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Παθογένεια της ΧΑΠ : νεώτερα δεδομένα

Παθογένεια της ΧΑΠ : νεώτερα δεδομένα. Καθηγητής : N.M. Σιαφάκας Ιατρική Σχολή Πανεπιστήμιο Κρήτης. Ορισμός της ΧΑΠ. Η Χρόνια αποφρακτική πνευμονοπάθεια (ΧΑΠ) χαρακτηρίζεται από απόφραξη των αεραγωγών, η οποία δεν είναι πλήρως αναστρέψιψη.

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Παθογένεια της ΧΑΠ : νεώτερα δεδομένα

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  1. Παθογένεια της ΧΑΠ: νεώτερα δεδομένα Καθηγητής: N.M.Σιαφάκας Ιατρική Σχολή Πανεπιστήμιο Κρήτης

  2. Ορισμός της ΧΑΠ • Η Χρόνια αποφρακτική πνευμονοπάθεια (ΧΑΠ) χαρακτηρίζεται από απόφραξη των αεραγωγών, η οποία δεν είναι πλήρως αναστρέψιψη. • Η απόφραξη των αεραγωγών είναι προοδευτική και σχετίζεται με μια ανώμαλη φλεγμονώδη απάντηση των αεραγωγών σε ερεθιστικά σωματίδια ή αέρια.

  3. Pathogenesis of COPD NOXIOUS AGENT(tobacco smoke, pollutants, occupational agent) COPD Genetic factors Respiratory infection Other

  4. Noxious particles and gases Host factors Lung inflammation Anti - proteinases Anti - oxidants Oxidative stress Proteinases Repair mechanisms COPD pathology

  5. COPD: AIRWAY INFLAMMATION Χρονίως εξελισσόμενη φλεγμονώδης διεργασία με καταστροφικές μη αναστρέψιμες βλάβες • Ευρήματα σε βιοψίες πνευμόνων (T-Lym, Mac) • BAL (Mac, Neu) • Βιοψίες βρογχικού βλεννογόνου (CD8+, Eos, Neu) • Induced sputum (Neu , ECP, EPO) • Δείκτες στον εκπνεόμενο αέρα (NO, CO, H2O2) • Κλινικοί δείκτες (BHR mch-his & 5-AMP)

  6. ΚΥΤΤΑΡΙΚΟΙ ΜΗΧΑΝΙΣΜΟΙ ΣΤΗ ΧΑΠ Cigarette smoke Alveolar macrophage ? CD8+ MCP-1 lymphocyte Neutrophil chemotactic factors Cytokines (IL-8) Mediators (LTB4) 4 ) ) Neutrophil PROTEASE INHIBITORS Neutrophil elastase - PROTEASES Cathepsins Matrix metalloproteinases Alveolar wall destruction Mucus hypersecretion (Emphysema) (Chronic bronchitis)

  7. TNF- και IL-8 στη ΧΑΠ Cigarette smoke TNF- Alveolar macrophage NF-B TNF- Epithelial cells IL-8 IL-8 gene IL-8 IL-8 Neutrophils

  8. Ο Υ Δ Ε Τ Ε Ρ Ο Φ Ι Λ Α …ενορχηστρωτές της φλεγμονής

  9. Μ Α Κ Ρ Ο Φ Α Γ Α … ο γνωστός άγνωστος

  10. EOSINOPHILS Active role or bystanders

  11. ? CD8+ lymphocyte Cytotoxicity Epithelial cells ΚΥΤΤΑΡΙΚΟΙ ΜΗΧΑΝΙΣΜΟΙ ΣΤΗ ΧΑΠ SECAM Cigarette smoke Alveolar macrophage MCP-1 Neut. chemotactic factors Cytokines (IL-8) Mediators (LTB4) Neutrophil PROTEASE INHIBITORS Neutrophil elastase PROTEASES Cathepsins Matrix metalloproteinases Alveolar wall destruction Mucus hypersecretion (Emphysema) (Chronic bronchitis)

  12. OVERLAP BETWEEN COPD AND ASTHMA COPD ASTHMA Neutrophils Eosinophils No AHR ~10% AHR No steroid response Steroid response “Wheezy bronchitis”

  13. REACTIVE OXYGEN SPECIES IN COPD ANTIOXIDANTS Vitamins C and E N-acetyl cysteine Glutathione analogues Anti-proteases Nitrones (spin trap) SLPI 1-AT NF-B Proteolysis IL-8 TNF- O2-, H202 OH., ONOO- Neutrophil recruitment Mucus secretion Isoprostanes Bronchoconstriction Plasma leak

  14. ΣΧΕΣΗ ΠΡΩΤΕΑΣΩΝ-ΑΝΤΙΠΡΩΤΕΑΣΩΝ ΣΤΗ ΧΑΠ 1-Antitrypsin SLPI Elafin TIMPs Neutrophil elastase Cathepsins MMP-1, MMP-9, MMP12 Granzymes, perforins Others……..

  15. ΥΠΕΡΕΚΡΙΣΗ ΒΛΕΝΝΑΣ ΣΤΗ ΧΑΠ • Acetylcholine • Tachykinins • Proteinases • neutrophil elastase • Cytokines • (TNF-) • Oxidants • Growth factors •  MUC genes • MUC5a, MUC8 Mucus Epithelium Goblet cell hyperplasia SP Sensory nerve Cholinergic nerve ACh Mucus gland hyperplasia NE Cytokines ROS INFLAMMATION Neutrophils

  16. Macrophage - Neutrophil - Epithelial cells interactions Cigarette smoke Macrophages CD8+ Epithelial cells cytotoxicity Activation Cytokine production TNF-α LTB4 IL-8

  17. T-LYMPHOCYTESSUBPOPULATIONS CD8 CD4 Tc1 Tc2 Tc0 Th1 Th2 ? INF-γ IL-2 TNFb IL-4 IL-5 IL-10 IL-6 Cytokine profile

  18. Τhe role of T-cells subpopulations in the pathogenesis of COPD Aim T-Lymphocyte represents a major effector cell of inflammation. The number and function of CD8+ cells were investigated in smokers with COPD and in smokers without COPD in order to verify their role in the pathogenesis of the disease.

  19. DESIGN 36 smokers with COPD 24 smokers without COPD 10 non smokers healthy •Matced for age •Sputum induction: CD4, CD8, Tc1, Tc2, cytotoxicity, expression of perforin

  20. T-CELLS SUBPOPULATION AND COPD

  21. T-CELLS SUBPOPULATIONS IN COPD

  22. CD8 SUBPOPULATIONS (Tc1)

  23. CD8 SUBPOPULATIONS (Tc2)

  24. Συσχέτιση FEV1 & Tc1/Tc2

  25. Cytotoxicity of sputum CD8 cells

  26. CONCLUSIONS There are differences in T-cells subpopulations between smokers with COPD and smokers without. The decreased numbers of Tc1 cells (producing subsequently amounts INF-γ) possibly is related to the pathogenesis of COPD. CD8 cells in COPD appeared to express increased cytotoxicity   The expression of perforin of CD8 cells is higher in smokers with COPD.

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