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

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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) Genetic factors Respiratory infection Other COPD

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

5 ASTHMA Sensitizing agent COPD Noxious agent Asthmatic airway inflammation CD4+ T-lymphocytes Eosinophils COPD airway inflammation CD8+ T-lymphocytes Macrophages Neutrophils Completely reversible Airflow limitation Completely irreversible

6 COPD: AIRWAY INFLAMMATION Χρονίως εξελισσόµενη φλεγµονώδης διεργασία µε καταστροφικές µη αναστρέψιµες βλάβες Ευρήµατα σε βιοψίες πνευµόνων (T-Lym( Lym,, Mac) BAL (Mac, Neu) Βιοψίες βρογχικού βλεννογόνου (CD8( +, Eos, Neu) Induced sputum (Neu, ECP, EPO) είκτες στον εκπνεόµενο αέρα (NO,( CO, H 2 O 2 ) Κλινικοί δείκτες (BHR( mch-his his & 5-AMP) 5

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

8 TNF-α και IL-8 στη ΧΑΠ Cigarette smoke TNF-α Alveolar macrophage TNF-α IL-8 Epithelial cells NF-κB IL-8 8 gene IL-8 Neutrophils IL-8

9 Ο Υ Ε Τ Ε Ρ Ο Φ Ι Λ Α ενορχηστρωτές της φλεγµονής

10 Μ Α Κ Ρ Ο Φ Α Γ Α ο γνωστός άγνωστος

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

13 OVERLAP BETWEEN COPD AND ASTHMA COPD Neutrophils No AHR No steroid response ~10% ASTHMA Eosinophils AHR Steroid response Wheezy bronchitis

14 REACTIVE OXYGEN SPECIES IN COPD Anti-proteases SLPI α 1 -AT ANTIOXIDANTS Vitamins C and E N-acetyl cysteine Glutathione analogues Nitrones (spin trap) NF-κB Proteolysis O - 2, H OH., ONOO - IL-8 Neutrophil recruitment TNF-α Mucus secretion Isoprostanes Plasma leak Bronchoconstriction

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

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

17 Macrophage - Neutrophil - Epithelial cells interactions Cigarette smoke Macrophages CD8+ cytotoxicity Activation Cytokine production Epithelial cells TNF-α LTB 4 IL-8

18 T-LYMPHOCYTES SUBPOPULATIONS CD 4 CD 8 Th1 Th2 Tc1 Tc2 Tc0? INF-γ IL-2 TNFb Cytokine profile IL-4 IL-5 IL-10 IL-6 6

19 Τhe role of T-cells T 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.

20 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

21 T-CELLS SUBPOPULATION AND COPD 80 % patients healthy 0 CD4 CD8

22 T-CELLS SUBPOPULATIONS IN COPD P<0.001 CD4/CD8 RATIO COPD HEALTHY

23 CD8 SUBPOPULATIONS (Tc1) p= p=0.001 NS TC1/CD8+ ratio COPD smokers Non- COPD smokers Non- smokers healthy

24 CD8 SUBPOPULATIONS (Tc2) 50 p=0.001 p=0.001 TC2/CD8+ ratio NS 10 0 COPD smokers Non- COPD smokers Non- smokers healthy

25 Συσχέτιση FEV 1 & Tc1/Tc2 FEV 1 (% of pred.) n=36 r=0.401 p= TC1/TC2 ratio

26 Cytotoxicity of sputum CD8 cells Cytotoxicity (%) COPD smokers Non- COPD smokers Non- smokers healthy

27 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.