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COPD&ASTHMA: Similarities and discrepancies

COPD&ASTHMA: Similarities and discrepancies. Gülfem Çelik, Ankara University School of Medicine Department of Chest Diseases Division of Allergy. What’s common?. Dyspnea; cough; wheezing. Environmental stimuli. Airway diseases. Chronic inflammation. Structural alterations.

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COPD&ASTHMA: Similarities and discrepancies

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  1. COPD&ASTHMA:Similarities and discrepancies Gülfem Çelik, Ankara University School of Medicine Department of Chest Diseases Division of Allergy

  2. What’s common? Dyspnea; cough; wheezing Environmental stimuli Airway diseases Chronic inflammation Structural alterations

  3. COPD&ASTHMA:Simmilarities and discrepancies • Initial stimuli and response • Airway inflammation • Remodelling • Outcomes

  4. Initial stimuli and response Eotaxins RANTES; GM-CSF IL-8 LTB4 TNFa IL1b GMCSF Endothelins TGFb Growth factors ICAM expression Oxidant and proteases release

  5. Inflammation

  6. CD45 CD8+ T cells Macrophages Neutrophils CD45 CD4+ T cells Eosinophils Mast cells IL-4; IL-5; IL-13 Histamine cLTs RANTES/Eotaxin IL-8 LTB4 CXCR2 CXCR3

  7. Naive T cells IL2 Effector Th2 cells Dendritic cell

  8. Timing of infection Duration of exposure Exposure route Hygen Hypothesis & Asthma Less microbial product More microbial product Th1 Th2 Endotoxin Switch

  9. TLR SIGNAL IL-4 IL-12 Th0 IL-4R IL-12R STAT4 T-bet STAT6GATA-3 Th1 Th2 TREG IL-2 IFN-g IL-4 IL-13 IL-5 Th1 Th2 IL-10 TGF-b Treg BACTERIA VIRUSES Dendritic cell Maturation TLR4 LPS CD14 TLR2 MD2 Naive T cell ‘priming’

  10. FceRII Th2 cell IL-3, IL-4, IL-5, IL-6 IL-9 GM-CSF ICAM-1 IL-4 B cell IL-13 VCAM-1 Activated B cell FceRI IL-5 GM-CSF IL-4, IL-13 TNFa Late phase response Histamine Leukotrienes PGD2 Early phase response

  11. IL-8 IL-8 LTB4 IL-8 LTB4 GRO-a IL-8 LTB4 CXCR2 CD8+ cells CXCR3 IP-10 I-TAC IL-8 LTB4 Perforin Granzyme-B TNFa Reactive Oxygen species MPO Proteases Decrease in antioxidants and anti-proteases

  12. Structural changes“REMODELLING”

  13. Epithelial shedding Increase in basal membran thickness Enlargement of bronchial muscle cell Rearrengement of matrix components Angiogenesis; goblet cell hypertrophy

  14. ICAM-1 NGF selectins TGFb Fibronectin Laminin VCAM-1 ECP MPO EPO Fibroblast Chemokines (RANTES; Eotaxin MIP1a; MCP-1) sLT, PAF, TxA2 Myofibroblast c VEGF MMP/TIMPs

  15. O2-; H2O2 OH; ONOO MMP-9 MMP-1 MMP-2 MMP-9 MMP-12 MMP-8 MMP-9 Elastolysis Cathepsins B Cathepsin L, Cathepsin K Neutrophil Elastase Cathepsin G Proteinase-3 Perforin Granzyme-B TNFa Increase alveolar cell apoptosis Elastin; Collagen; Fibronectin + Loss of alveolar attachtments Isoprostanes

  16. Outcomes

  17. Causative factors Allergens, self antigens Large airways Small airways Involvement site Inflammatory cells Mucus Hyper production Fibrosis Elastolysis Smooth muscle hyperplasia Pathology Ongoing inflammation BM and ECM Reduced elastic fibers Exacerbations And BHR Marked mucus secretion during exacerbation Airway obstruction during exacerbation Outcome Non reversible airway obstruction

  18. Proteolysis (Loss of walls/ capillaries) Glandular hypertrophy Reduced no of cilia Goblet cell metaplasia Smooth muscle hypertrophy Fibrosis Intimal fibrosis Thickened media Chronic bronchitis Obstructive broncholiolitis Emphysema Cor pulmonale Airway obstruction Hyperinflation Gas-exchange abnormalities Hypoxic resp. failure Right sided heart failure Cough with sputum Cigarette smoking; biomass fuel oxidants; Industrial pollution; mineral dusts and particulates Causative factors Inflammation Large airways Vessels Small airways Involvement site Alveoli Remodeling Pathology Outcome

  19. Summary

  20. Pathogenesis ASTHMA COPD Epithelium* Dendritic cells T cells Epithelium* Dendritic cells Macrophages Initiative cells Regulatory T cells TLRs Regulatory T cells? TLRs Response modifier CD8+ T cells Macrophages Neutrophils CD8+ T cells Eosinophils Neutrophils CD4+ T cells Eosinophils Mast cells Inflammatory cells Neutrophils Eosinophils Predominant mediators; Cytokines; chemokines IL8; LTB4 CXCR2;3 GRO-a IL-4; IL-5 IL-13 RANTES Eotaxin RANTES Eotaxins CXCR2 Others Oxidant Antioxidant Proteases antiproteases Lipoxin PGE2

  21. Remodeling ASTHMA COPD • Epithelial shedding • Increase in basal membran thickness • Enlargement of bronchial muscle cell • Rearrengement of matrix components • Angiogenesis; • goblet cell hypertrophy • Goblet cell metaplasia • Glandular hypertrophy • Reduced no of cilia • Smooth muscle hypertrophy • Fibrosis • Proteolysis (Loss of walls/ • Attachtments/Capillaries) Large airways (small airways in severe cases) Large airways; small airways;

  22. BHR Eosinophil dominancy Initial FEV1 Initial FEV1 Initial FEV1 Eosinophil dominancy Reversibility of airways Neutrophil dominancy Reversibility of airways Reversibility of airways Neutrophil dominancy

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