11 Inflammation

11TH LECTURE Physiotherapy

INFLAMMATION

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

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

MAJOR COMPONENTS OF INFLAMMATION: 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. Eselectin, ICAM 2. Cellular response  Migration of leukocytes (diapedesis/extravasation), accumulation, effector functions

THE CLASSIC SYMPTOMS OF INFLAMMATION

• • • • •

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

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)

ORDER OF INNATE CELLS APPEARANCE IN THE INFLAMED SITE

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

NEUTROPHIL CHEMOTAXIS

NEUTROPHIL TRANSENDOTHELIAL MIGRATION (DIAPEDESIS)

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

THE EFFECTS OF CYTOKINES ON VARIOUS TISSUES Local effect

Systemic effect

THE ARACHIDONIC ACID PATHWAY

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

CHEMICAL MEDIATORS AND INFLAMMATION COMPONENTS II

 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, LTB4, chemokines (e.g. IL-8)

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

TREATING INFLAMMATION Goals 1) Pain relief 2) Slow or arrest tissue-damaging processes

NSAIDs Aspirin DMARDs Corticosteroids

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 NON-STEROIDAL ANTI-INFLAMMATORY DRUGS

Flurbiprofen

Naproxen

Ibuprofen

Diclofenac

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

SALICYLATES

ASA Mesalazine / Mesalamine

CORTICOSTEROIDS

Prednisolone Methylprednisolone

Triamcinolone betamethasone

Budesonide

THE ACUTE PHASE RESPONSE IL- 6 C-reactive protein

Mannose binding lectin/protein

Opsonization Complement activation

MBL/MBP Opsonization Complement activation

Liver

SP-A and SP-D Opsonization in the lung

Serum Amyloid Protein (SAP) Opsonization Binding of mannose/galactose (chromatin, DNA, influenza) Complement activation

Fibrinogen Blood clot formation Converts thrombin  fibrin

ACUTE-PHASE RESPONSE PROTEINS

Opsonization Complement activation

RESOLUTION OF ACUTE INFLAMMATION

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

BIOLOGICAL THERAPY

MONOCLONAL ANTIBODIES (MAB)

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.

!!!

1) Anti-TNF-α therapy 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!)

2) Anti tumor therapy

2) Anti tumor therapy

Transtuzumab

Rituximab

Anti-ErbB2 For breast cancer

Anti CD20 for non-hodgkin’s lymphoma

Cetuximab Anti EGFR

Bevacizumab Anti VEGF

For colorectal cancer

3) Immunosuppression

Daclizumab

Basiliximab

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