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