chemical mediators of inflammation تحت اشراف أ.د/ كوكب طالب/ محمد محمود...
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CHEMICAL MEDIATORS OF INFLAMMATION
/ . كوكب د أ اشراف تحتمشالى/ محمد محمود محمد طالب
الحميد عبد07274رقم/
Cairo University Faculty of Veterinary MedicineDepartment of Pathology
Introduction: Inflammation
• provoked response to tissue injury• chemical agents• cold, heat• trauma • invasion of microbes
• serves to destroy, dilute or wall off the injurious agent
• induces repair
• protective response
• can be potentially harmful
CARDINAL SIGNS OF ACUTE INFLAMMATION
Heat Redness Swelling Pain Loss of functionHeat Redness Swelling Pain Loss of function
Inflammation - Mechanism
1. Vaso dilatation
2. Exudation - Edema
3. Emigration of cells
4. Chemotaxis
5. Phagocytosis
CHEMICAL MEDIATORS OF INFLAMMATION
Definition: Any messenger that acts on blood vessels, inflammatory cells, or other cells to contribute to an inflammatory response. (Pretty much anything...)
• Exogenous– Endotoxins
• Endogenous–Plasma –Leukocytes–Endothelial cells–Fibroblasts
Chemical Mediators of Inflammation:
• Locally produced• Histamine• Seratonin/5HT• Interleukins. • Prostaglandins• Leukotrienes
• Plasma derived• Kinins• Complements• Coagulation system• Plasminolysis system• Others: H2O2, NO
CHEMICAL MEDIATORS OF INFLAMMATION
Facts• Mechanism of action
– Receptor-ligand interactions (1o)– Direct enzymatic activity– Mediate oxidative damage
• Extensive network of interacting chemicals
• High degree of redundancy
• Guarantees amplification and maintenance of inflammatory response
• Short t ½ and are harmful
CHEMICAL MEDIATORS • Vasodilation
– Prostaglandins, Nitric Oxide
• Increased Vascular Permeability– Vasoactive amines (histamine, serotonin), C3a
and C5a, Bradykinin, Leukotrienes, PAF,
• Chemotaxic Leukocyte Activation– C5a, LTB4, Chemokines
CHEMICAL MEDIATORS OF INFLAMMATION
• Fever– IL-1, IL-6, TNF, Prostaglandins
• Pain– Prostaglandins, Bradykinin
• Tissue Damage– Neutrophil and Macrophage products
–Lysosomal enzymes–Oxygen metabolites–NO
Bradykinin
VASOACTIVE AMINES • Increase Vascular Permeability and Vascular
Permeability
• Histamine and Serotonin– Mediators in the immediate active phase of
increased permeability–Promotes contraction of smooth muscle–Stimulates to cells to produce eotaxins
– Serotonin found in rodent mast cells
Vasoactive AminesContinued
• Releasing Stimulators – Direct physical or chemical
injury– Binding of IgE- Ag-
complexes – Fragments of C3a and
C5a– Histamine releasing
factors (pmn’s and θ)– Cytokines (IL-1, IL-8)– Neuropeptides
PLASMA PROTEASES
1. Kinin system– Highly vasoactive
2. Complement system• Vasoactive • Chemotactic
3.Clotting system • Vasoactive• Cleaves C3
3 interrelated systems are active within this category
Interaction of Kinin-, Coagulation- and Complement system during acute inflammation
Kallikrein
HMWK
Plasminogen
Prekallikrein
Factor XII (Hageman)
XIIa
Collagen, basement membrane, platelets and microbial surfaces
Kinin cascade Clotting cascade
Fibrinolysis
Plasmin
Complement
Bradykinin
Acute Inflammation
Fibrin Fibrinogen
C3 C3a
Prothrombin ThrombinPAR*
Intrinsic
pathway
* Protease activated receptors
COMPLEMENT SYSTEM• Plasma proteins - act against microbial agents• Products of activated complement
– Vascular permeability– Chemotaxis– Opsonization– Lysis
COMPLEMENT SYSTEMFew reminders
• Classical pathway• Alternate pathway• Common pathway• Important inflammatory mediators
– C3a and C5a (anaphylatoxins)–Cause release of histamine from mast cells
–Lysosomal enzyme release in inflammatory cells
– C5a–Activates lipoxygenase pathway
–Chemotactic many inflammatory cells
–Increases adhesion of leukocytes
COMPLEMENT SYSTEMAnd Inflammation
• C5b-9 membrane attack complex– Lyses cells– Stimulates arachidonic acid
metabolism– Produces reactive oxygen
metabolites
Complement Cascade
KININ SYSTEMBRADYKININ
• Activated by Hageman factor (XIIa) • Bradykinin
– Release of vasoactive nonapeptide bradykinin– Generated from the plasma
• Potent vasodilator • Increased vascular permeability• Contraction of smooth muscle• Produce pain• Stimulates release of histamine• Activates the arachidonic acid cascade
COAGULATION SYSTEMClotting system
• Plasma proteins – Can be activated by Hageman factor
• Thrombin converts fibrinogen to fibrin – Fibrinopeptides are formed
–↑vascular permeability
–Chemotactic for leucocytes
• Plasmin is important in lysing fibrin clots,– Activates Hageman factor (XII) bradykinin⇨– Cleaves C3 C3a ⇨– "fibrin-split products" formed from fibrin breakdown
–↑ vascular permeability
COAGULATION CASCADE
TF: tissue factor; HK: high-molecular-weightkininogen; PK: prekallikrein; PL: phospholipid; PT: prothrombin; TH: thrombin.
Clotting System
HAGEMAN FACTOR Dependent Factors
• Factor XII of intrinsic coagulation cascade• Activated by
– Negatively charged surfaces– Platelets– Proteases from inflammatory cells
• Causes– Coagulation– Activation of fibrinolytic system– Produces bradykinin– Activates complement– Provides an amplification system
IMPORTANT NOTE
• Activated Hageman factor (factor XIIA) initiates the clotting, fibrinolytic and kinin systems. The products of this initiation (kallikrein, factor XIIA, and plasmin, but particularly, kallikrein) can, by feedback, activate Hageman factor, resulting in significant amplification of the effects of the initial stimulus.
CYTOKINES
• Transmitters for cell-to-cell chatting– Modulate cell function
• Primarily from activated macrophages and lymphocytes
• IL-1, IL-8, TNF
IL-I and TNF“Master Cytokines”
• Origin– Monocytes– Macrophages
• Similar in action• Endothelium• Acute phase proteins• Fibroblasts
Other CytokinesChemokines???
• IL-5– Eosinophils
• IL-6– B and T cells
• IL-8 – Neutrophils – Lesser degree monocytes and eosinophils
GROWTH FACTORS
• Platelet derived growth factor
• Transforming growth factor β– Chemokines
- Leukocytes and Mesenchymal Cells
• Important in regeneration and repair
NITRIC OXIDE (NO) Just say NO!
• Nitric oxide is synthesized from L-arginine• 2 enzymes and many factors produce NO• 3 effects
– ♥♥ physical mediator of vascular tone– Host defense (forms perroxynitrite)– Signaling molecule – especially brain– Reduces platelet aggregation and adhesion– Inhibits several features of mast cell induced inflammation
• Uncontrolled NO production– Can lead to massive peripheral
-Vasodilation
-Shock
LYSOSOMAL CONSTITUENTS
• Neutrophils, Monocyte/Macrophages– Enzymes and proteins within granules
• Cationic proteins – ↑ vascular permeability– Chemotactic
• Neutral proteases – Degrade ECM
OXYGEN-DERIVED FREE RADICALS
• Cause endothelial damage
• Protein destruction by inhibiting antiproteases
• Injury to variety of cells
• Don’t forget the antioxidants– Ceruloplasmin– Transferrin– Superoxide dismutase– Catalase– Glutathione peroxidase