Session 9: Chemical mediators of Inflammation

Session 9: Chemical mediators of Inflammation

• Felician Sikujua (MD)

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Learning tasks

Learning tasks

At the end of this session, students are expected to be able to:

Define chemical mediators of inflammation.

Identify general properties of chemical mediators of inflammation.

Identify different types of chemical mediators of inflammation.

Explain mechanisms of action of different types of chemical mediators of inflammation.

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Definition

Definition

Chemical mediators of inflammation can be defined as any soluble substance that act on the blood vessel, inflammatory cells or any other cell to contribute to an inflammatory response.

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Different chemical mediators

Different chemical mediators

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General properties of chemical mediators of Inflammation

General properties of chemical mediators of Inflammation

Mediators may be produced locally by cells at the site of inflammation, or may be derived from circulating inactive precursors (typically synthesized by the liver).

Most mediators act by binding to specific receptors on different target cells.

The actions of most mediators are tightly regulated and short lived.

Mediators may stimulate target cells to release secondary effector molecules.

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Types of chemical mediators of Inflammation

Types of chemical mediators of Inflammation

According to their source

Cellular derived

Plasma derived

OR can be derived

Exogenous

Endotoxins

Endogenous

Plasma

Leukocytes

Endothelial cells

Fibroblasts

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Cellular derived chemical mediators of inflammation

Cellular derived chemical mediators of inflammation

Cells which produce chemical mediators of inflammation are

Tissue macrophages, mast cells and endothelial cells at the site of inflammation.

Leukocytes that are recruited to the site from the blood.

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Cellular derived chemical mediators of inflammation cont…

Cellular derived chemical mediators of inflammation cont…

• Vasoactive amines:

Histamine.

Serotonin.

• Arachidonic acid metabolites:

Prostaglandins.

Thromboxanes.

Leukotrienes.

Lipoxins.

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Cellular derived chemical mediators of inflammation cont…

Cellular derived chemical mediators of inflammation cont…

• Platelet Activating Factor (PAF).
• Cytokines:

Tumor Necrosis Factor (TNF).

Interleukin 1 (IL-1).

Interleukin 6 (1L-6).

Chemokines.

• Reactive oxygen species (ROS).

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Cellular derived chemical mediators of inflammation cont…

Cellular derived chemical mediators of inflammation cont…

• Nitric oxide (NO).
• Lysosomal enzymes:

Neutral proteases.

• Neuropeptides:

Substance P.

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Vasoactive Amines

Vasoactive Amines

The two vasoactive amines are

Histamine.

Serotonin.

These are stored as preformed molecules in mast cells and other cells (like lysosomal enzymes are also preformed mediators).

These are among the first mediators to be released in acute inflammatory reactions.

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Histamine

Histamine

Histamine is produced by many cell types: mast cells adjacent to vessels, circulating basophils and platelets.

Histamine causes

Arteriolar dilation.

Increases vascular permeability.

Endothelial activation.

Soon after its release, histamine is inactivated by histaminase.

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Histamine cont…

Histamine cont…

Preformed histamine is released from mast cell granules in response to a variety of stimuli:

Physical injury such as trauma or heat.

Immune reactions involving binding of IgE antibodies to Fc receptors on mast cells.

C3a and C5a fragments of complement, the so-called anaphylatoxins.

Leukocyte-derived histamine-releasing proteins.

Neuropeptides (e.g., substance P).

Certain cytokines (e.g., Interleukins 1 and 8).

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Serotonin

Serotonin

Serotonin (5-hydroxytryptamine) is a preformed vasoactive mediator found within platelet granules that is released during platelet aggregation.

It induces vasoconstriction during clotting.

It is produced mainly in some neurons and enterochromaffin cells.

It is a neurotransmitter and regulates intestinal motility.

Causes vasodilation and increase vascular permeability.

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Arachidonic Acid (AA) Metabolites

Arachidonic Acid (AA) Metabolites

Prostaglandins.

Thromboxanes.

Leukotrienes.

Lipoxins.

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Arachidonic Acid (AA) Metabolites cont…

Arachidonic Acid (AA) Metabolites cont…

Sources of AA metabolites in inflammation are

Leukocytes.

Mast cells.

Endothelial cells.

Platelets.

These AA-derived mediators act locally at the site of generation and then decay spontaneously or are enzymatically destroyed.

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Prostaglandins and thromboxanes

Prostaglandins and thromboxanes

Prostaglandin E2 (PGE2).

PGD2.

PGF2α.

PGI2 (Prostacyclin).

TXA2 (Thromboxane A2).

Each derived by the action of a specific enzyme on an intermediate.

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Prostaglandins and thromboxanes cont…

Prostaglandins and thromboxanes cont…

PGD2 along with PGE2 and PGF2α causes vasodilation and potentiates edema formation by increase vascular permeability.

PGE2 also contribute to the pain and fever that accompany inflammation.

PGI2 (Prostacyclin), a vasodilator and a potent inhibitor of platelet aggregation.

TXA2 (Thromboxanes) is a potent platelet-aggregating agent and vasoconstrictor.

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Leukotrienes

Leukotrienes

LTB4

It is produced by neutrophils and some macrophages.

It is a potent chemotactic agent for neutrophils.

Cause leukocyte activation and adhesion.

LTC4, LTD4 and LTE4

Are produced mainly in mast cells.

They cause

Bronchoconstriction.

Increased vascular permeability.

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Lipoxins

Lipoxins

Platelets that are activated and adherent to leukocytes also are important sources of lipoxins.

Lipoxins inhibit neutrophil chemotaxis and adhesion to endothelium.

Antagonists of leukotrienes B4 (LTB4).

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Platelet-activating factor

Platelet-activating factor

Produced from leukocytes, mast cells.

Causes

Vasodilation.

Increased vascular permeability.

Leukocyte adhesion.

Chemotaxis.

Degranulation.

Oxidative burst.

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Cytokines

Cytokines

Cytokines are polypeptide products of many cell types that function as mediators of inflammation and immune responses.

The major cytokines in acute inflammation are

Tumor Necrosis Factor (TNF).

Interleukin-1 (IL-1).

Interleukin-6 (1L-6).

Chemokines (a group of chemoattractant cytokines).

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Cytokines cont…

Cytokines cont…

Other cytokines that are more important in chronic inflammation include

Interferon-γ (IFN-γ)

Interleukin-12 (IL-12).

A cytokine called Interleukin-17 (IL-17), produced by T lymphocytes and other cells, plays an important role in recruiting neutrophils

It is involved in host defense against infections and in inflammatory diseases.

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Tumor Necrosis Factor and Interleukin-1

Tumor Necrosis Factor and Interleukin-1

Tumor Necrotic Factor (TNF) and Interleukin 1 (IL-1) are produced by activated macrophages, as well as mast cells, endothelial cells.

Their secretion is stimulated by: microbial products and products of T lymphocytes

The principal role of these cytokines in inflammation is endothelial activation.

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Tumor Necrosis Factor and Interleukin-1 cont…

Tumor Necrosis Factor and Interleukin-1 cont…

Stimulate the expression of adhesion molecules on endothelial cells.

TNF also increases the thrombogenicity of endothelium.

IL-1 activates tissue fibroblasts, resulting in increased proliferation and production of Extracellular Matrix (ECM).

They can also induce the systemic acute-phase reaction like fever, lethargy.

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Chemokines

Chemokines

The chemokines are structurally related proteins that act primarily as chemoattractants for different subsets of leukocytes.

Their main functions of chemokines is recruit leukocytes to the site of inflammation.

They also activate leukocytes.

Two major groups are present

CXC chemokines.

CC chemokines.

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Chemokines cont…

Chemokines cont…

CXC chemokines

Interleukin-8 (IL- 8) is produced by activated macrophages, endothelial cells, mast cells, and fibroblasts.

Causes

Chemotaxis.

Phagocytosis.

CC chemokines.

Eotaxin (chemotactic for eosinophils).

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Nitric oxide (NO)

Nitric oxide (NO)

An important function is a microbicidal (cytotoxic) agent in activated macrophages.

Other roles in inflammation, including

Vasodilation

Antagonism of all stages of platelet activation (adhesion, aggregation, and degranulation).

Reduction of leukocyte recruitment at inflammatory sites.

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Lysosomal enzymes of leukocytes

Lysosomal enzymes of leukocytes

The lysosomal granules of neutrophils and monocytes contain many enzymes that destroy phagocytosed substances and are capable of causing tissue damage.

Acid proteases generally are active only in the low-pH environment of phagolysosomes.

Neutral proteases, including elastase, collagenase, and cathepsin

Degrade extracellular matrix components.

Cleave the complement proteins.

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Neuropeptides

Neuropeptides

These are small proteins, such as substance P, that transmit pain signals, regulate vessel tone, and modulate vascular permeability.

Nerve fibers that secrete neuropeptides are especially prominent in the lung and gastrointestinal tract.

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Plasma protein–derived mediators

Plasma protein–derived mediators

Circulating proteins of three interrelated systems.

Complement

Kinin

Coagulation proteins

They are all produced primarily in the liver.

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Complement Plasma

Complement Plasma

They causes

Leukocyte chemotaxis and activation.

Direct target killing.

Vasodilation (mast cell stimulation).

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Kinins Plasma

Kinins Plasma

Bradykinin is one of the example.

They causes

Increased vascular permeability.

Smooth muscle contraction (bronchial).

Vasodilation.

Pain.

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Coagulation proteins

Coagulation proteins

They causes

Endothelial activation.

Leukocyte recruitment.

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Key points

Key points

Chemical mediators of inflammation can be derived from cells or plasma.

Prostaglandins and bradykinins induce pain.

Fever is induced by TNF, IL-1, IL-6 and PGDE2.

Prostaglandins potentiate other chemical mediators (like Histamine) to cause vascular leakage.

Most mediators have the potential to cause harmful effects if are unchecked.

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Review questions

Review questions

Mention three (3) general properties of chemical mediators of inflammation.

List five (5) chemical mediators which cause vascular leakage.

Mention three (3) chemical mediators which causes tissue damage.

List three (3) chemical mediators which cause vasodilation.

Enumerate three (3) reactions of inflammation caused by histamine.

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References

References

Bezabeh M.; Tesfaye A.; Ergicho B. et al (2004): General pathology lecture notes for Health Sciences students. Ethiopia Public Health Training Initiative. Pg. 30-31.

Kumar V.; Abbas A. K.; Aster J. C.;(2013): Robbins and Contran Pathologic Basis of Disease (9th Ed.) Elsevier Saunders, China. Pg. 44-52.

Mohan H.;(2010): Text book of Pathology (6th Ed.) Jaypee Brothers Medical Publishers, India . Pg. 136-140.

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