Non-Respiratory Functions of The Respiratory System | Jindal Chest Clinic

Presentation on "Non-Respiratory Functions of The Respiratory System"

1. NON-RESPIRATORY
FUNCTIONSOFTHE
RESPIRATORYSYSTEM

2. INTRODUCTION
•Thehumanrespiratorytractisacomplexorgansystemspecialized
forexchangeofgasesbetweenenvironmentalairandblood
circulatingthroughthepulmonaryvascularbed.
•Therespiratorysystemalsoperformsaspectrumofimportant
nonrespiratoryfunctions.
•Certainoftheselungfunctions,suchasspeech,heatandwater
conservation,hostdefense,andfiltrationofsystemicblood,area
consequenceofuniqueanatomicfeaturesoftherespiratorysystem.

3. •Functionaldiversityofthelungsalsoarisesfromaheterogeneous
populationofconstituentcellsthatparticipateinwaterand
electrolytetransfer,airspacedefense,localneuroendocrine
regulation,xenobioticmetabolism,andexcretionofvolatile
substances.
•Thenonrespiratoryfunctionsofhumanrespiratorytractrelateto
morphologicorganizationwithinfunctionallydistinct
compartments,includingtheconductingairways,alveolarregion,
andvascularstructures.

4. NON-RESPIRATORYFUNCTIONSOFTHE
RESPIRATORYSYSTEM
•Speech
•Heatandwaterconservation
•Electrolytetransport
•Hostdefense
•Neuroendocrinesecretion
•Xenobioticmetabolism
•Surfactantsynthesisandturnover
•Antioxidantdefense
•Excretionofvolatilesubstances
•Filtration
•Hemofluidity

5. FUNCTIONS RELATED TO
CONDUCTING AIRWAYS

6. SPEECH
•Speechandlanguageareuniquelyhumancharacteristicsgeneratedby
coordinatedactivityofthecerebralcortex,thebrainstemrespiratory
drivecenter,andstructuralcomponentsoftheupperairway.
•Speechiscomposedoftwomechanicalfunctions:
(1)phonation,whichisachievedbythelarynx,and
(2)articulation,whichisachievedbythestructuresofthemouth.
•Phonation,orcreationofsound,resultsfrompurposefulexpirationofair
throughthevocalcordslocatedwithinthelarynx.

7. Changesinthepitchofsoundemittedbythelarynxareachievedby
stretchingorrelaxingthevocalcordsandbyalteringtheshapeandmass
ofvocalcordedges.
Resonanceisaddedbyseveralstructures,includingthemouth,noseand
paranasalsinuses,pharynx,andchestcavity.
Finalarticulationofsoundintolanguageisaccomplishedwiththelips,
tongue,andsoftpalate.

8. A, Anatomy of the larynx. B, Laryngeal function in phonation, showing
the positions of the vocal cords during different types of phonation.

9. HEAT AND WATER CONSERVATION
•Duringnormalspontaneousrespirationincomingambientairiswarmed
byconductionandconvectionasitpassesthroughthenasopharynxand
tracheobronchialtree.
•Asinspiredairiswarmed,itisalsohumidifiedbyevaporationofwater
fromtheairwayliningwhichtransfersthermalenergytothepassingair
streamandresultsinnetcoolingoftheairwaysurface.
•Duringexpiration,temperatureandvaporpressuregradientsarereversed,
andairlosesthermalenergytothecoolerairwaysurface.
•Asaircoolsduringexpiration,itsabilitytoholdwaterdecreases,and
watercondensesalongtheairwaysurface.

10. •Countercurrentexchangeofheatandwaterduringnormaltidal
respirationallowsconditioningofinspiredairwhilethermalenergyand
waterareconservedduringexpiration.
•Undernormalcircumstances,tidalrespirationresultsinanetlossofonly
about250mLofwaterand350kcalofheatfromtheairwaysina24-hr
period.
•Nettransferofheatandwaterdependontemperatureandvaporpressure
gradientsbetweentheairwaysurfaceandpassingairstream.
•Lowenvironmentaltemperaturesincreaseconvectivecoolingofthe
airwaysurface;lowhumidityenhancesevaporativecoolingofthe
airways.
•Theadditionalheatandwaterrequiredtoconditioninspiredairraise
caloricrequirementsincoldclimates.

11. Transferofheatandwaterfromthemucosalsurfacetoinspiredairisalso
relatedtolinearvelocityofairflow.
Higherflowvelocitiesareassociatedwithlowerratesofheatandwater
transfertotheairstreamduringinspirationandreducedcondensation
duringexpiration.
Increasesinventilationduringphysicalactivityorotherstressesthereby
augmentthenetlossofheatandwaterfromthemucosalsurface.
Temperatureoftheinternalmilieucanalsoaffectnetheatandwater
transfer.
Thereductionintemperaturegradientbetweenairleavingthelungsand
themucosalsurfacethatoccursatelevatedbodytemperaturesfacilitates
waterloss.

12. •Netwaterlossinthesettingoffeverorphysicalexertionmayactuallyserve
asamechanismfortemperatureregulation.
•Therespiratorytracthasamajorroleintemperaturecontrolinfur-bearing
animals;however,itisnotthoughttoaffectcoretemperatureregulation
significantlyinhumansundernormalcircumstances.
•Airwayheatandwaterexchangemayhaveimportantclinicalimplications
inasthmaticpatients,inwhomairwaycoolingcausedbylowambient
temperaturesorincreasedminuteventilationmayprovokebronchospasm.
•Bronchoconstrictionincoolerenvironmentsmayresultfromacute
stimulationofthermallysensitivebodysurfaceandmucosalreceptors;
however,airwayconstrictioninsomeasthmaticpatientsmayoutlastthe
durationofthermalreceptorstimulation.

13. •Inthissetting,bronchoconstrictionisthoughttorelatetoenhancedheat
andwaterlossfromthemucosalsurface.
•Heatandwaterexchangeintheconductingairwaysalsoaffectsthe
mucociliarytransportmechanism.

14. ELECTROLYTE TRANSPORT
•Airwayepithelialcellsactivelytransportelectrolytesbetweentheairway
lumenandtheinterstitialcompartmentofthealveolarwall.
•WaterabsorptionpassivelyfollowsnetNa+transferfromthemucosal
surfacetotheinterstitialcompartment.
•Incontrast,netfluidsecretionisafunctionofactiveepithelialcellCl–
transportfromtheinterstitiumtotheairwaylumen;waterpassively
followsCl–movementintothelumen.
•ThebalancebetweenNa+absorptionandCl–secretion,andhencenet
watermovement,dependsonairwayregion,pharmacologicintervention,
andneurohumoralinfluences.

15. •Furthermore,Cl–secretionmaybestimulatedbyseveralneurohumoral
agents.
•Thepredominantdirectionoffluidmovementunderbasalconditionsis
fromairwaylumentointerstitium
•Fluidaccumulatesintheproximalairwaysassecretionsconvergefrom
distalregionsofgreatercross-sectionalareaviamucociliarytransport.
•FluidhomeostasisismaintainedprimarilybyabsorptionofNa+fromthe
airwaylumendownanelectrochemicalgradient.Cl–andwaterfollow
Na+throughpermeableparacellularpathways.
•NetCl–secretionbyepithelialcellsisunusualunderbasalcircumstances.

16. •However,inhibitionofNa+absorption,withamiloride,forexample,mayshift
theelectrochemicalgradientinfavorofCl–secretion.
•ProstaglandinsE2andF2a,b-adrenergicagents,leukotrienes,adenosine,
vasoactiveintestinalpeptide(VIP),andbradykininstimulateepithelial
Cl–andwatersecretion.
•Aspreviouslynoted,effectivemucociliaryclearancedependsonmucosal
epithelialcellelectrolyteandfluidtransport.
•Mucociliarytransportformsanimportantdefenseagainstforeignmaterial
thatcomesincontactwiththemucosalsurfaceoftheairway.

17. Thefluidcomponentofthemucociliarytransportsystemisproducedby
secretoryepithelialcellsandsubmucosalglands.
Theclinicalimpactofepithelialsecretoryfunctionisdemonstratedin
cysticfibrosis.
Incysticfibrosis,abnormallyincreasedepithelialNa+absorptionand
decreasedCl–secretionresultinrelativelydehydratedmucusand
defectivemucociliarytransport.
Asaresult,individualswithcysticfibrosisfrequentlyhavesevere
respiratoryinfections.

18. HOST DEFENSE
•Everydaythelungsareexposedtomorethan7000Lofairanditsfine
tissuesrequireprotectionfromthedailybombardmentofparticles,
includingdust,pollenandpollutants,andthevirusesandbacteriathat
havethepotential,respectively,tocauselunginjuryortoinvadethelung
andgeneratelifethreateninginfections.
•However,theseproblemsrarelyoccurbecausethelungpossessesvery
effectivelocalprotectivemechanisms.

19. Integrated System for Defenseof the Respiratory Tract
Natural mechanical defenses
Filtration and impaction remove particles
Sneeze, cough, and bronchospasmexpel particles
Epithelial barriers and mucus limit particle penetration
Mucociliaryescalator transports particles cephalad
Natural phagocyticdefenses
Effected by airway, interstitial, and alveolar macrophages; polymorphonuclear
leukocytes
Phagocytosisof particulates, organisms, and debris
Microbicidaland tumoricidalactivities
Degradation of organic particles

20. Integrated System for Defenseof the Respiratory Tract
Acquired specific immune defenses
Humoralimmunity
Effected by B lymphocytes
Biologic activities mediated by specific antibody
Augments phagocyticand microbicidaldefensemechanisms
Initiates acute inflammatory responses
Cell-mediated immunity
Effected by T lymphocytes
Biologic activities mediated by
Delayed-type hypersensitivity reaction
T cell cytotoxicity
Augments microbicidaland cytotoxicactivities of macrophages
Mediates subacute, chronic, and granulomatousinflammatory responses

21. FILTRATION & REMOVAL OF
INSPIRED PARTICLES
•FiltrationofInspiredAir:
•Airpassingthroughthenoseisfirstfilteredbypassingthroughthenasal
hairs,orvibrissae.
•Thisremovesmostparticleslargerthan10to15mindiameter.Mostofthe
particlesgreaterthan10mindiameterareremovedbyimpactinginthelarge
surfaceareaofthenasalseptumandturbinates.
•Theinspiredairstreamchangesdirectionabruptlyatthenasopharynxsothat
manyoftheselargerparticlesimpactontheposteriorwallofthepharynx
becauseoftheirinertia.
•Thetonsilsandadenoidsarelocatednearthisimpactionsite,providing
immunologicdefenseagainstbiologicallyactivematerialfilteredatthispoint.

22. •Airenteringthetracheacontainsfewparticleslargerthan10m,andmost
ofthesewillimpactmainlyatthecarinaorwithinthebronchi.
•Sedimentationofmostparticlesinthesizerangeof2to5moccursby
gravityinthesmallerairways,whereairflowratesareextremelylow.
•Thus,mostoftheparticlesbetween2to10mindiameterareremovedby
impactionorsedimentationandbecometrappedinthemucusthatlines
theupperairways,trachea,bronchi,andbronchioles.
•Smallerparticlesandallforeigngasesreachthealveolarductsandalveoli.
Somesmallerparticles(0.1mandsmaller)aredepositedasaresultof
Brownianmotionduetotheirbombardmentbygasmolecules.
•Theotherparticles,between0.1and0.5mindiameter,mainlystay
suspendedasaerosols,andabout80%ofthemareexhaled.

23. REMOVAL OF FILTERED MATERIAL
ReflexesintheAirways:
•Mechanicalorchemicalstimulationofreceptorsinthenose,trachea,larynx,or
elsewhereintherespiratorytractmayproducebronchoconstrictiontopreventdeeper
penetrationoftheirritantintotheairwaysandmayalsoproduceacoughorasneeze.
•Asneezeresultsfromstimulationofreceptorsinthenoseornasopharynx;acough
resultsfromstimulationofreceptorsinthetrachea.
•Ineithercase,adeepinspiration,oftentonearthetotallungcapacity,isfollowedbya
forcedexpirationagainstaclosedglottis.
•Theglottisopenssuddenly,andpressureintheairwaysfallsrapidly,resultingin
compressionoftheairwaysandanexplosiveexpiration,withlinearairflowvelocities
saidtoapproachthespeedofsound.
•Suchhighairflowratesthroughthenarrowedairwaysarelikelytocarrytheirritant,
alongwithsomemucus,outoftherespiratorytract.

24. TracheobronchialSecretionsandMucociliaryTransport:The
"MucociliaryEscalator“:
•Theentirerespiratorytract,fromtheupperairwaysdowntotheterminal
bronchioles,islinedbyamucus-coveredciliatedepithelium.
•Thecilialiningtheairwaysbeatinsuchawaythatthemucuscovering
themisalwaysmoveduptheairway,awayfromthealveoliandtoward
thepharynx.
•Theciliadonotappeartobeatsynchronouslybutinsteadprobably
producelocalwaves.
•Theciliabeatatfrequenciesbetween600and900beatsperminute.

25. •Insmallairways(1to2mmindiameter),linearvelocitiesrangefrom0.5
to1mm/min;inthetracheaandbronchi,linearvelocitiesrangefrom5to
20mm/min.
•The"mucociliaryescalator"isanespeciallyimportantmechanismforthe
removalofinhaledparticlesthatcometorestintheairways.Material
trappedinthemucusiscontinuouslymovedupwardtowardthepharynx.
•Itisimportanttorememberthatpatientswhocannotcleartheir
tracheobronchialsecretionscontinuetoproducesecretions.
•Ifthesecretionsarenotremovedfromthepatientbysuctionorother
means,airwayobstructionwilldevelop.

26. DEFENSEMECHANISMSOFTHE
TERMINALRESPIRATORYUNITS
•Inspiredmaterialthatreachestheterminalairwaysandalveolimaybe
removedinseveralways.Theseinclude:
i.Ingestionbyalveolarmacrophages
ii.Nonspecificenzymaticdestruction.
iii.Entranceintothelymphaticsand
iv.Immunologicreactions.

27. ALVEOLAR MACROPHAGES
•Alveolarmacrophagesarederivedfromblood-bornemonocytesthat
originateinthebonemarrow.
•Theyarehighlydifferentiatedcellsthatnormallypatrolthealveolar
lining.
•Alveolarmacrophagespossessmarkedphagocyticability,beingableto
ingestanddestroypathogenicbacteriaandparticles
•Theyalsohavethecapacitytogeneratemediatorsofcentralimportancein
theinitiationofinflammationandtopresentantigenintheinitiationof
immuneresponses.
•Thealveolarmacrophagehasavastarrayofreceptorsonitssurfaceand
canrespondtoawiderangeofexternalstimuliandsubsequentlygenerate
awiderangeofsecretoryproducts.

28. •Macrophagescanrecognizeopsonizedornon-opsonizedparticles.
•Withinthephagolysosomeingestedparticlesaresubjectedtothe
combineddestructiveforcesofbothreactiveoxygenintermediates
generatedviathemetabolicburstandawiderangeofdegradative
enzymesthathavethecapacitytodigestproteins,lipidsandcarbohydrates
•Itappearsthatthelocalintracellulargenerationofnitricoxide(NO)isan
importantdefencemechanismagainstavarietyofmicroorganisms.
•Mineralssuchasasbestosandquartzandanumberofmicroorganisms,
includingMycobacteriumtuberculosisandtrypanosomesatvariousstages
oftheirlifecycle,areabletoresistdestructionwithinmacrophages.

29. IMMUNOLOGIC RESPONSES
•Immunologicresponsescanbeclassifiedasinnateimmuneresponses(actionsof
macrophages,monocytes,lymphocytes,andgranulocytes)oragent-specific
immuneresponses(immunologicmemoryofTandBcells).
•Theinnatedefensemechanismsincludeacombinationofphagocytosisand
cytotoxiceffectsbyeffectorcellsandactivationofthecomplementcascade.
•Intheadaptiveresponse,alargepopulationofantigen-specificlymphocytesis
producedthatresultsinapotentiallygreaterandprolongedimmunesystem
response.
•Theadaptiveresponseoccurswhenanantigenderivedfromthetoxicantexposure
isprocessedandpresentedbyadendriticcell,macrophage,ormonocytetoa
lymphocyte.
•Thelymphocytethenundergoesclonalexpansiontoproducelargenumbersof
cellsthatarespecificfortheparticulartoxicagent..

30. •CytotoxicT-cellproductionoccursbythisprocesswhenmajor
histocompatibility(MHC)isexpressedbytheantigen-presentingcellsin
associationwithtoxicant-derivedantigen.
•ActivatedTcellsproducenumerouscytokines,suchastumornecrosis
factor,thatsignificantlyenhancestheimmuneresponseandthe
inflammatoryresponsesofresidentlungcells.
•AntibodiesspecifictotheantigenareproducedbyBcells,whichare
stimulatedbytheinterleukinstoproducememorycellsandplasmacells.
•Thepulmonaryimmunesystemdiffersfromthesystemicimmunesystem
initsabilitytoproducelocalizedcell-mediatedimmuneresponseson
repeatedexposuretoinhaledantigenicmaterials.
•Suchlocalizedresponsemayplayasignificantroleinhypersensitivity
pneumonitis.

31. XENOBIOTIC METABOLISM
•Xenobioticmetabolismislargelyafunctionoftheliver;however,the
presenceofxenobioticmetabolizingenzymesinthehumanlungiswell
documented.
•Thesepathwaysgenerallyinvolvebothmetabolic(phaseI)andconjugative
(phaseII)reactions.
•PhaseIreactionsincludeoxidation(CYP450),reduction,orhydrolysis;they
generatemetabolitesthatmayormaynotretainpharmacologicactivityofthe
originalxenobiotic.
•PhaseIIreactionsinvolveglucuronidation,sulfation,acetylation,or
conjugationwithglutathioneoraminoacids.
•Thesereactionsrendertheparentxenobiotic,oritsmetabolite,water-soluble
anddevoidofpharmacologicactivity.

32. •Relativelylowconcentrationsofseveralxenobioticdeactivatingenzymes
havebeenidentifiedinthelung.
•Thefactthatthedistributionofxenobioticmetabolizingenzymesis
limitedtoClaracellsandtypeIIalveolarepithelialcellsmayaccountfor
therelativelylowlevelsoftheseenzymesinthelungasawhole.
•CytochromeP450mono-oxygenaseactivityhasbeenlocalizedwithin
Claracellsoftheconductingairways.
•OtherphaseIenzymes,includingethoxycoumarin-O-de-ethylase,a
microsomalenzymethatcatalyzesO-demethylation,andepoxide
hydrolase,whichcatalyzeshydrolysisofepoxidesarisingfromoxidative
metabolism,havebeenidentifiedinthelung.
•Activityofseveralconjugativeenzymeshasalsobeendemonstratedinthe
lung;theseenzymesincludeglutathione-S-transferases,acetyltransferase,
andsulfotransferases.

33. •Manycirculatingbasiclipophilicaminesundergofirst-passretentionin
thelungasaresultofendothelialmetabolism.
•Significantfirst-passremovalhasbeendemonstratedforpropranolol,
meperidine,fentanyl,andsufentanil,asexamples.
•Retentionandextractionofdrugsisafunctionofdiffusionoractive
transportofthesubstanceintotheintracellularcompartment,followed
byenzymaticmodification.
•First-passretentionappearstobeapartiallysaturablephenomenon,
whereasoverallextractionoccursindependentlyofsubstance
concentration.

34. ANTI-OXIDANT DEFENSE
•Byvirtueofitslargesurfaceareathatiscontinuouslyexposedto
environmentalair,therespiratoryepitheliumisatriskfordamagecaused
byfreeradicaloxygenmetabolites.
•Generationoffreeradicalsfromexogenoussourcesmaybeachievedby
directinteractionbetweeninhaledagentsandepithelialcells,andindirectly
viaactivationofairwayinflammatorycellsthatgeneratelargequantitiesof
reactiveoxygenspecies.
•Endogenousoxidativemetabolismalsogeneratesoxygen-derivedfree
radicalspeciesthatmayinteractwithcellmembranephospholipidmoieties
andglycoproteinsandtherebydisrupttheirstructuralintegrity.

35. •Reactionofoxygen-derivedfreeradicalswithcellularcomponentsis
thoughttocontributetothepathogenesisofmanydiseaseprocesses,
includingbronchopulmonarydysplasia,asthma,emphysema,pulmonary
fibrosis,andARDS(adultrespiratorydiseasesyndrome).
•Themostbiologicallyactiveoxygenspeciesincludesuperoxide,
hydrogenperoxide,hydroxylradical,andnitricoxide,althoughseveral
otherspecieshavebeenidentified.
•Freeradicalsmaybereleasedintotheextracellularenvironmentifthey
areproducedinquantitiesthatexceedintracellularscavenging
mechanisms.
•Lungantioxidantdefensemechanismsprotectairwayepithelialandother
celltypesfromharmfuleffectsofreactiveoxygenspeciesgeneratedby
endogenousmetabolismandinhaledchemicals.

36. •Themajorintracellulardefensemechanismsagainstreactiveoxygen
speciesincludesuperoxidedismutase,catalase,andglutathioneredox
enzymes.
•Althoughknowledgeofantioxidantenzymedistributioninthehuman
respiratorytractislimited,mostantioxidantenzymesintherespiratory
tractappeartobelocalizedintheairways.
•Lowerrelativeconcentrationsofmitochondrialsuperoxidedismutaseand
catalasearepresentinthebronchialepithelium.
•Extracellularsuperoxidedismutaseisfoundinhighconcentrationsin
areasrichintypeIcollagen,inconnectivetissuessurroundingsmooth
muscle,andinthejunctionsbetweenepithelialcells.

37. NEUROENDOCRINE FUNCTION
Cellswithneuroendocrinecharacteristicshavebeenidentifiedinthe
respiratorytractofhumansandseveralotheranimals.
Sensitiveimmunocytochemicalandradiolabelingtechniqueshave
localizedawidevarietyofpeptidemediatorsinthelung.

38. NeuroendocrineEpithelialCells:
•Epithelialcellsthatproducepeptidemediatorshavebeenidentified
throughoutthetracheobronchialtree.
•Theseneuroendocrineepithelialcellsaredemonstratedwithsilver
impregnationstainingorantibodiestogeneralendocrinemarkers,such
aschromogranin.
•Neuroendocrineepithelialcellsoftheairwayssharemanycharacteristics
withAPUD(amineprecursoruptakeanddecarboxylation)cellsofthe
diffuseneuroendocrinesystem.
•Inhumans,pulmonaryneuroendocrineepithelialcellsareidentifiedby
expressionofpeptidemediators,suchasgastrin-releasingpeptide
(bombesin)andserotonin.

39. •Inhumanfetalbronchi,neuroendocrineepithelialcellsappearasearlyas
at8weeks'gestationandmaybeinvolvedinregulationofnormallung
development.
•Peptidesareexpressedinadifferentialpatternduringhumanairway
development.
•Gastrin-releasingpeptideistheprimarypeptideproducedduringearly
humanfetaldevelopment,whereascalcitoninpredominateslaterin
development.

40. •Limitedevidencesuggeststhattracheobronchialneuroendocrineepithelial
cellscommunicatewithnonadrenergic,noncholinergicneuronslocated
withintheairways.
•Thesignificanceofthiscommunicationisunclear.
•Largenumbersofneuroendocrineepithelialcellsdevelopintheairwaysof
animalssubjectedtoexperimentalhypoxiaandinhumanswholiveathigh
altitudes.
•Fromtheseobservations,ithasbeenpostulatedthatneuroendocrine
epithelialcellsserveachemosensitivefunctionandrelayinformation
aboutairoxygencontenttothecentralnervoussystem.

41. FUNCTIONS RELATED TO
THE ALVEOLAR SPACE

42. METABOLISM
•Thealveolarsurfaceislinedbytwodistinctpopulationsofepithelialcells.
•TypeIalveolarepithelialcellsarethin,flattenedcellsthatcover
approximately95%ofthealveolarsurface;theyarethoughttobe
relativelyquiescentmetabolicallyandformtheepithelialsurfaceofthegas
diffusionbarrier.
•TypeIIalveolarcells,incontrast,arecuboidal,metabolicallyactive
epithelialcellsthatcovertheremainderofthealveolarsurface.

43. •TypeIIalveolarepithelialcellsarethesourceofpulmonarysurfactant,as
discussedbelow.
•Theyalsodemonstrateacapacityforxenobioticmetabolism,aswellas
enzymeactivitiesthatprotectagainstoxidantstress.
•TypeIIcellssecretesolublefactorsthatactlocallytomodulatefunctions
ofotherlungcells,suchasfibroblasts.
•Theseregulatorymediatorsmaybeimportantinthecoordinationof
normallungdevelopment,aswellasinrepairofadamagedalveolar
region.
•AmongsolublefactorsproducedbytypeIIcellsareseveraleicosanoids
(PGI2,PGE2,TXB2,LTB4,andLTC4),whichmaybeimportantin
regulationofregionalbloodflowandventilation-perfusionmatching.

44. •SeveralinvestigatorshaveshownthattypeIIalveolarcellssynthesize
andsecreteextracellularmatrixcomponentsinvitro.
•Moreover,culturedtypeIIcellsparticipateintheturnoveroftheir
underlyingsubstratum.
•IthasbeenpostulatedthattypeIIcellmatrixsynthesisandturnovermay
beimportantinrepairingdamagedsubstratumsuchthatitwillsupport
restorationofdifferentiatedalveolarepithelialcellfunction

45. SURFACTANT SYNTHESIS AND
TURNOVER
•Pulmonarysurfactantisacomplexlipoproteinsubstanceformingathin
fluidfilmoverthealveolarsurface.
•Surfactantisaheterogeneoussubstancecomposedoflipid(primarily
phospholipid)andspecificsurfactant-associatedproteins(SP-A,SP-B,
SP-C,andSP-D).
•Surfactantisbestknownforitsroleinloweringsurfacetensionatthe
alveolarair-liquidinterface;morerecentevidencesuggeststhatsurfactant
isalsoimportantinhostdefenseagainstinvadingorganisms,andthatit
containsantioxidantenzymeactivity.

46. •TypeIIalveolarepithelialcellssynthesizeandsecretethelipidand
apoproteincomponents(SP-A,SP-B,SP-C,andSP-D).
•Surfactantisstoredincytoplasmiclamellarbodiesthatfusewiththecell
membranetoreleasesurfactantcomponentsintothealveolarspaceby
exocytosis.
•Surfactantsecretionisregulatedbysolublemediators,suchas
glucocorticoidsandb-adrenergicagonists,aswellasbyintracellular
secondmessengersignalsgeneratedbymechanicalstraininthetypeII
cell.

47. •Followingsecretion,surfactantcomponentstransformintoathree-
dimensional,latticelikestructure,tubularmyelin.
•Tubularmyelinisthoughttobeaprecursortothesurfacetension-
loweringfilmofdipalmitoylphosphatidylcholine.
•Alveolarsurfactantisinaconstantstateofflux;itturnsoverevery5to
10hrs.
•Thequantityofsurfactantinthealveolarspaceisadjustedwithchanges
inalveolarvolume,sothatanadequatereductioninsurfacetensionis
providedatalltimes.
•Adjustmentsinthesurfactantpooloccurrapidly;alveolarsurfactantcan
increaseby60%duringexerciseandquicklyreturntopre-exerciselevels
withrest.

48. •Clearanceofsurfactantfromthealveolusmayinvolveuptakeand
resecretion,degradationandincorporationintonewsurfactant,or
completeremovalfromthesurfactantpool.
•ItissuggestedthatsurfactantisdegradedbytypeIIcells,alveolar
macrophages,orwithinthesurfactantfluidlayer,anditsdegradation
productsareincorporatedintonewlysynthesizedsurfactantcomponents.
•Removalofsurfactantfromthelungmayalsooccurbymovementupthe
mucociliaryescalatorandswallowing,transferacrossthealveolar
endothelial-epithelialbarrierintothelymphandblood,ordegradation
andtransferofbreakdownproductstootherorgans.

49. EXCRETIONOFVOLATILESUBSTANCES
•Theimportanceofhumanlunginexcretionisreadilydemonstratedbyits
abilitytoeliminatetheequivalentofmorethan10,000mEqofcarbonicacid
eachday.
•Severalnonrespiratorymetabolitesthatarevolatileatbodytemperatureare
alsoexcretedfromthealveolarsurface.
•Alargenumberofvolatilecompoundsarisefromnormalendogenous
metabolismandpathologicmetabolicpathwayscharacteristicofcertain
diseasestates.
•Measurementofvolatilesubstancesinexpiredaircanprovideuseful
diagnosticinformationrelatingtoabnormalmetabolicprocessesoringestion
oftoxicsubstances.
•Measurementofbreathalcoholconcentration,forinstance,isusedcommonly
todeterminethedegreeofintoxication.

50. •Morethan300volatileorganiccompoundshavebeendetectedin
exhaledair,mainlyhydrocarbonsthatareeitheraliphatic(alkanes,
alkenes,alkynes)oraromatic(benzene)innature.
•Cigarettesmokingisasourceofhydrocarbonssuchasethene,propene,
andpropane.
•HydrocarbonsareprimarilyeliminatedbycytochromeP450metabolism
intheliver;asmallernumberareexcretedasvolatilegasfromthe
alveolarsurface.
•Lunghydrocarbonexcretionassumesamoreimportantroleinconditions
associatedwithdecreasedhepaticcytochromeP450activity.

51. •Certainvolatileconstituentsofexhaledairreflectspecificunderlying
disordersofmetabolism.
•Forinstance,elevatedbreathlevelsofisoprenehavebeenreportedin
hypercholesterolemia.
•Isopreneisabreakdownproductofdimethylallylpyrophosphateand
therebyislinkedtothesynthesisofthecholesterolprecursor,mevalonic
acid.
•Methylmercaptan,aderivativeofmethioninemetabolism,isexcreted
fromthealveolarsurfaceinhepaticfailureandimpartsadistinctiveodor
(fetorhepatis)toexhaledair.

52. •Thepresenceofacetoneinexhaledbreathduringketoacidosisisawell-
knownphenomenon.
•Limitedglucoseavailabilityinconditionssuchasdiabetesmellitusand
starvationresultsinincreasedmobilizationandoxidationoffattyacids.
•Inturn,theproductionofacetoacetate,acetone,and/orb-
hydroxybutyrateincreases,andconsequentlyacetonecanbedetectedin
urineandexhaledbreath.
•Measurementofbreathhydrogenconcentrationhasbeenemployedasan
indicatorofcarbohydratemalabsorption;bacterialbreakdownof
unabsorbedcarbohydrateintheintestinereleaseshydrogen.

53. •Alargegroupofvolatilehydrocarbonsisgeneratedbyoxygenradical-
inducedperoxidationofcellularlipidsandproteins.
•Themajorendproductsoflipidperoxidationinhumansareethaneand
pentane.
•Lipidperoxidationhasbeenimplicatedinthepathobiologyofagingand
amultitudeofotherpathophysiologicprocesses.
•Measurementofbreathhydrocarbonlevelsmayhavediagnostic
potentialindiseaseprocessesthatinvolvelipidperoxidation.
•Elevatedbreathlevelsofhydrocarbonshavebeenreportedafteracute
myocardialinfarction,inrelationtolungmalignancy,incirrhosis,andin
neurologicillnesses,includingmultiplesclerosisandschizophrenia.

54. FUNCTIONS RELATED TO THE
VASCULAR COMPARTMENT

55. FILTRATION
•Thepulmonarycapillarybedservesasafilterthatdetainsformedblood
elementsandparticulatematterlargerthantheaveragecapillarydiameterof8
to10µm.
•Pulmonaryarteriolesmayremovelargerparticlesastheytaperdistallyinto
thecapillarynetwork.
•Filtrationinthelungprotectsother,moresensitiveorgans,suchasthebrain
andheart,fromdisabling,orevenfatal,effectsofparticulateembolism.
•Thelungscommonlyremovethrombithatmigratefromtheperipheralvenous
circulation.
•Mostofthesethrombiaresmallanddonotsignificantlycompromisegas
exchangefunctionofthelung.

56. •Filtrationofcellularelementsinthelungmayprovideamechanismfor
modifyingthecellularcompositionofcirculatingblood.
•Studiesofvenousandarterialblooddemonstratehighernumbersof
megakaryocytesinvenousbloodandgreaternumbersofplateletsin
arterialblood.
•Thesefindingssuggestthatmegakaryocytesreleasedfromthebone
marrowaredetainedandfragmentedinthepulmonarycirculation.
•Bothwhiteandredbloodcellsareremovedfromcirculatingbloodasit
traversesthelungs.
•Lymphocytesandleukocytesmaybedetainedinthepulmonaryvascular
bed.
•Thelungalsoremovesdamagedorlysederythrocytes.

57. •Thelungtrapsanumberofotherphysiologicemboli,includingair,fat,
bonemarrow,andfragmentsofplacentaltissueoramnioticfluidduring
pregnancy.
•Malignantcellsthathavemigratedfromothertissuesmaybecapturedby
thelungandestablishpulmonarymetastases.
•Infectiousorganismscanalsomigratefromothersitesandestablish
infectioninthelung.
•Pulmonarycomplicationsofinfectiousembolimostcommonlyresultfrom
tricuspidorpulmonicvalveendocarditis.
•Foreignmaterials,suchastalc,maybefilteredfromthevenous
circulationinintravenousdrugusers.
•Enzymaticdestructionorphagocytosisofparticulatematerialinlungmay
preventfatalemboliceventsinmoresensitiveorgans,suchasthebrain.

58. METABOLISM
•Thepulmonaryvascularendotheliumformsanexpansiveblood-tissue
barrierthatisexposedtotheentirevolumeofcardiacoutputand,thereby,
isuniquelypositionedformetabolicfunctions.
•Severalpeptidemediatorsarisefrompulmonaryvascularstructures.
•Atrialnatriureticpeptide(ANP)isproduced,stored,andreleasedfrom
specializedmyocardialcellsthatextendintothepulmonaryveins.
•ANPmediatespulmonarybloodvesselandairwaysmoothmuscle
relaxation.Pulmonaryvascularendotheliumproducesanumberof
vasoactiveandbronchoactivemediators.

59. Prostacyclinandendothelial-derivedrelaxantfactor(EDRF/nitricoxide)
havevasodilatorproperties,whereasendothelinproduces
vasoconstrictionandbronchoconstriction.
Endothelinhasbeenshowntohavetrophiceffectsonsmoothmuscle
cellsandfibroblaststhatmaybeimportantinrepairofdamagedlung.

60. Serotonin
ProstaglandinsE&F
Leukotrienes
Norepinephrine
Substances metabolised
afterendothelialuptake
Substancesmetabolisedatthe
edothelialsurface
Bradykinin
Angiotensin
Adeninenucleotides.

61. •Somecirculatingsubstancesareprocessedbylungendothelialcellsafter
beingtransportedfromthecirculationtotheintracellularcompartment.
•Thebest-knownexampleofintracellularmetabolismofcirculating
compoundsisserotonin.
•Serotonin,or5-hydroxytryptamine(5-HT),isprimarilysynthesizedfrom
tryptophaninendocrinecellsofthegastrointestinaltract.

62. •5-HTservesasacentralnervoussystemneurotransmitter;itsreleasefrom
circulatingplateletspromotesplateletaggregation.
•Aftersecretionbythegastrointestinaltract,5-HTistakenupandstored
bynerveendingsandplatelets,orremovedfromthecirculationbyliver
andlung.
•After5-HTistakenupbyendothelialcells,itisrapidlymetabolizedby
monoamineoxidaseandaldehydedehydrogenasetophysiologically
inactive5-hydroxyindoleaceticacid(5-HIAA).
•Elevatedurinaryexcretionof5-HIAAisnotedinpatientswithcarcinoid
syndrome,aneoplasmofendocrineargentaffincells(APUDcells)
characterizedbyoversecretionof5-HT

63. •Metabolicprocessingofothersubstancesoccursatthecellsurface
withoutintracellularuptake.
•Perhapsthebest-knownexampleofasubstancethatundergoes
metabolismatthecellsurfaceisangiotensin.
•Angiotensin-convertingenzyme,acarboxypeptidase,activatesthe
vasoconstrictor,angiotensinII,fromadecapeptideprecursormolecule,
angiotensinI.
•AngiotensinIisproducedbytheenzymaticactionofreninoncirculating
angiotensinogensecretedbytheliver.
•Bradykininandadeninenucleotidesalsoareinactivatedatthepulmonary
endothelialcellsurface.

64. HEMOFLUIDITY
•Normalrespiratoryfunctionsofthelungdependoncontinuousbloodflow
throughthepulmonaryvascularbed.
•Theentirecardiacoutputpassesthroughthepulmonaryvascularsystem,
makingthesevesselsvulnerabletodamagebycirculatingorganisms,
toxins,andembolicmaterial.
•Whereasinjuredpulmonaryvesselsmayprovideanidusforbleedingor
clotformation,intrinsicmechanismsthatdeterminehemostasisand
anticoagulationaremodulatedbythepulmonaryvascularendothelium.
•Generationofthrombininthelungisalsomediatedbythromboplastin.
•Thromboplastinisaphosphatide-proteincomplex,foundinabundancein
thelung,thataugmentsconversionofprothrombintothrombin.

65. •Thrombinisinvolvedinlimitation,aswellasinitiation,ofclot
formation.
•Thrombininteractswiththeendotheliumviathrombomodulintoactivate
proteinC,whichinhibitsclottingfactorsVandVIIIandactivates
fibrinolysis.
•InadditiontoactivatingproteinC,thrombinalsoinitiatesreleaseof
plasminogenactivatorfromendothelialcells.
•Plasminogenactivatorinturncleavescirculatingplasminogento
plasmin,whichdigestsfibrin.
•Thevascularendotheliumcanalsobindandinactivatethrombin;
furthermore,itcanmodifycoagulationbyreleasingthevasodilator
prostacyclininresponsetothrombin.

66. THANK YOU