Inflammation

and Repair - 5

Dr.CSBR.Prasad, M.D.

v3-CSBRP-May-2012

Sequence of events in Inflammation

Vascular

• Vasodilation

• Increased vascular

permeability

Cellular

• Margination

• Rolling

• Adhesion

• Diapedesis

• Chemotaxis

• Phagocytosis

• Killing & degradation

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Events are reflected clinically by

Cardinal signs of inflammation

• Rubor

• Calor

• Dolar

• Tumor

• Loss of function

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Chemical Mediators of Inflammation

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Chemical Mediators

Def: Any messenger that acts on blood

vessels, leucocytes, or other cells to

contribute to an inflammatory response

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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

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Chemical Mediators

• Fever

– IL-1, IL-6, TNF, PGE2

• Pain

– Prostaglandins, Bradykinin

• Tissue Damage

– Neutrophil and Macrophage products – Lysosomal enzymes

– Oxygen metabolites

– NO

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Chemical Mediators General properties:

• They are generated from:

Cells

Plasma proteins

• Mediators are produced in response to various stimuli

• One mediator can stimulate the release of other [Guarantees amplification and maintenance of inflammatory response]

• Mediators vary in their range of cellular targets

• Majority are short-lived [Short t ½ and are harmful]

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Cell derived mediators

Vasoactive Amines: Histamine and Serotonin

AA Metabolites: PGs, LTs, and Lipoxins

Platelet-Activating Factor (PAF)

ROS

Nitric Oxide (NO)

Cytokines and Chemokines

Tumor Necrosis Factor and Interleukin-1

Chemokines

Other Cytokines IL6, IL17

Lysosomal Constituents of Leukocytes

Neuropeptides

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Plasma derived mediators PLASMA PROTEASES

3 interrelated systems are active within this category

1.Kinin system Highly vasoactive

2.Complement system Vasoactive

Chemotactic

3.Clotting system Vasoactive

Cleaves C3

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Cell derived mediators

Vasoactive Amines: Histamine and Serotonin

AA Metabolites: PGs, LTs, and Lipoxins

Platelet-Activating Factor (PAF)

ROS

Nitric Oxide (NO)

Cytokines and Chemokines

Tumor Necrosis Factor and Interleukin-1

Chemokines

Other Cytokines IL6, IL17

Lysosomal Constituents of Leukocytes

Neuropeptides

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Cell derived mediators

Vasoactive Amines: Histamine and Serotonin

• Increase 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

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Cell derived mediators

Vasoactive Amines: Histamine and Serotonin

• 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

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ARACHIDONIC ACID

METABOLITES • Roles in many biologic and

pathologic processes – Inflammation

• 20-carbon polyunsaturated fatty acid – Derived directly from dietary

sources or by conversion of essential fatty acid linoleic acid

• Esterified in membrane phospholipids – Must first be released from

phospholipids

• Via activation of cellular phospholipases – By mechanical, chemical

and physical stimuli or by other mediators

• 2 major pathways – Cyclooxygenase pathway

– Lipoxygenase pathway.

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CYCLOOXYGENASE PATHWAY

• 2 cyclooxygenase enzymes – COX-1

– COX-2

• 3 important products – Thromboxane A2

– Aggregates platelets and causes vasoconstriction

– Prostacyclin (PGI2) – Endothelial cells inhibits platelet aggregation and causes

vasodilation

– Prostaglandins PGE2, PGF2 and PGD2 – Variety of actions on vascular tone and permeability

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LIPOXYGENASE PATHWAY

Leukotrienes - LT

• LT B4 is a potent chemotactic agent

• Leukotrienes C4, D4, E4

– Potent vasoconstrictors

– Potent mediators of increased vascular

permeability on venules only

– Up to 1000 times as potent as histamine in

producing increased vascular permeability

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NOTE:

Some anti-inflammatory drugs interfere

with arachidonic acid metabolism – Corticosteroids interfere with phospholipase

– Aspirin interferes with cyclooxygenase

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PLATELET ACTIVATING

FACTOR - PAF

• Aggregate platelets and cause release

• Bronchoconstriction and Vasoconstriction

• ↑ vascular permeability

• ↑ leukocyte adhesion

• Leukocyte chemotaxis

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CYTOKINES

• Transmitters for cell-to-cell chatting

– Modulate cell function

• Primarily from activated macrophages and

lymphocytes

• IL-1, IL-8, TNF

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IL-I and TNF

“Master Cytokines”

• Origin

– Monocytes

– Macrophages

• Similar in action

• Endothelium

• Acute phase proteins

• Fibroblasts v3-CSBRP-May-2012

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Other Cytokines

• IL-5

– Eosinophils

• IL-6

– B and T cells

• IL-8

– Neutrophils

– Lesser degree monocytes and eosinophils

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GROWTH FACTORS

• Platelet derived growth factor - PGDF

• Transforming growth factor β

– Chemokines - Leukocytes and Mesenchymal Cells

• Important in regeneration and repair

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LYSOSOMAL CONSTITUENTS

• Neutrophils, Monocyte/Macrophages

– Enzymes and proteins within granules

• Cationic proteins

– ↑ vascular permeability

– Chemotactic

• Neutral proteases

– Degrade ECM

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Plasma derived mediators PLASMA PROTEASES

3 interrelated systems are active within this category

1.Kinin system Highly vasoactive

2.Complement system Vasoactive

Chemotactic

3.Clotting system Vasoactive

Cleaves C3

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BRADYKININ

• Released by activated Hageman factor (XIIa)

• Bradykinin • Release of vasoactive nonapeptide bradykinin

• Generated from the plasma HMWK

• Potent vasodilator

• Increased vascular permeability

• Contraction of smooth muscle

• Produce pain

• Stimulates release of histamine

• Activates the arachidonic acid cascade

PAIN

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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

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Complement system

• Plasma proteins - act against microbial

agents

• Products of activated complement

– Vascular permeability

– Chemotaxis

– Opsonization

– Lysis

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E N D

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