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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

11TH LECTURE

Physiotherapy

INFLAMMATION


11 th lecture physiotherapy inflammation

ACUTE INFLAMMATION

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


Triggers of acute inflammation
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


11 th lecture physiotherapy inflammation

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


11 th lecture physiotherapy inflammation

  • THE CLASSIC SYMPTOMS OF INFLAMMATION

  • Redness(rubor)

  • Swelling(tumor)

  • Heat(calor)

  • Pain(dolor)

  • Lossof function (functio laesa)


11 th lecture physiotherapy inflammation

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)



11 th lecture physiotherapy inflammation

NEUTROPHIL GRANULOCYTES recognition of danger signals

  • 68% of circulatingleukocytes, 99% ofcirculating granulocytes

  • Phagocyticcells

  • Notpresent in healthy tissues

  • Migrationelimination ofpathogens (enzymes, reactive oxygen intermediates)

  • Main participants in acute inflammatory processes


Neutrophil chemotaxis
NEUTROPHIL CHEMOTAXIS recognition of danger signals



11 th lecture physiotherapy inflammation

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


11 th lecture physiotherapy inflammation

THE EFFECTS OF CYTOKINES ON VARIOUS TISSUES THEN PHAGOCYTIZED AND DIGESTED IN PHAGOLYSOSOMES

Local effect

Systemic effect


11 th lecture physiotherapy inflammation

THE ARACHIDONIC ACID PATHWAY THEN PHAGOCYTIZED AND DIGESTED IN PHAGOLYSOSOMES

NSAIDs and Paracetamolprevent the synthesis of prostaglandins by inhibiting COX-1 and COX-2


11 th lecture physiotherapy inflammation

CHEMICAL MEDIATORS AND INFLAMMATION COMPONENTS II THEN PHAGOCYTIZED AND DIGESTED IN PHAGOLYSOSOMES

  • 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)


  • 11 th lecture physiotherapy inflammation

    CHEMICAL MEDIATORS AND INFLAMMATION COMPONENTS II THEN PHAGOCYTIZED AND DIGESTED IN PHAGOLYSOSOMES

    • Fever

      • IL-1, IL-6, TNFα, PGE2

  • Pain

    • Prostaglandins, bradykinin

  • Tissue damage

    • Neutrophil and Macrophage products

      • lysosomal enzymes

      • Reactiveoxygen species (ROS)

      • NO


  • Treating inflammation
    TREATING INFLAMMATION THEN PHAGOCYTIZED AND DIGESTED IN PHAGOLYSOSOMES

    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


    11 th lecture physiotherapy inflammation

    NSAIDs THEN PHAGOCYTIZED AND DIGESTED IN PHAGOLYSOSOMES

    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


    11 th lecture physiotherapy inflammation

    SALICYLATES THEN PHAGOCYTIZED AND DIGESTED IN PHAGOLYSOSOMES

    ASA

    Mesalazine / Mesalamine


    Corticosteroids

    CORTICOSTEROIDS THEN PHAGOCYTIZED AND DIGESTED IN PHAGOLYSOSOMES

    Prednisolone

    Methylprednisolone

    Budesonide

    Triamcinolone

    betamethasone


    11 th lecture physiotherapy inflammation

    THE ACUTE PHASE RESPONSE THEN PHAGOCYTIZED AND DIGESTED IN PHAGOLYSOSOMES

    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


    Acute phase response proteins
    ACUTE-PHASE RESPONSE PROTEINS THEN PHAGOCYTIZED AND DIGESTED IN PHAGOLYSOSOMES

    Opsonization

    Complement activation


    11 th lecture physiotherapy inflammation

    RESOLUTION OF ACUTE INFLAMMATION THEN PHAGOCYTIZED AND DIGESTED IN PHAGOLYSOSOMES


    11 th lecture physiotherapy inflammation

    Monoclonal antibodies THEN PHAGOCYTIZED AND DIGESTED IN PHAGOLYSOSOMES (MAb)

    • Products of one B-lymphocyte clone

    • Homogeneous in antigenspecificity, affinity, and isotype


    11 th lecture physiotherapy inflammation

    BIOLOGICAL THERAPY THEN PHAGOCYTIZED AND DIGESTED IN PHAGOLYSOSOMES

    MONOCLONAL ANTIBODIES (MAB)


    11 th lecture physiotherapy inflammation

    THERAPEUTIC USE OF MAB THEN PHAGOCYTIZED AND DIGESTED IN PHAGOLYSOSOMES

    • 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.


    11 th lecture physiotherapy inflammation

    !!! THEN PHAGOCYTIZED AND DIGESTED IN PHAGOLYSOSOMES

    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!)


    11 th lecture physiotherapy inflammation

    2) Anti tumor therapy THEN PHAGOCYTIZED AND DIGESTED IN PHAGOLYSOSOMES


    11 th lecture physiotherapy inflammation

    2) Anti tumor therapy THEN PHAGOCYTIZED AND DIGESTED IN PHAGOLYSOSOMES

    Transtuzumab

    Rituximab

    Anti-ErbB2

    For breast cancer

    Anti CD20

    for non-hodgkin’s lymphoma

    Bevacizumab

    Cetuximab

    Anti EGFR

    Anti VEGF

    For colorectal cancer


    11 th lecture physiotherapy inflammation

    3) Immunosuppression THEN PHAGOCYTIZED AND DIGESTED IN PHAGOLYSOSOMES

    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