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. Η απόφραξη των αεραγωγών είναι προοδευτική και σχετίζεται με μια ανώμαλη φλεγμονώδη απάντηση των αεραγωγών σε ερεθιστικά σωματίδια ή αέρια.

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

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

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)

- ΚΥΤΤΑΡΙΚΟΙ ΜΗΧΑΝΙΣΜΟΙ ΣΤΗ ΧΑΠ Neutrophil PROTEASE INHIBITORS 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)

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

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

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

Active role or bystanders EOSINOPHILS Active role or bystanders

ΚΥΤΤΑΡΙΚΟΙ ΜΗΧΑΝΙΣΜΟΙ ΣΤΗ ΧΑΠ SECAM Cigarette smoke ? CD8+ lymphocyte Cytotoxicity Epithelial cells 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)

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

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 Plasma leak Bronchoconstriction

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

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

Macrophage - Neutrophil - Epithelial cells interactions Cigarette smoke Macrophages CD8+ Epithelial cells cytotoxicity Slightly modified graph according to our hypothesis in regard to T-Lym and CD8+ cells Activation Cytokine production TNF-α LTB4 IL-8

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

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. 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.

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

T-CELLS SUBPOPULATION AND COPD

T-CELLS SUBPOPULATIONS IN COPD

CD8 SUBPOPULATIONS (Tc1)

CD8 SUBPOPULATIONS (Tc2)

Συσχέτιση FEV1 & Tc1/Tc2

Cytotoxicity of sputum CD8 cells

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. 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.