Chemical Mediators of Inflammation - Types, Pathophysiology, and Functions

Introduction

The vascular and cellular changes that take place during inflammation are due to the result of chemical mediators. These are obtained from the plasma (complement system) or the cells via activating cell surface receptors (histamine). Chemical mediators also act as chemotactic substances and attract other cells and molecules to the area of inflammatory reaction (chemokines). These mediators are capable of causing edema at the site on injection sites, causing contraction of smooth muscles, and changing blood pressure.

What Are the Types of Chemical Mediators?

The chemical mediators are cell and plasma-derived. The different types of chemical mediators are:

Cell-Derived:

1. Preformed Chemical Mediators From the Secretory Granules:

• Histamine.

• Serotonin.

• The mast cells, basophils, and neutrophils release histamine and serotonin.

2. Synthesized Mediators:

• Prostaglandins - Released by leukocytes and mast cells.

• Leukotrienes - Released by leukocytes and mast cells.

• Platelet-Activating Factor- Released by leukocytes.

• Reactive Oxygen Species - Released by macrophages.

• Cytokines - Released by macrophages and leukocytes.

• Neuropeptides - Released by leukocytes and nerve fibers.

Plasma-Derived:

1. Complement Activation:

• C3a.

• C5a.

• C3b.

• C5b-9.

2. Factor 12 Activation:

• Kinin system (bradykinin).

• Coagulation System.

What Are the Features of Chemical Mediators?

• Active chemical mediators of inflammation are produced only due to external stimulus, usually in response to microbial infection.

• Usually, chemical mediators have a very short life. They either become inactive due to enzymatic action or are inhibited by the inhibitors. Some of them have a short half-life period.

• Once a single mediator is active, it can activate other chemical mediators.

• The chemical mediators act by attaching to receptors on the target cells, by their enzyme activity, and by oxidative damage.

The circulatory system, the inflammatory cells, and the injured tissue release chemical mediators. They initiate the inflammatory reaction in the body. The chemical nature of the chemical mediators can be grouped as follows:

• Vasoactive Amines - Histamine and serotonin.

• Peptide Amines - Bradykinin.

• Eicosanoids - Prostaglandins, leukotrienes, and thromboxanes.

What Is the Pathophysiology of Chemical Mediators?

Plasma Factors:

The plasma factors are discussed below.

1. Products of Complement System - The complement system is a part of the body’s immune system that promotes phagocytosis and inflammatory reaction.

• Antigen-antibody reaction.

• C3a - It boosts vascular penetration and permeability.

• C5a - It increases vascular permeability and attracts leucocytes.

2. Kinin System - Once factor 12 or Hageman factor is activated, it produces factor 12a. Factor 12a changes prekallikrein to kallikrein, which shows chemotactic properties. In addition, it releases bradykinin which increases vascular permeability and dilatation. As a result, it brings skin pain and causes contraction of the muscles.

3. By-Product of the Fibrinolytic and Clotting System - Plasmin is formed as a byproduct of activation of the fibrinolytic system. Plasmin causes activation of the complement system and enhances vascular permeability.

Tissue Factors:

The tissue factors are as follows.

1. Vascular Amines - Histamine and serotonin are secreted by basophils, mast cells, and platelets. It enhances vascular permeability and dilation.

2. Arachidonic Acid Metabolites:

• PG12 (Prostaglandin 12) - It causes vasodilation.

• Thromboxane A2 - It causes vasoconstriction.

• Leukotrienes C4, D4, and E4 - It enhances vascular permeability and vasoconstriction.

3. Platelet-Activating Factor - It causes platelet aggregation, bronchodilation, vasoconstriction, and chemotaxis.

4. Cytokines - Lymphocytes and macrophages produce cytokines. They comprise interleukins and tumor necrosis factors. They have the below-mentioned effects:

• Endothelium activation increases leukocytic adhesion and activates other cytokines.

• They show acute inflammatory responses like fever.

• They cause the proliferation of fibroblasts, the formation of collagen, and the synthesis of collagenase.

• They cause the secretion of interleukin.

What Are Histamine and Serotonin?

Histamine and serotonin are vasoactive amines. They are the first released chemical mediators and act on blood vessels.

Histamine:

• Histamines are stored as granules in the mast cells. They are released in response to physical injury, antibody-mediated hypersensitivity reaction, activation of the complement system, and activation of neuropeptides.

• They cause dilation of the blood vessels and increase vascular permeability.

• Histamine acts through the H1 receptor present in the endothelial cells.

Serotonin:

• They are the chemical mediators seen in the platelets.

• They also act as neurotransmitters.

• They cause constriction of the blood vessels.

What Are Arachidonic Acid Metabolites?

Arachidonic acid is an important eicosanoid substrate, a lipid signaling molecule, and a chemical mediator of inflammation. Leukotrienes, prostaglandins, prostacyclins, and thromboxanes are produced from arachidonic acid. They cause many reactions at cellular and vascular levels.

Prostaglandins:

• Endothelial cells, macrophages, and mast cells release them.

• It causes systemic and vascular inflammatory reactions.

• It also dilates the blood vessels.

Thromboaxone (A2):

• It causes constriction of the blood vessels and helps bind the platelets together.

• Thromboaxone is obtained by the action of thromboxane synthetase available in the platelets.

Prostacyclins:

• Prostacyclin synthetase is present in the vascular endothelium.

• It increases the permeability of the blood vessels and stops platelet aggregation.

Leukotrienes:

• Mast cells and leukocytes produce leukotrienes. The enzyme involved is lipoxygenase.

• It has chemotactic action and attracts more leukocytes. It is also engaged in smooth muscle and vascular muscle reactions.

What Are Tumor Necrosis Factors and Interleukins?

• T-lymphocytes, mast cells, macrophages, and dendritic cells produce tumor necrosis factors.

• Macrophages and dendritic cells produce interleukins.

• They enhance leukocytic adhesion to the vascular endothelium and help in their transportation through the blood vessels.

• They are released in response to microbial action, physical injuries, and foreign bodies.

What Are Chemokines?

Chemokines are proteins that attract leukocytes and act as chemoattractants. It helps to maintain tissue architecture. During inflammation, it acts on leukocytes and increases integrin affinity, thus stimulating leukocytic attachment to the endothelial cell wall. There are four main groups of chemokines:

C-X-C Chemokines:

• The macrophages and the endothelial cells release them.

• It acts mainly on the neutrophils and causes their activation, and guides their movement. For example, IL8 (interleukin 8).

C-C Chemokines:

• They act as chemoattractants for eosinophils, monocytes, lymphocytes, and basophils.

• C-C chemokines include monocyte chemoattractant protein 1 (MCP1) and eotaxin (causes migration of eosinophils at the site of inflammation).

C-Chemokines:

• They act specifically on lymphocytes. For example, lymphotactin.

CX3C Chemokines:

• They act specifically on monocytes and T-cells.

What Is the Complement System?

It comprises soluble proteins and receptors on the surface of the membranes that play a role in the body’s defense system and inflammatory reactions. It helps in both innate and adaptive immunity. It causes inflammation, phagocytosis, and cellular lysis.

What Is the Platelet-Activating Factor?

• The platelets, basophils, mast cells, endothelial cells, and neutrophils release platelet-activating factors.

• It causes clumping of the platelets.

• It causes constriction of the blood vessels and acts as a bronchoconstrictor.

• At very low concentrations, it causes dilation of the blood vessels.

Conclusion

Inflammation is vital in removing pathogenic agents and other causes that result in the inflammatory process. However, if the inflammatory process acts on the body for a long time, it can result in organ damage. So, it is very important to restrict the inflammatory process by restricting the actions of chemical mediators seen during the inflammation. A better understanding of these chemical mediators of inflammation will help to develop anti-inflammatory mediators that can restrict the process of inflammation and prevent the negative impact.