155142507 fiziopatologia-bpoc-2
TRANSCRIPT
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DR BIANCA DOMOKOS
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FACTORII DE RISC PATOGENIE CITOKINE PROINFLAMATORII FACTORI DE CRESTERE CHEMOKINE CITOKINE ANTIINFLAMATORII IMPLICATII TERAPEUTICE
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Identificarea factorilor de riscstrategii de preventie si tratament
Identificarea fumatului: factorul de risc principalprograme stopare a fumatului
2 pacientii cu acelasi istoric de fumatunul dezvolta BPOC(interactiune gene-gazda)
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Afectiune poligenica-clasic, documentatdeficitul α1AT
Agregare familiala Gene susceptibile –cromosomul 2qfactorul de crestere si transformare
TGFß1epoxid hidrolasa 1factorul de necroza tumorala TNFα
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Expunerea profesionala-10-20% numarul total de cazuri: noxe, pulberi, agenti iritanti
Fumatul pasiv Poluarea exterioara-rol ↓comparativ cu
fumatul, gazele eliminate prin arderea combustibilului
Poluarea interioara
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Stressul oxidativ- oxidanti endogeni (fagocite), exogeni (poluarea aerului)injurie directa, activarea mecanismelor moleculare ce initiaza procesul inflamator
Genul-repartitie egala Infectiile( virale/bacteriene)-progresia si
patogeneza BPOC Statusul socioeconomic-relatie invers
proportionala cu riscul BPOC
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Poluare, gaze
Inflamatie
Factori individuali
BPCO
ProteinaseStress Oxidativ
Anti-proteinaseAnti-oxidanti
Mecanisme reparatorii
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INFLAMATIE
BOALA CAILOR AERIENE MICI DISTRUCTII DE PARENCHIM
LIMITAREA FLUXULUI AERIAN
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Biopsiile bronsice, parenchim pulmonarinfiltrat limfocitar, neutrofile , macrofage
Imunitatea innascuta-activata in toate stadiile BPOC
Formele severemecanisme adaptative:↑ LT, LB
Ambele tipuri-mediate de citokine Distructia peretilor alveolaridegardarii elastinei
mediata de proteaze, apoptozei pneumocitelor de tip I, celulelor endoteliale
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TNFα, IL1ß, IL6 ↑ BPOC, amplifica inflamatia activarea factorului de transcriptie nucleara
expresia crescuta a unor gene inflamatorii AR, RCH- blocarea activitatii citokinelor-beneficii
cliniceinteres crescut daca acceasi abordare ar putea fi benefica la pacientii cu BPOC
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Secretat:celule epiteliale, macrofage, LT, celulele musculare netede
Valori ↑ sputa indusa BPOC Valori ↑↑ BPOC si scadere ponderala Implicat in inducerea emfizemului secundar
expunerii la fumul de tigara la modele animale Infliximab-fara beneficii asupra
simptomatologiei,capacitatii de efort, functiei pulmonare
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Studiu observational-BPOC, AR –terapie anti TNFexacerbari ↓ etanrcept
neinfluentat infliximab Incidenta crescuta-pneumoniilor, cancerului de
tract respirator-terapia cu Infliximabsupresia TNFα detrimentul pacientilor BPOC
(imunitate aberanta, risc crescut de cancer pulmonar)
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Rol –activarea macrofagelorsecretie citokine inflamatorii, chemokine, metaloproteinaze (MMP)
↑IL1ß sputa indusa, corelata cu severitatea BPOC
Studii clinice-canakinumab(agonist IL1)- in desfasurare, rolul incert
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Actioneaza impreuna cu alte citokine inflamtorii
↑ sputa, plasma BPOC,↑↑ exacerbari Corelata cu valori crescute ale PCR Mecanismul major de stimulare a secretiei PCR la
nivelul ficatului Implicata in alterarea functiei celulelor endoteliale,
rezistenta la insulina, osteoporoza, depresie Tocilizumab –eficient RA, RCH, necesita testare
BPOC, posibil util in tratamentul comorbiditatilor
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Citokina nou descrisa Expresie crescuta –celulele epiteliale,
macrofage , CD8+ la pacientii BPOC Corelata cu severitatea IL32 este indusa de IFNᵧsecretie TNFα, IL1β
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TSLP-citokina din familia IL7,↑ BPOC Rol esential –programarea cel dendritice secretie
de CCL 17 (ligand chemokine), CCL22 Secretia liganziloratrage LTcd4+ helper tip 2 TSLP-secretia CXCL10atrage Th1, celulele T
citotoxice Pattern inflamator similar –astmul
sever(TSLP↑)
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Proeminente, secreta limfokine Nr crescut-stadii avansate
(GOLDIII,IV)reactia imuna adaptataiva apanajul formelor severe
LT-BPOC-predominant CD8+citotoxice, nr usor↑ CD4+
Subtipurile Th1,Tc1IFNγ, IL2 IFNγ-orchestreaza infiltrarea cu cel
Th1,Tc1 la nivel pulmonar
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Subset CD4+, rol important afectiuni inflamatori, autoimune
↑sputa BPOC, biopsiile bronsice Reglata de factorul de transcriptie IL6,IL1ß,IL23-diferentierea celulelor Th17
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Inflamatie pulmonara, emfizem la soareci BPOC-expresie crescuta –macrofagelor
alveolare, LTCD8+ ↑sputa Concentratia-corelata severitatea bolii Rol –manifestarilor sistemice ale BPOC
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diferentierea/supravietuirea cel inflamatorii
proliferarea/activarea celulelor structurale, contribuind la remodelarea cailor aeriene
GM-CSF-diferentierea /supravietuirea neutrofilelor, secretat macrofage, cel epiteliale, LT
Concentratii ↑BAL(exacerbari)↔nr crescut neutrofile BPOC
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Multifunctional, expimat la nivelul celulelor epiteliale, macrofagele din caile aeriene mici
proliferare fibroblasti, celule musculare netede, matrice extracelulara, repararea epitelialafibroza pulmonara
efecte imunoreglatoare ↓ Th1,Th2,Th17
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EGF(epidermal growth factor)—rol critic reglarea secretiei de mucus
Activat –stressul oxidativfosforilarea EGFexpresia genelor mucinei(MUC5A,5B)
Factorul de crestere al endoteliului vascular↓BPOC
Blocarea FCEapoptoza cel endoteliale alveolare, emfizem
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Rol-recrutarea cel inflamatorii din circulatie
Mai multe chemokine pot activa acelasi receptor, rolul lor receptorul activat:
receptori pt chemochine CC(CCRs)receptori pt chemoxine CXC (CXCRs) CCR2-monocite, macrofage CCR5-recruteaza LT, Eo, macrofage CXCR1,CXCR2-neutrofilel, excerbarea
BPOC
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IL10 inhiba TNFα, IL1β,GM-CSF Concentratii↓ sputa BPOC IL22,IL24,IL26,IL28-structura asemanatoare IL10,
rolul BPOC incert
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AR,RCH-blocarea unor citokine-beneficiu clinic(Anti TNFα-50%)
Blocarea mai multor citokine-TSLP,IL1βposibil beneficii clinice
Tocilizumab-blocheaza IL6eficienta la pacientii refractari la terapia anti TNF
Dezvoltarea unor anticorpi multivalenti benefica(administrare inhalatorie/sistemica)
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BPOC-rezistenta la corticoterapie crescuta (nu reusesc sa suprime activitatea citokinelor)
Droguri-efect inhibitor mai general –necesareinhibitorii 4 fosfodiesteraza (roflumilast)
Trialuri clinice-in curs , inhibitori citokine BPOC (multiple efecte adverse in adm sistemica!administrare inhalatorie)
2studii recente-blocant IL5 mepolizumab efecte benefice exacerbarea BPOC