbetweenhandednessandthe
nostrilwhichisopenforalargerpercentofa24-hourperiod,suchthatleft-handedindividualsaremore
likelytohaveamore openleftnostrilandviceversaforrighthanders.Therelationshipamong single-
nostrilolfactoryability,binasalolfactoryability,andthenasalcyclehasnotyetbeenwelldescribed.
11
Fig.2.4Magneticresonanceimagesshowingtheeffectofthenasalcycleonnasalpatency.
aThewhitearrowispointingtotheairspaceintheleftnostrildefinedbytheinferiorturbinate.
bThenasalcavityofthesamepatient75minuteslater.Thewhite arrowispointingtotheairspaceintherightnostrildefinedbytheinferior
turbinate.In75minutesthedominantnostrilhaschangedfromtheleftnostriltotherightnostril.
HumidificationandthePartitioningofOdorantMoleculesintheNasalMucus
The humidificationofincomingairispossible asthe respiratoryandolfactorymucuslayersaremostly
composedofwater.Thus,whentheinspiredairisdry,waterevaporatesfromthemucusintotheinspired
air. The watery mucus can also sorb odorants as they make their way through the nose toward the
olfactory receptors. As described in detail below, this sorption is especially noteworthy for water-
soluble odorants and it can significantly reduce the number of odorant molecules delivered to the
headspaceadjacenttotheolfactoryreceptors.
12
Usingacombinationofexperimentalandmodelingtechniques,odorantsolubilityinhumannasaland
olfactorymucosahasbeendeterminedforsomeodorants.Mucosalodorantsolubilityisodorantspecific
andusuallyfollowsthe trendthatodorants with lower watersolubilityaremoresolubleinthemucosa
thanwouldbe predicted from theirwatersolubilityalone.Additionally there is a odorant-independent
increaseintheeffectivediffusiveresistanceoftheolfactorymucosacomparedwiththatofwateralone.
13
In addition to supplying water for humidification purposes, the nasal mucus serves as a trap for
particulatematter,including smoke anddustparticles, andevenairbornebacteria. The respiratoryand
olfactorycellsliningthenasalpassagewayscontaincilia,whichbeatinaslowwavelikeactionandso
movethemucusthroughthenosetothebackofthethroat.Theflowofmucustowardthebackofthethroat
is one of themechanisms by which water-soluble odorant molecules sorbed tothe mucusbathing the
olfactory receptors arecleared.Moleculessorbed inthe mucuscan also be clearedfromthe olfactory
mucosathroughodorantuptakebythecirculatorysystem.
1
Ciliopathies,diseasesinwhich thestructureandfunction ofcilia aresignificantly altered,are often
accompanied by olfactory problems. This observation underscores the important role cilia play in
olfactorytransduction.
14
InherentandImposedPatterns
Whenodorantmoleculesaredeliveredtotheheadspaceabovethemucus-coatedolfactoryreceptors,they
bindtoreceptorsitesontheciliaofolfactoryreceptorneurons(ORNs).Thisproducesachangeinthe
membranepotentialatthetipoftheolfactoryreceptorcellthat,inturn,createsanelectronicsignalthat
flows along theaxon ofthe olfactory neurontothe olfactory bulb. Theolfactorybulbis composed of
severaldifferenttypesofcell,althoughtheaxonsoftheolfactoryreceptorcellsfirstmakecontactwith
glomerularcells.
1
Like-tuned receptor cells (there are ~400 different functioning receptor cell types in the human
olfactory mucosa) send their signals to specific glomerular cells. With a few exceptions, like-tuned
olfactorysensoryneuronsaresegregatedtoalimitedpartoftheolfactoryepithelium(OE)andarethought
tobeconfinedtooneofthefournonoverlappingzones(Fig.2.5).
15–17
The physiochemical properties of incoming odorants and the distribution of like-tuned olfactory
receptorsareapparentlybothimportantintheperipheralcodingofolfactoryinformation.
Mostodorantsstimulatemorethanonetypeofreceptorcellandallproducearesponsepatternacrossthe
olfactory mucosa that is unique for that particular odorant.The axons for like-tunedolfactory neurons
innervate a limited number of glomeruli which are usually found in a specific locus in the medial
glomerular layer and another specific locus in the lateral glomerular layer. As a result, the mucosal
activitypatternismaintained,andperhapseven sharpened,intheglomerularcelllayeroftheolfactory
bulb.
15–17
There is also recent evidencefromOErecordings that is consistent withthehypothesisthat
thereisazonalexpressionofORNsinhumans.
18
ORNsareexpressedincertainzonesoftheolfactoryepithelium.
Thereisanincreasingbodyofevidencetosuggestthatthemucosaandbulbpatternsplayakeyrolein
odorantdetectionanddiscrimination.
19,20
Forexample,usingvoltage-sensitivedyes,Youngentobandhis
coworkersdemonstratedthatodorant-inducedactivitypatternsinthemucosaweresharpenedasanimals
learnedanodorantidentificationtask(Figs.2.5and2.6).
21
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Fig.2.5Mouseseptalolfactorymucosalactivitypatternsrecordedusingopticaltechniquesandthevoltage-sensitivedyedi-4-ANEPPS.The
panelsshowthecompositeaverageresponseofasetoftrainedanduntrained(control)micetoC7–C9aldehydes.Thepinkareasshowwhen
the response for the odorant of interest is larger than the response averaged across all animals and all pixels. Black represents equal
responsiveness. Forthe control animals, the response patternsfor eachof the aldehydes is differentfromthe patterns for the othertwo,
indicatingthateachodorantproducesadifferentmucosalactivitypattern.Comparingthecontrolandtrainedresponsesforeachodorant,the
areaof responsivenessseenaftertraining islarger thantheresponseseenbefore training,indicating that training increasesthe size ofthe
activitypatterns.(FigurecourtesyofDr.StevenYoungentob,SUNY,UpstateMedicalUniversity,Syracuse,NY.)
Fig.2.6Compositecolorscale-enhancedsurfaceplotsfortheseptalolfactorymucosaofthedatashowninFig.2.5.Theheightofthez-axis
correspondstoachangeinresponseforagivenodorantataparticularpixelcomparedwiththeaverageofallodorantsforthatpixel.Onlythe
regionofmaximal activityor“hotspot”fortheodorantsisshown.Theremainingareasaresettozero(greenpixels).Again,forthecontrol
animals, the response patternsfor eachaldehyde are different fromthe patternsfor theothertwo,andcomparing the control andtrained
responsesforeachodorant,theareaofresponsivenessseenaftertrainingislargerthantheresponseseenbeforetraining.(Figurecourtesyof
Dr.StevenYoungentob,SUNY,UpstateMedicalUniversity,Syracuse,NY.)
In summary, as receptor cells ofsimilar sensitivityare grouped in particular locations along the
olfactoryreceptorsheet,differentsmellsproducedifferentpatternsofelectricalactivityinboththe
mucosaandtheolfactorybulb.Thesepatternsarethoughttobeoneofthewaysinwhichthebrain
canidentifyaparticularsmell. Theelectricalpattern ofactivitycreatedbythespecifictuningand
location of olfactory receptor cells is called the “inherent” mucosal activity pattern. Again, this
patternismaintainedattheleveloftheolfactorybulb.
22
Inrats,odorantreceptor(OR)expressionpatternsintheolfactorymucosaarerestoredevenafterahigh
exposuretomethylbromidegas.Thesereconstitutedneuronshavebeenshowntohaveolfactoryfunction.
Thisobservationsuggeststhatolfactoryproblemsobservedaftersevereperipheralinjuriesarenotlikely
tobecausedbyalackofregrownolfactoryneurons,butratherbyamorecentralproblem.
22
Becausetheolfactoryreceptorsarelocatedatsomedistancefromthetipofthenose,incomingodorant
moleculesinteractwiththemucoussurfaceoftherespiratoryepitheliumastheyaredirectedtowardthe
airspace adjacent to the superior concha. The nature of this interaction depends on the physical and
chemical properties ofthe odorantmolecules themselves. For example, onewould expectthere tobe
considerablesorptionofmucosa-solubleodorantmoleculestothesurfaceoftherespiratorymucosa.Asa
result,fewerofthesemoleculeswouldreachtheolfactory receptorarea,andthosethatdidwouldtake
longerthanmoleculesofodorantsthatwerenotverysolubleinthemucosa.Inaddition,therewouldbea
spatial distribution pattern across the receptor sheet itself, with most of the mucosa-soluble odorant
molecules being concentrated earlyin the flow path comparedwith a more evenmucosal distribution
patternfor less mucosa-soluble odorants.Thedifferent arrival times and mucosal distributionpatterns
resulting from anodorant's solubility may be another ofthemechanisms bywhichthecentral nervous
systemidentifiessmells.Thesedistributionpatternsarecalled“imposed”patterns,
23,24
andarelikelyto
bethebasisforthedifferencesbetweennasalandretronasalperceptionofodors.
25,26
There is considerable evidence supporting the existence of imposed patterns in animals.
Electrophysiological, gas chromatographic, and radioisotopic studies in frogs and rats have provided
strongevidencethatthedegreeofmucosalsolubilitycanaffectspatialandtemporaldistributionpatterns
alongtherespiratoryandolfactorymucosas.
1
StimulusParameters
Regardlessoftheodorant,withinphysiologicallimits,thereisthoughttobeadirectrelationshipbetween
theolfactoryresponseandthenumberofodorantmoleculesdeliveredtotheolfactoryreceptors.Thatis,
moreodorantmoleculesmeansamoreintensesmell.However,theolfactorystimulusisactuallydefined
bythree“primary”variables:thenumberofmolecules(N);thedurationofthesniff(T);andthevolumeof
thesniff(V).Theseprimaryvariablesinturndefinethethree“derived”variablesofconcentration:(C=
N/V);deliveryrate(D=N/T);andflowrate(F=V/T).
1,27
Fromananalysisofvariance,Mozellandhiscoworkers
27
generatedamodelusingthethreeprimary
variables (NVT) toaccountforthe variability(R) inthe olfactory receptorneuralactivityinbullfrogs.
Themodelwas:
The model proposes that the magnitude of the response increases as the sniff volume decreases,
whereas themagnitudeoftheolfactorynerveresponseincreases as thenumber ofmolecules andsniff
timeincrease.Thismodelprovidesagoodexplanationofthevariabilityintheresponseofthebullfrog
olfactorynervetosubthresholdconcentrationsofoctane.
The relationship among the sniff variables, which influences the interaction of odorants and the
olfactory mucosa, iscomplex,andchanging avariablesuch as flowrate,eitherexperimentallyor
clinically,alsochangesothervariablesthatcanaffecttheolfactoryresponse.
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Because theprimaryvariables canbe represented asderived variables,Mozell was able totestother
possiblemodelsthatincludedcombinationsoftheprimaryandderivedvariables.Fromthisanalysis,a
model emerged that was evenbetterthan the NVT model in explaining thevariability inthe olfactory
nerveresponse.Thismodelwas:
In the FN model, the effects of volume and time are equal and opposite, whereas the number of
molecules is independent of the other two. Of all 11 models tested, the FN model was the best at
explainingthevariabilityintheolfactorynerveresponse.
1,27
TheFNmodelwasgeneratedfrombullfrogneuralactivity.As,inthebullfrog,thereisnosplittingof
the inspired air into different flow channels, all of the inspired air flows over the olfactory sheet.
Therefore,ifapplicabletohumansatall,perhapstheFNmodelbestdescribestheresultsoftheairflow
deliveredtotheolfactorysheet,notwhatcomesintothetipofthenose.
The results from human psychophysical studies looking at the relationship between the olfactory
response and changes in the primary and secondary variables have been equivocal. As changing the
primaryvariablesalsoobviouslychangesthederivedvariables,determiningtheappropriatenessofany
oftheabovemodelstohumanolfactoryresponsehasbeendifficult.
TechniquesusingNasalDilatorsandComputationalFluidDynamics
As a research tool, nasal dilators provide a way to temporarily alter nasal anatomy and thus, when
combinedwithcomputationalfluiddynamics,provideawayofbeginningtoevaluatetheFNmodel.
Nasal dilators are elastic strips with plastic springs running along their long axis. When applied
externallytotheskincoveringthenose,thespringsincreasethediameterofthenasalcavityintheregion
ofthenasalvalve.Psychophysicalrecordingshaveshownthatnasaldilatorsincreaseperceivedodorant
intensity, reduce odorant detection thresholds, and increase odorant identification. In addition,
pneumotachographrecordingshavedemonstratedthatthemeanflowrate,maximumflowrate,andvolume
anddurationofthesniffatthetipofthenoseareallincreasedwhennasaldilatorsareworn.
28,29
At first glance, there appears to be a contradiction between the results of the FN model and the
observation that when wearing nasal dilators the olfactory perception is increased because of higher
flows,largersniffvolumes,andlongersniffs.However,theincreasesintheflowcharacteristicsreported
fromthenasaldilatorstudieswererecordedatthetipofthenose.Anyestimatesoftheactualflowtothe
olfactoryreceptorregionandthesubsequentodorantdepositionpatternsinthispartofthenosehavebeen
amatterofonlyspeculation.
Computationalfluiddynamicstechniqueshavebeenusedinthepasttopredicttheimpactofregional
airwaychangesonairflowandodorantdistributionpatterns,especiallytotheolfactoryregion.
23
Three-
dimensionalnumericalnasalmodelsfornumericalsimulationofnasalairflowwereconstructedindilated
andnondilatedconditions.
ThedatafromthesemodelingstudiesmayprovideaglimpseintotheappropriatenessoftheFNmodel
inhumans.Thedilator-inducedincreaseinsizeofthelowerpartofthenosedirectsmoreoftheinspired
airalongthefloorofthenoseandthereforereducestheflowtotheolfactoryarea.
30
Obviously,thereis
some limittotheapplicabilityoftheFNmodelinexplainingtheolfactory response.Atits extreme,a
reallylowflowwouldnotbeexpectedtogenerateanyolfactoryresponse.Therefore,themodelneedsto
be considered as describing events within certainphysiologicallimits.The descriptionofthese limits
awaitsfurtherstudies.
Becauseofthelocationoftheolfactoryreceptorsinhumans,changesalongtheflowconduitleading
up to the receptors may have surprising effects on olfactory ability. Widening the nasal air
passagewaysorincreasingtheairflowatthetipofthenosemaynotnecessarilyimproveolfactory
ability.
Clearlythereisnotyetafullunderstandingoftherelationshipbetweenolfactoryabilityandtheprimary
andsecondarystimulusvariables.TheFNmodel(andsimilarattemptstoquantifytheolfactoryresponse
intermsofstimuluscharacteristics)atbestprovidesasteppingstoneforfuturework.Thepossibilityof
nasalcyclechangeseithercomplementingorreducingtheeffectofanyexperimental nasalmanipulation
addsanotherlevelofcomplexitytotheanalysisofanydatagenerated.
The relationship betweennasalanatomyandolfactoryabilityiscomplex.Patientsshould bewarned
aboutthecomplexnatureofthisrelationship,sothattheywillnothaveunrealisticexpectationsfollowing
nasalsurgery.
NeurophysiologicalConsiderations
NancyE.Rawson
TheOEisuniquelysuitedtoitsfunctionandpositionasthechemosensorysentinelinformingtheowner
about the nature of a host of volatile compounds present in our environment. The anatomy and
neurophysiologicalcapacityoftheOEisspecializedforsensitivity,scopeofresponse,androbustnessin
thefaceofaharshandchangingenvironment.Thissensoryneuroepitheliumoccupiestheolfactorycleft
andprojectsonto thedorsalportionofthe superiorturbinate.By5 monthsofgestation,theOEis well
orderedandcontiguous,extendingfromtheroofofthenasalcavitytothemid-portionofthenasalseptum
andontothesuperiorturbinate.
31,32
IthasbeenestimatedthatthehumanOEoccupiesanareaof1–4cm
2
containing~6millionolfactoryneurons.
31–33
Whilecomprehensivestudieshavenotbeenreported,inour
studiesofseveralhundredbiopsyspecimensfromgenerallyhealthypatients,wedidnotobservemarked
gender-or ethnicity-relateddifferences inthe likelihoodofobtainingfunctionalneuronsfrom biopsies
obtainedfromthesuperiorturbinate(refs.34and35andunpublishedobservations),suggestingthatthe
overall numbermaybe relatively consistent. In adulthumans, sensory epithelium is often intermingled
withnonsensorytissuealongthesuperiorturbinateandseptum,incontrasttotherodent,inwhichthereis
acleardelineationbetweenepithelialtypes.
36
Functionally,humanORNsexhibitgeneralcharacteristics
similar to thoseof mostmammals, with a largediversity of receptorproteinsanda signaling cascade
designedtoamplifyandspecificallytransmitodorant-bindingeventstotheolfactorybulbusingelectrical
actionpotentials(Fig.2.7).However,specificaspectsofORNfunctiondivergeacrossspecies,including
the diversity and number ofreceptorproteintypesandcertainaspectsofthe signaling cascades. Such
similarities and differences should be considered in evaluating the clinical relevance of research on
rodentmodels.
The olfactorysensoryepitheliumisdesigned for detectionofandprotectionfromvolatilestimuli,
andiscomposedofmultiplecelltypesinapseudostratifiedarrangement.
Theolfactoryneuroepitheliumisapseudostratifiedepitheliumconsistingofmultiplecelltypessittingon
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abasallaminathatseparatestheepitheliumfromthesubmucosallaminapropria(Fig. 2.8). Thelamina
propriaincludesfibrousandglandulartissue,alongwithaxonalfibers,bloodvesselsandimmunecells.
Bowmanglandssecretewaterymucus,whichformsaprotectivelayercoatingtheOEsurface.Odorant-
binding proteins, related to lipocalins, are a family of proteins that bind distinct classes of volatile
compoundsandarethoughttofacilitateodoranttransport.
37,38
Apopulationofresidentmacrophagesand
otherimmunecelltypesisalsotypicalwithinbothhealthyandpathologicalOE.
39,40
Inadditiontoaxons
oftheORNs,fibers ofthe trigeminalnerveprojecttothesurface ofthe OE,andboth cholinergicand
adrenergicfibers arealso present withinthe epitheliumandlaminapropria.
41
Adrenergicfiberswithin
thelaminapropriaactonglandstocontrolnasalmucussecretion,andonvascular elementstoregulate
bloodflow.Dispersalofodorantsviathemucusandthroughthelaminapropriaintothebloodconstitutes
an important mechanism for odorant removal.
42
Accordingly, age-related decline in the density of
adrenergicfibers,ormedicationsthatinfluenceadrenergicpathways,canimpairolfactoryperformancein
partviareducedodorantclearancerates.
43
Fig. 2.7 When an odorous substance (e.g., L-carvone, which smells like mint) makes contact with olfactory receptors on the cilia of a
receptorcell,itsetsoffachainofeventsleadingtoactivationofelectricalcurrents.Thismakesthecellfireasequenceofactionpotentials—
voltage signals orspikes—thefrequencyofwhich relates totheintensityofthe odor.The spikes aresentoutalongthenerve fibertothe
glomeruliintheolfactorybulb(seeChapter3).
Fig.2.8a,bCelltypesoftheolfactoryepithelium.
aDiagramdepictingcelltypeswithintheolfactoryepithelium.
bHumanolfactoryepitheliumimmunostainedwithanantibodytoolfactorymarkerproteintoshowmatureodorantreceptorneurons(brown
cellbodies).
Olfactorysensoryneuronsarebipolarreceptorcellsthatarereplacedthroughoutlife.
ORNsarebipolarcellswithanapicaldendriticknobbearingciliaandabasalcellbodywithasingle
axonalprocessthatprojectsthroughthesubmucosa.Theaxonalprocessesassembleintoabundlewithin
nonmyelinating ensheathing glial cells and extend through the cribriform plate to synapse within the
olfactorybulb(seeChapter3).MatureORNsareclassicallyidentifiedbytheirexpressionofolfactory
marker protein (OMP), and also express characteristic signaling, structural, and receptor proteins.
44
MatureORNsarederivedfromapopulationofslowlydividingbasalcellsthatreplicateasynchronously
toproducemorerapidlydividingprogenitors, andaretheonlyprimarysensoryneurontype toundergo
replacementthroughoutlife.Thisfeaturehelpsensurethemaintenanceofthisvitalsensorysystem,andthe
lifespanofmatureORNsdependsinpartonexposuretotoxicorinfectiousxenobiotics.WhileORNsare
susceptibletodestructionbyneurovirulentinfluenzaA,preventingitstransmissiontothebrain,theyare
resistanttoothervirusesandcanserveasanavenueforinfectionofthecentralnervoussystembyseveral
viruses(e.g.,herpessimplex,parainfluenza).
45
WhileneuronalcellreplacementispartofthenormalOE,
activationbyodorantsappearstopromotesurvivalofORNs.
46
Thus,thepopulationofORNsisplastic
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andresponsivetotheenvironmentinawaythathelpstoensuretheabilitytosensebothnovelanddiverse
compounds,while alsobeingtunedtothemostsalientandprevalentvolatilesignalsintheindividual's
environment.
NonolfactorysensoryandsupportingcelltypesalsooccurwithintheOE.
SeveralothertypesofsensoryorcelltypeshavebeenreportedintheOEofrodents,buthaveyettobe
describedinhumanOE.Amongthesearesolitarychemoreceptorcells(SCCs),whichexpressbittertaste
receptorsandsignalingcomponentscommontotastereceptorcells.
47
Thesecellsappeartosynapsewith
nerve endingsfrom the trigeminal system, andhaveapical processes positionedtodetecta varietyof
noxiousstimulitoolipophilictopenetratethemucosatoreachthetrigeminalnerveendings.
48,49
Liketaste
cellsandolfactoryneurons,theyarereplacedthroughoutlife,althoughthelocalprogenitorisunclear.
50
In
rodent OE,SCCsarepresentinboththenasopharyngealregion andthe anteriornasal cavitywithin the
respiratoryepithelium,andhaverecentlybeenreportedinthenasalepitheliumandvomeronasalglandsof
humans.
51
Twopopulationsofmicrovillouscellsexpressingthethermallysensitive,nonselectivecation
channeltransientreceptorpotentialM5(TRPM5)havealsobeenidentifiedinrodentOE.
52
Onetypeis
morphologicallyandimmunocytochemicallysimilartothebipolarORNs,issparselydistributed,andis
restrictedto thelateral andventral OE.Theother is scattered throughout the OE,andhas a pear- or
flasklikecell bodysmaller than anORN,residing in theapicalthirdoftheOE.Themicrovillimaybe
shortandbrushlikeorhavea moretuftlikearrangement.
52
Thesemicrovillouscells do notexpress the
neuronalmarkerprotein gene product9.5orproteinscharacteristicofORNs(e.g.,OMPand thecyclic
nucleotide-gatedchannel), nor do theyexpress markers seeninSCCs (e.g.,phospholipase Cβ2 orα-
gustducin). Neither do they express markers of neuroendocrinecells (e.g. chromogranin),but mostdo
expresscytokeratin18,amarkerofbrushcells.WhilenotyetestablishedinhumanOE,brushcellsare
presentin other parts ofthe human respiratorytract, and cells withthis morphology are observed in
human OE specimens (personal observation). It is possible that the microvillar cells expressing the
retinoic acid receptor reported by Yee and Rawson
53
are a subset of these TRPM5-expressing cells,
based on morphology. However, further studies are needed to establish the distribution, molecular
identity,androleofthesecellsinthehumanOE.
Supportingcellsservetrophicanddetoxificationroles.
Supportingor sustentacular cells are large,columnar cellsthatextendnearlythefull widthofthe OE.
Theyareidentifiedinrodentsbythesustentacularcellantibody(SUSantibody),andexpresscytokeratin
8.
54
Incontrast,cytokeratin5labelsthiscellpopulationinhumanOE,andtheSUSantibodyisineffective
(Borgmann-WinterK,personalcommunication).Supportingcellsprovidetrophicandprotectivesupport,
expressingdetoxificationenzymessuchascytochromeP450
55
andglutathione-S-peroxidase.
56
HorizontalbasalcellsarelessdefinedinhumanthanrodentOE.
Horizontalbasalcellsmayserveafunctioncomparabletoablood–brainbarrier,andprovidestructural
andtrophicsupportforproliferatingcells,althoughlittleisknownabouttheirphysiologicalproperties.
Theyaremolecularlydefinedbytheexpressionofspecificcytokeratinsandtheepidermalgrowthfactor
receptorandinadulthuman,butnotrodent,OE,expressp75-nervegrowthfactorreceptor.
57,58
Whilethis
cellclassiseasilyrecognizedmorphologicallywithintherodentOE,itappearsmoresparse,orperhaps
more heterogeneousmorphologically, in the human OE (Borgmann-Winter K, personal communication,
andref.36).
The developmentand lifespanofolfactoryreceptorneuronsare dependent onthecellular context
andtheexternalenvironment.
In the rodent, globose basal cells (GBCs) can be selected on the basis of expression of the GBC-2
protein, and represent multipotent precursors capable of giving rise to ORNs, supporting cells and
additionalGBCs.
59–61
Thismarker failstoidentify anycells inhumanOE,andit hasbeendifficultto
identify aspecificpopulationofslowlydividing precursorswith characteristicsofstemcells orearly
fate-specifiedprogenitorswithintheOE.
62
However,thepresenceofsuchcellsissupportedbothbythe
regenerative capacity ofthe tissue,demonstratedeveninto advancedage,and bystudies showing that
biopsiedhumanOEcanbeusedtogeneratelong-termprimaryculturescontainingcellswithmultipotent
capabilities.
63,64
ORN precursors differentiate into immature neurons expressing Gap-43 and neuron-
specific tubulin,
65
and ultimately to mature ORNs expressing OMP along with receptors and their
associated signaling molecules.
61,66,67
ORNs whose axons fail to synapse withtheir respective mitral
cellswithintheolfactorybulb,becauseofinjury,inflammation,orsurgicalintrusion,undergoapoptosis.
68
Cells expressing markers of most stages of this lineage have beencharacterized and localizedwithin
human OE,
36,62
but questions remain regarding the molecular characteristics and localization of the
earliest progenitor.Cells expressing markers of proliferation andcell death are more numerousunder
conditions of inflammation, reflecting the capacity of the tissue to respond to the need for neuronal
replacementundertheseconditions(Fig.2.9).
58
HumanOEtendstobelessorganizedandlessrobustinthefaceofageanddiseasethanrodentOE.
ThestructureoftheOEinadulthumanstendstobefarlessorganizedthanthatinrodents,withrespectto
both apical to basal stratification andto homogeneity of sensoryversus respiratory regions across the
epithelial sheet. Whether this is due to a true species difference, or to differences in environmental
exposure,incidenceofallergy,andsinusinfectionsandinflammation,isunclear.Unliketheveryorderly
layersofOMP-immuno-reactive(OMP-ir)–ORNsobservedintherodentOE,thefrequencyofOMP-ir–
ORNsinthehumanmiddleturbinatetendstobesparseandscattered.Thisaccountsforthecomparatively
smallerlikelihoodofobtainingsensoryepitheliumfrombiopsiesobtainedfromthisregionthanfromthe
olfactorycleft.
69,70
Itisclearthat,withageanddisease,thehumanOEbecomesincreasinglypatchyand
interspersedwithrespiratoryorfibrotictissue.
71
Undertheseconditions,olfactoryneuronsmaypersistas
apopulationwithinthetissue,butexhibitabnormalmorphology, maybe displacedbelowakeratinized
epithelium,ormaybeentirelyabsent(Fig.2.9).
39,58,72
ItispossiblethatthecomparativeOEdisorderoftenobservedinhumanbiopsyspecimensreflectsa
lessrobustregenerativecapacitythanrodentOE.Inrodents,theregenerativecapacityoftheOEissuch
thatevenfollowingtotalablationwithchemicalirritant,completerecoverycanbeaccomplishedwithina
fewmonths.
73
In humanpatients, OE recoveryfollowing damage duetoinfection, trauma,or chemical
irritants may be prolonged and accompanied by long-term or permanent olfactory impairment.
72,74,75
Unfortunately, OE integrity based on tissue biopsies typically does not correlate well with olfactory
function,
58,76
anditislikelythatsubstantialdamagecanoccurwithoutovertconsequencesonperformance
dependingonthelocation and nature ofthe damage. Withage,inboth humansandanimalmodels,this
neuroepithelialsheetbecomesincreasinglydisorderedandpatchy,withahigherproportionofrespiratory
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