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11 TH LECTURE Physiotherapy INFLAMMATION

11 TH LECTURE Physiotherapy INFLAMMATION. ACUTE INFLAMMATION A rapid response to an injurious agent that serves to deliver l eukocytes and plasma proteins to the site of injury. TRIGGERS OF ACUTE INFLAMMATION. Infections (bacteria, virus, parasite)

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11 TH LECTURE Physiotherapy INFLAMMATION

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  1. 11TH LECTURE Physiotherapy INFLAMMATION

  2. ACUTE INFLAMMATION A rapid response to an injurious agent that servesto deliver leukocytes and plasma proteinsto the site of injury

  3. TRIGGERS OF ACUTE INFLAMMATION • Infections (bacteria, virus, parasite) • Physical and chemical agents (thermal injury, irradiation, chemicals) • Tissue Necrosis • Trauma • Foreign bodies (splinters, dirt, sutures) • Hypersensitivity or autoimmune reactions

  4. MAJOR COMPONENTS OF INFLAMMATION: • Vascular response • Increased vascular diameter  Increased flood flow • Endothelialcellactivation • increased permeability that permits plasmaproteins and leukocytes to leave the circulation and enter the tissue edema • increasedexpression of celladhesionmoleculese.g. E-selectin, ICAM • Cellular response • Migration of leukocytes (diapedesis/extravasation), accumulation, effectorfunctions

  5. THE CLASSIC SYMPTOMS OF INFLAMMATION • Redness(rubor) • Swelling(tumor) • Heat(calor) • Pain(dolor) • Lossof function (functio laesa)

  6. Resident phagocytes get activated by PRR signalization upon recognition of danger signals  • Production of cytokines and chemokines, • Intracellular killing • Antigen presentation (activation of adaptive responses)

  7. ORDER OF INNATE CELLS APPEARANCE IN THE INFLAMED SITE

  8. NEUTROPHIL GRANULOCYTES • 68% of circulatingleukocytes, 99% ofcirculating granulocytes • Phagocyticcells • Notpresent in healthy tissues • Migrationelimination ofpathogens (enzymes, reactive oxygen intermediates) • Main participants in acute inflammatory processes

  9. NEUTROPHIL CHEMOTAXIS

  10. NEUTROPHIL TRANSENDOTHELIAL MIGRATION (DIAPEDESIS)

  11. PATHOGENS ACTIVATE MACROPHAGES TO RELEASE CYTOKINES AND ARE THEN PHAGOCYTIZED AND DIGESTED IN PHAGOLYSOSOMES

  12. THE EFFECTS OF CYTOKINES ON VARIOUS TISSUES Local effect Systemic effect

  13. THE ARACHIDONIC ACID PATHWAY NSAIDs and Paracetamolprevent the synthesis of prostaglandins by inhibiting COX-1 and COX-2

  14. CHEMICAL MEDIATORS AND INFLAMMATION COMPONENTS II • Vasodilation • Prostaglandins (PG), nitricoxide (NO) • Increased vascularpermeability • vasoactive amines (histamine, serotonin), C3a and C5a (complementsystem), bradykinin, leukotrienes (LT), PAF • Chemotacticleukocyteactivation • C3a, C5a, LTB4, chemokines (e.g. IL-8)

  15. CHEMICAL MEDIATORS AND INFLAMMATION COMPONENTS II • Fever • IL-1, IL-6, TNFα, PGE2 • Pain • Prostaglandins, bradykinin • Tissue damage • Neutrophil and Macrophage products • lysosomal enzymes • Reactiveoxygen species (ROS) • NO

  16. TREATING INFLAMMATION NSAIDs Aspirin DMARDs Corticosteroids Goals • Pain relief • Slow or arrest tissue-damaging processes NSAIDs have analgesic and antipyretic effects, but its their anti-inflammatory action that makes them useful in management of disorders where pain is related to the intensity of an inflammatory process (rheumatic diseases for ex.) NSAIDs mechanism of action: 1. Inhibiting prostaglandin synthesis 2. Inhibiting chemotaxis 3. Downregulation of IL-1 expression 4. Decrease free radicals and superoxides

  17. NSAIDs NON-STEROIDAL ANTI-INFLAMMATORY DRUGS Flurbiprofen Ibuprofen Gels containing an anti-inflammatory agent are commonly used in physiotherapy, both for pain relief and for minimizing the tissue damage related to chronic inflammation Naproxen Diclofenac

  18. SALICYLATES ASA Mesalazine / Mesalamine

  19. CORTICOSTEROIDS Prednisolone Methylprednisolone Budesonide Triamcinolone betamethasone

  20. THE ACUTE PHASE RESPONSE IL- 6 Mannose binding lectin/protein MBL/MBP C-reactive protein Fibrinogen Serum Amyloid Protein (SAP) Opsonization Complement activation Opsonization Complement activation Liver SP-A and SP-D Opsonization in the lung Blood clot formation Converts thrombin  fibrin Opsonization Binding of mannose/galactose (chromatin, DNA, influenza) Complement activation

  21. ACUTE-PHASE RESPONSE PROTEINS Opsonization Complement activation

  22. RESOLUTION OF ACUTE INFLAMMATION

  23. Monoclonal antibodies (MAb) • Products of one B-lymphocyte clone • Homogeneous in antigenspecificity, affinity, and isotype

  24. BIOLOGICAL THERAPY MONOCLONAL ANTIBODIES (MAB)

  25. THERAPEUTIC USE OF MAB • 1) Anti-TNF-α therapy in rheumatology • 2) Anti tumor therapy / Targeted chemotherapy. • CD20+ anti-B-cell monoclonals in non-Hodgkin lymphoma. • Monoclonal antibodies are cell-type specific, but not specific to malignant cells! • 3) Immunsuppression. cell-type specific. • Prevention of organ rejection after transplantation.

  26. !!! 1) Anti-TNF-α therapy • Anti-TNF-α antibodies Infliximab (Remicade): since 1998, chimeric Adalimumab (Humira): since 2002, recombinant human • Etanercept (Enbrel) – dimer fusion protein,TNF-α receptor + Ig Fc-part Not a real monoclonal antibody, no Fab end,the specificity is given by TNF-receptor! • Indications of anti-TNF-αtherapy • Rheumatoid arthritis • Spondylitis ankylopoetica (SPA - M. Bechterew) • Psoriasis vulgaris, arthritis psoriatica • Crohns’ disease, colitis ulcerosa • (usually - still – not in the first line!)

  27. 2) Anti tumor therapy

  28. 2) Anti tumor therapy Transtuzumab Rituximab Anti-ErbB2 For breast cancer Anti CD20 for non-hodgkin’s lymphoma Bevacizumab Cetuximab Anti EGFR Anti VEGF For colorectal cancer

  29. 3) Immunosuppression Basiliximab Daclizumab Immunosuppresion by targeting IL-2Rs on T cells prevention of transplantation rejection Others: Omalizumab Anti-IgE for moderate to severe allergic asthma (binds mIgE-expressing B cells, not those already bound to the high affinity FcεRI

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