11 Inflammation

Report
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

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