Παθογένεια της ΧΑΠ: νεώτερα δεδομένα

Παρουσίαση με θέμα: "Παθογένεια της ΧΑΠ: νεώτερα δεδομένα"— Μεταγράφημα παρουσίασης:

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

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

5

6 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)

7 - 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)

8 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

9 …ενορχηστρωτές της φλεγμονής
Ο Υ Δ 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

11 Active role or bystanders
EOSINOPHILS Active role or bystanders

12 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)

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

14 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

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

16 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

17 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

18 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

19 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.

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 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

21 T-CELLS SUBPOPULATION AND COPD

22 T-CELLS SUBPOPULATIONS IN COPD

23 CD8 SUBPOPULATIONS (Tc1)

24 CD8 SUBPOPULATIONS (Tc2)

25 Συσχέτιση FEV1 & Tc1/Tc2

26 Cytotoxicity of sputum CD8 cells

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. 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.