1. 11 TH LECTURE PhysiotherapyINFLAMMATION

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

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

4. 1.Vascular response  Increased vascular diameter  Increased flood flow  Endothelial cell activation  increased permeability that permits plasma proteins and leukocytes to leave the circulation and enter the tissue  edema  increased expression of cell adhesion molecules e.g. E- selectin, ICAM 2.Cellular response  Migration of leukocytes (diapedesis/extravasation), accumulation, effector functions MAJOR COMPONENTS OF INFLAMMATION:

5. THE CLASSIC SYMPTOMS OF INFLAMMATION Redness (rubor) Swelling (tumor) Heat (calor) Pain (dolor) Loss of 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 circulating leukocytes, 99% of circulating granulocytes Phagocytic cells Not present in healthy tissues Migration  elimination of pathogens (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

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

14. THE ARACHIDONIC ACID PATHWAY NSAIDs and Paracetamol prevent the synthesis of prostaglandins by inhibiting COX-1 and COX-2

15.  Vasodilation –Prostaglandins (PG), nitric oxide (NO)  Increased vascular permeability –vasoactive amines (histamine, serotonin), C3a and C5a (complement system), bradykinin, leukotrienes (LT), PAF  Chemotactic leukocyte activation –C3a, C5a, LTB 4, chemokines (e.g. IL-8) CHEMICAL MEDIATORS AND INFLAMMATION COMPONENTS II

16.  Fever IL-1, IL-6, TNFα, PGE2  Pain Prostaglandins, bradykinin  Tissue damage Neutrophil and Macrophage products –lysosomal enzymes –Reactive oxygen species (ROS) –NO CHEMICAL MEDIATORS AND INFLAMMATION COMPONENTS II

17. TREATING INFLAMMATION Goals 1)Pain relief 2)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 NSAIDs Aspirin DMARDs Corticosteroids

18. Flurbiprofen Ibuprofen Naproxen Diclofenac NSAIDs NON-STEROIDAL ANTI-INFLAMMATORY DRUGS 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

19. Mesalazine / Mesalamine ASA SALICYLATES

20. CORTICOSTEROIDS Methylprednisolone Prednisolone betamethasone Budesonide Triamcinolone

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

22. Opsonization Complement activation ACUTE-PHASE RESPONSE PROTEINS

23. RESOLUTION OF ACUTE INFLAMMATION

24. Monoclonal antibodies (MAb)  Products of one B-lymphocyte clone  Homogeneous in antigen specificity, affinity, and isotype

25. BIOLOGICAL THERAPY MONOCLONAL ANTIBODIES (MAB)

26. 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. THERAPEUTIC USE OF MAB

27. 1.Anti-TNF-α antibodies Infliximab (Remicade): since 1998, chimeric Adalimumab (Humira): since 2002, recombinant human 2.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-α therapy Rheumatoid arthritis Spondylitis ankylopoetica (SPA - M. Bechterew) Psoriasis vulgaris, arthritis psoriatica Crohns’ disease, colitis ulcerosa (usually - still – not in the first line!) 1) Anti-TNF-α therapy !!!

28. 2) Anti tumor therapy

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

30. Basiliximab Daclizumab 3) Immunosuppression 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 Fc εRI