11 TH LECTURE PhysiotherapyINFLAMMATION. ACUTE INFLAMMATION A rapid response to an injurious agent...
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- 11 TH LECTURE PhysiotherapyINFLAMMATION
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- ACUTE INFLAMMATION A rapid response to an injurious agent that
serves to deliver leukocytes and plasma proteins to the site of
injury
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- 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
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- 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:
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- THE CLASSIC SYMPTOMS OF INFLAMMATION Redness (rubor) Swelling
(tumor) Heat (calor) Pain (dolor) Loss of function (functio
laesa)
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- 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)
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- ORDER OF INNATE CELLS APPEARANCE IN THE INFLAMED SITE
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- 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
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- NEUTROPHIL CHEMOTAXIS
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- NEUTROPHIL TRANSENDOTHELIAL MIGRATION (DIAPEDESIS)
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- PATHOGENS ACTIVATE MACROPHAGES TO RELEASE CYTOKINES AND ARE
THEN PHAGOCYTIZED AND DIGESTED IN PHAGOLYSOSOMES
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- THE EFFECTS OF CYTOKINES ON VARIOUS TISSUES Local effect
Systemic effect
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- THE ARACHIDONIC ACID PATHWAY NSAIDs and Paracetamol prevent the
synthesis of prostaglandins by inhibiting COX-1 and COX-2
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- 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
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- Fever IL-1, IL-6, TNF, PGE2 Pain Prostaglandins, bradykinin
Tissue damage Neutrophil and Macrophage products lysosomal enzymes
Reactive oxygen species (ROS) NO CHEMICAL MEDIATORS AND
INFLAMMATION COMPONENTS II
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- 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
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- 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
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- Mesalazine / Mesalamine ASA SALICYLATES
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- CORTICOSTEROIDS Methylprednisolone Prednisolone betamethasone
Budesonide Triamcinolone
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- 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
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- Opsonization Complement activation ACUTE-PHASE RESPONSE
PROTEINS
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- RESOLUTION OF ACUTE INFLAMMATION
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- Monoclonal antibodies (MAb) Products of one B-lymphocyte clone
Homogeneous in antigen specificity, affinity, and isotype
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- BIOLOGICAL THERAPY MONOCLONAL ANTIBODIES (MAB)
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- 1) Anti-TNF- 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
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- 1.Anti-TNF- antibodies Infliximab (Remicade): since 1998,
chimeric Adalimumab (Humira): since 2002, recombinant human
2.Etanercept (Enbrel) dimer fusion protein, TNF- receptor + Ig
Fc-part Not a real monoclonal antibody, no Fab end, the specificity
is given by TNF-receptor! Indications of anti-TNF- 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-
therapy !!!
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- 2) Anti tumor therapy
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- Rituximab Transtuzumab Bevacizumab Cetuximab 2) Anti tumor
therapy Anti CD20 for non-hodgkins lymphoma Anti EGFRAnti VEGF For
colorectal cancer Anti-ErbB2 For breast cancer
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- 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 RI