PowerPoint Presentation

11TH LECTUREPhysiotherapy

INFLAMMATIONACUTE INFLAMMATION

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

Infections (bacteria, virus, parasite)Physical and chemical agents (thermal injury, irradiation, chemicals)Tissue NecrosisTraumaForeign bodies (splinters, dirt, sutures)Hypersensitivity or autoimmune reactionsTRIGGERS OF ACUTE INFLAMMATIONVascular responseIncreased vascular diameter Increased flood flowEndothelial cell activationincreased permeability that permits plasma proteins and leukocytes to leave the circulation and enter the tissue edemaincreased expression of cell adhesion molecules e.g. E-selectin, ICAM

Cellular responseMigration of leukocytes (diapedesis/extravasation), accumulation, effector functionsMAJOR COMPONENTS OF INFLAMMATION:THE CLASSIC SYMPTOMS OF INFLAMMATION

Redness (rubor) Swelling (tumor) Heat (calor) Pain (dolor)Loss of function (functio laesa)

You ought to know which classic symptom is caused by which pathophysiological process5

Resident phagocytes get activated by PRR signalization upon recognition of danger signals Production of cytokines and chemokines, Intracellular killingAntigen presentation (activation of adaptive responses)

ORDER OF INNATE CELLS APPEARANCE IN THE INFLAMED SITE

NEUTROPHIL GRANULOCYTES68% of circulating leukocytes, 99% of circulating granulocytesPhagocytic cellsNot present in healthy tissuesMigration elimination of pathogens (enzymes, reactive oxygen intermediates) Main participants in acute inflammatory processes

8LFA-1: Lymphocyte-function associated antigen-1Sialylated Lewis X Ag

NEUTROPHIL CHEMOTAXIS9acPGP: N-acetyl Proline-Glycine-Proline neutrophil chemoattractantMMP: matrix metalloproteinase

NEUTROPHIL TRANSENDOTHELIAL MIGRATION (DIAPEDESIS)PATHOGENS ACTIVATE MACROPHAGES TO RELEASE CYTOKINES AND ARE THEN PHAGOCYTIZED AND DIGESTED IN PHAGOLYSOSOMES

THE EFFECTS OF CYTOKINES ON VARIOUS TISSUESLocal effectSystemic effectTHE ARACHIDONIC ACID PATHWAY

NSAIDs and Paracetamol prevent the synthesis of prostaglandins by inhibiting COX-1 and COX-2VasodilationProstaglandins (PG), nitric oxide (NO)Increased vascular permeabilityvasoactive amines (histamine, serotonin), C3a and C5a (complement system), bradykinin, leukotrienes (LT), PAF Chemotactic leukocyte activationC3a, C5a, LTB4, chemokines (e.g. IL-8)CHEMICAL MEDIATORS AND INFLAMMATION COMPONENTS II15FeverIL-1, IL-6, TNF, PGE2PainProstaglandins, bradykininTissue damageNeutrophil and Macrophage productslysosomal enzymesReactive oxygen species (ROS)NOCHEMICAL MEDIATORS AND INFLAMMATION COMPONENTS IITREATING INFLAMMATIONGoalsPain 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 synthesis2. Inhibiting chemotaxis3. Downregulation of IL-1 expression4. Decrease free radicals and superoxidesNSAIDsAspirinDMARDsCorticosteroidsDMARDs- disease modifying antirheumatic drugs. Anti-TNF antibodies and other MABs.For further reading and table of drugs in this group: http://en.wikipedia.org/wiki/DMARD

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Flurbiprofen

Ibuprofen

Naproxen

Diclofenac

NSAIDsNON-STEROIDAL ANTI-INFLAMMATORY DRUGSGels containing an anti-inflammatory agent are commonly used in physiotherapy, both for pain relief and for minimizing the tissue damage related to chronic inflammation18

Mesalazine / Mesalamine ASASALICYLATES

CORTICOSTEROIDS

MethylprednisolonePrednisolone

betamethasone

Budesonide

Triamcinolone

LiverC-reactive proteinSerum Amyloid Protein (SAP)FibrinogenMannose binding lectin/proteinMBL/MBPIL- 6THE ACUTE PHASE RESPONSEOpsonizationComplement activationOpsonizationComplement activationOpsonization Binding of mannose/galactose (chromatin, DNA, influenza) Complement activationSP-A and SP-DOpsonization in the lungBlood clot formation Converts thrombin fibrin

Opsonization Complement activation ACUTE-PHASE RESPONSE PROTEINSSP-A/D: Surfactant Protein A and D22

RESOLUTION OF ACUTE INFLAMMATIONMonoclonal antibodies (MAb) Products of one B-lymphocyte clone Homogeneous in antigen specificity, affinity, and isotype

BIOLOGICAL THERAPY

MONOCLONAL ANTIBODIES (MAB)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 26

Anti-TNF- antibodiesInfliximab (Remicade): since 1998, chimericAdalimumab (Humira): since 2002, recombinant human

Etanercept (Enbrel) dimer fusion protein,TNF- receptor + Ig Fc-partNot a real monoclonal antibody, no Fab end, the specificity is given by TNF-receptor!Indications of anti-TNF- therapyRheumatoid arthritisSpondylitis ankylopoetica (SPA - M. Bechterew)Psoriasis vulgaris, arthritis psoriaticaCrohns disease, colitis ulcerosa(usually - still not in the first line!)

1) Anti-TNF- therapy

!!!

2) Anti tumor therapy 28

Rituximab

Transtuzumab

Bevacizumab

Cetuximab2) Anti tumor therapy Anti CD20 for non-hodgkins lymphoma

Anti EGFRAnti VEGFFor colorectal cancerAnti-ErbB2For breast cancerRituximab- anti CD20 for non-hodgkins lymphoma.Transtuzumab- anti-ErbB2 for breast cancer. Cetuximab- anti EGFR and Bevacizumab- anti VEGF for colorectal cancer.

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Basiliximab

Daclizumab3) 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 FcRIDaclizumab and Basiliximab- binds IL-2 Rs on T cells. For prevention of organ rejection.

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