Pathogenesis of COPD NOXIOUS AGENT tobacco smoke pollutants

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

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

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

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

ΚΥΤΤΑΡΙΚΟΙ ΜΗΧΑΝΙΣΜΟΙ ΣΤΗ ΧΑΠ CD 8+ lymphocyte SECAM Alveolar macrophage ? MCP-1 ity c i ox t to y C Neut. chemotactic factors Cytokines (IL-8) Mediators (LTB 4) Epithelial cells PROTEASE INHIBITORS Cigarette smoke Neutrophil elastase Cathepsins PROTEASES Matrix metalloproteinases Alveolar wall destruction (Emphysema) Mucus hypersecretion (Chronic bronchitis)

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

REACTIVE OXYGEN SPECIES IN COPD ANTIOXIDANTS Anti-proteases SLPI 1 -AT Vitamins C and E N-acetyl cysteine Glutathione analogues Nitrones (spin trap) NF- B Proteolysis IL-8 O 2 -, H 2 0 2 OH. , ONOO- Mucus secretion Isoprostanes TNF- Neutrophil recruitment Plasma leak Bronchoconstriction

Neutrophil elastase Cathepsins MMP-1, MMP-9, MMP 12 Granzymes, perforins Others……. . TIMPs Elafin SLPI 1 -Antitrypsin ΣΧΕΣΗ ΠΡΩΤΕΑΣΩΝ-ΑΝΤΙΠΡΩΤΕΑΣΩΝ ΣΤΗ ΧΑΠ

ΥΠΕΡΕΚΡΙΣΗ ΒΛΕΝΝΑΣ ΣΤΗ ΧΑΠ Epithelium Mucus • Acetylcholine • Tachykinins • Proteinases neutrophil elastase Goblet cell hyperplasia SP Sensory nerve Cholinergic ACh nerve Mucus gland hyperplasia NE Cytokines ROS INFLAMMATION Neutrophils • Cytokines (TNF- ) • Oxidants • Growth factors • MUC genes MUC 5 a, MUC 8

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

T-LYMPHOCYTES SUBPOPULATIONS CD 8 CD 4 Th 1 Tc 1 Th 2 Tc 0 ? INF-γ IL-2 TNFb Cytokine profile IL-4 IL-5 IL-10 IL-6

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 CD 8+ 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: CD 4, CD 8, Tc 1, Tc 2, cytotoxicity, expression of perforin

T-CELLS SUBPOPULATION AND COPD

T-CELLS SUBPOPULATIONS IN COPD

CD 8 SUBPOPULATIONS (Tc 1)

CD 8 SUBPOPULATIONS (Tc 2)

Cytotoxicity of sputum CD 8 cells

CONCLUSIONS There are differences in T-cells subpopulations between smokers with COPD and smokers without. The decreased numbers of Tc 1 cells (producing subsequently amounts INF-γ) possibly is related to the pathogenesis of COPD. CD 8 cells in COPD appeared to express increased cytotoxicity The expression of perforin of CD 8 cells is higher in smokers with COPD.