1

Enero 2006Enero 2006

DraDra Consuelo MartConsuelo Martíínez nez CCóóceracera

Servicio de AlergologServicio de Alergologííaa

Hospital ClHospital Clíínico San Carlosnico San Carlos

Madrid (EspaMadrid (Españña)a)

www.alergomurcia.comwww.alergomurcia.com

El óxido nítrico (NO) es un radical libre, gaseoso, con múltiples acciones biológicas.

Las mejor definidas son:la regulación del tono vascularla regulación de la neurotransmisión la participación en la inmunidad no

específicala participación en la inflamación

2

Enzima Enzima SintetasaSintetasa de ONde ON

Almeida Almeida TellezTellez 20012001

AgullAgullóó 20042004

3

Almeida Almeida TellezTellez 20012001

AgullAgullóó 20042004

AUTACOIDES: Histamina, Serotonina, Bradiquinina AUTACOIDES: Histamina, Serotonina, Bradiquinina …………

Ada Cuevas. Ada Cuevas. MedwaveMedwave. A. Añño 3, No. 1, Enero 2003. o 3, No. 1, Enero 2003.

4

CONSTITUTIVA

Las regiones encefálicas que regulan el estado de activación neuronal (tronco del encéfalo y prosencéfalo basal) utilizan dos mediadores químicos, la acetilcolina (Ach) y el NO.

CudeiroCudeiro, J. y , J. y RivadullaRivadulla, C. , C. TrendsTrends in in NeuroscienceNeuroscience 19991999

Armando PArmando Péérez Gonzrez Gonzáález.lez. Facultad Miguel EnrFacultad Miguel Enrííquezquez . . CubaCuba 20002000

CONSTITUTIVA

5

Vila Petroff Rev Fed Arg Cardiol 29: 501-507, 2000

INDUCIBLE

iNOSM

MUSCULO LISO

MUSCULO LISO

NO

Ronco J, Ronco J, PhangPhang P, P, AmAm RevRev RespirRespir DisDis 1991 1991

INDUCIBLE

6

Secreción de mocoActivación neural

Extravasación PlasmaVasodilatación

Activación Células

RespuestaBronquial

NOAire exhaladoAire exhalado

Maniobras EFRManiobras EFREjercicoEjercico FFíísicosicoCiclo MenstrualCiclo MenstrualReducciReduccióón Temperaturan TemperaturaHHáábito bito TabTabááquicoquicoExposiciExposicióón pasiva n pasiva Ingesta de alcoholIngesta de alcohol

LL--argininaargininaEnalaprilEnalaprilLechuga/EspinacasLechuga/EspinacasFormaldehFormaldehíídodoInfecInfec. Respiratorias. RespiratoriasNONO22 ambientalambiental

REDUCCIONREDUCCIONINCREMENTOINCREMENTO

Prieto L. Alergol Inmunol Clin 2002

7

Tos crTos cróónica sin HRBnica sin HRBFibrosis Fibrosis ququíísticasticaEsclerosis sistEsclerosis sistéémica sin HPmica sin HPDiscinesiaDiscinesia bronquial primariabronquial primariaHipertensiHipertensióón pulmonar primarian pulmonar primariaDistressDistress respiratorio del adultorespiratorio del adulto

AsmaAsmaRinitis AlRinitis AléérgicargicaInfecciones VInfecciones VííricasricasBronquiectasiasBronquiectasiasTos crTos cróónica + HRBnica + HRBBronquiolitisBronquiolitis obliteranteobliteranteEsclerosis sistEsclerosis sistéémicamicaFibrosis PulmonarFibrosis PulmonarTuberculosis pulmonarTuberculosis pulmonarCCááncer Pulmonarncer Pulmonar

REDUCCIONREDUCCIONINCREMENTOINCREMENTO

Prieto L. Alergol Inmunol Clin 2002

EurEur RespirRespir J. 1993 Oct;6(9):1368J. 1993 Oct;6(9):1368--70. 70. Increased amount of nitric oxide in exhaled air of asthmatics.

Alving K, Weitzberg E, Lundberg JM.Dept of Pharmacology, Karolinska Institute, Stockholm, Sweden.

The presence of nitric oxide (NO) in the exhaled air of humans has recently been described.We wanted to assess at what level exhaled NO originates in normal airways, and to determine whether airway inflammation induces changes in the levels of exhaled NO. Exhaled NO was continuously measured by chemiluminescence technique during normal tidal breathing throughthe nose or mouth, with a detection limit of 1 part per billion (ppb). Twelve control subjects were compared to eight patients with mild atopic asthma and rhinitis caused by occupational allergen. In control subjects, the major part of NO in exhaled air (up to 30 ppb) seemed to originatein the nasal airways, with only minor contribution from the lower airways and the oral cavity. However,in mild asthmatics, the level of exhaled NO during oral breathing, indicating the involvement of the lower airways, was increased 2-3 fold. Since increased production of NO in the lower airways may involve activated macrophages or neutrophils, we suggest that exhaled NO may be used to instantly monitor ongoing bronchial inflammation, at least when involving inducible NO synthase.

PMID: 7507065 [PubMed - indexed for MEDLINE]

8

LancetLancet.. 1994 1994 JanJan 15;343(8890):13315;343(8890):133--5.5.

IncreasedIncreased nitricnitric oxide in oxide in exhaledexhaled airair ofof asthmaticasthmatic patientspatients..KharitonovKharitonov SASA, , Yates DYates D, , RobbinsRobbins RARA, , LoganLogan--SinclairSinclair RR, , ShinebourneShinebourne EAEA, ,

BarnesBarnes PJPJ..DDepartmentepartment ofof ThoracicThoracic Medicine, Medicine, NationalNational HeartHeart andand LungLung InstituteInstitute, , LondonLondon, UK., UK.

NitricNitric oxide (NO) gas oxide (NO) gas isis producedproduced byby variousvarious cellscells withinwithin thethe lowerlower respiratoryrespiratory tracttract, , includingincluding inflammatoryinflammatory andand epithelialepithelial cellscells,,andand isis detectable in detectable in thethe exhaledexhaled airair ofof normal human normal human subjectssubjects. . WeWe havehave measuredmeasured exhaledexhaled NO in NO in patientspatients withwith asthmaasthma, ,

sincesince severalseveral cellcell typestypes thatthat are are activatedactivated in in asthmaasthma can producecan produceNO NO afterafter inductioninduction. NO . NO waswas measuredmeasured reproduciblyreproducibly by a by a slowslow vital vital capacitycapacity manoeuvremanoeuvre andand anan adaptedadapted chemiluminescencechemiluminescence analyseranalyser..NO NO waswas detectable in detectable in exhaledexhaled airair ofof 67 control 67 control subjectssubjects (mean (mean peakpeak concentrationconcentration 80.2 [SE 4.1] 80.2 [SE 4.1] ppbppb) ) andand waswas significantlysignificantly reducedreduced bybyinhalationinhalation ofof thethe specificspecific NO NO synthasesynthase inhibitorinhibitor NGNG--monomethylmonomethyl--LL--argininearginine. 61 non. 61 non--steroidsteroid--treatedtreated asthmaticasthmatic subjectssubjects hadhad significantlysignificantly

higherhigher peakpeak expiredexpired NO NO concentrationsconcentrations thanthan controlscontrols (283 [16] (283 [16] ppbppb, p < 0.001) , p < 0.001) butbut 52 52 asthmaticasthmatic patientspatients receivingreceiving inhaledinhaled corticosteroidscorticosteroidshadhad levelslevels similar similar toto controlscontrols (101 [7] (101 [7] ppbppb). ). HighHigh exhaledexhaled NO NO concentrationsconcentrations in in asthmaticasthmatic patientspatients may may reflectreflect inductioninduction ofof NO NO synthasesynthase, , whichwhich isis knownknown toto be be inhibitedinhibited by by steroidssteroids. . MeasurementMeasurement ofof exhaledexhaled NO NO concentrationsconcentrations may be may be clinicallyclinically usefuluseful in in detectiondetection andandmanagementmanagement ofof cytokinecytokine--mediatedmediated inflammatoryinflammatory lunglung disordersdisorders..

PMID: 7904001 [PMID: 7904001 [PubMedPubMed -- indexedindexed forfor MEDLINE]MEDLINE]

InducciInduccióón de NOS2 n de NOS2 óó iNOSiNOS en Asmaen Asma

D- arginina

NOAire exhaladoAire exhalado

Almeida Almeida TellezTellez 20012001

CitocinasCitocinas inflamatoriasinflamatorias

EndotoxinasEndotoxinas

Infecciones VInfecciones Vííricasricas

9

NOAire exhaladoAire exhalado

Th2

A. NietoHistaminaTriptasa

PAFLTC4PGD2

IL-3, IL-13, IL-5GM-CSFIL-6, IL-8TNF-αTHFIOF

ECPMBPMCPMRPLTC4

ProteasasPAFLTC4

Th0 CPATh2 IL-2

IL-4CCR3

B

NK 1.1 IL-13IL-4

IL-5

IL-13IL-4

Inflamación AgudaRinitis

Broncoespasmo

InflamaciónCrónica

Rinitis/asma

Remodelingde la Vía Aérea

inferior

EOTAXINA

F. Crecimiento- TGF-ß- Endotelinas

IL-4 Th1

IL-12IFN γ

IL-9IL-10

IL-4

Quemoquinas(RANTES)

M. Adhesión(ICAM-1, Selectinas)

QuemoquinasQuemoquinas(RANTES)(RANTES)

M. M. AdhesiAdhesióónn(ICAM(ICAM--1, 1, SelectinasSelectinas))

10

Th2

A. NietoHistaminaTriptasa

PAFLTC4PGD2

IL-3, IL-13, IL-5GM-CSFIL-6, IL-8TNF-αTHFIOF

ECPMBPMCPMRPLTC4

ProteasasPAFLTC4

Th0 CPATh2 IL-2

IL-4CCR3

B

NK 1.1 IL-13IL-4

IL-5

IL-13IL-4

Inflamación AgudaRinitis

Broncoespasmo

InflamaciónCrónica

Rinitis/asma

Remodelingde la Vía Aérea

inferior

EOTAXINA

F. Crecimiento- TGF-ß- Endotelinas

IL-4 Th1

IL-12IFN γ

IL-9IL-10

IL-4

Quemoquinas(RANTES)

M. Adhesión(ICAM-1, Selectinas)

QuemoquinasQuemoquinas(RANTES)(RANTES)

M. M. AdhesiAdhesióónn(ICAM(ICAM--1, 1, SelectinasSelectinas))

ECPECP

LTsLTsPgPg

EPXEPX

ILsILs

adenosinaadenosina

ccéélulaslulas

NOe