Mechanism of action and main functions
Inflammation always begins as a local reaction. Primary tissue injury (alteration) triggers complex biochemical processes that attract mediator-producing cells to the lesion.
These substances act as chemical «couriers», altering metabolism in the damaged zone. Their main tasks are:
- Regulation of phagocytosis and recruitment of new leukocytes.
- Alteration of tone and sharp increase in microvascular permeability.
- Bactericidal action to destroy the pathogen.
- Destruction of damaged tissues in the lesion (secondary alteration).
- Activation of systemic immune mechanisms.
- Regulation of cell division (proliferation) and maturation during the healing phase.
Biogenic amines
Biogenic amines are the first to engage in the vascular response, providing the early signs of inflammation.
- Histamine. Released by mast cells, basophils, and platelets. It causes acute dilation of arterioles and microvessels, sharply increases their permeability, which leads to edema development. Additionally, histamine stimulates mucus secretion, causes pain, smooth muscle contraction, and increases endothelial adhesiveness for leukocyte attachment.
- Serotonin. Produced by platelets and eosinophils. It also increases vascular permeability and causes pain. Its distinguishing feature is the ability to cause vasospasm in damaged vessels while simultaneously dilating undamaged ones, as well as stimulating platelet aggregation.
- Adrenaline and noradrenaline. Released by sympathetic nervous system neurons and adrenal glands. They cause vasospasm, activate glycolysis, lipolysis, and lipid peroxidation.
- Acetylcholine. A neurotransmitter of the parasympathetic nervous system. It dilates microvessels and stimulates phagocytosis and cell proliferation.
Peptides and proteins
This group of mediators is responsible for complex immune interactions and systemic effects.
- Interleukins (IL-1–4, 6, 8). Synthesized by macrophages, lymphocytes, and endothelium. They are responsible for directed leukocyte movement (chemotaxis), leukocytosis development, acute-phase protein synthesis, and lymphocyte differentiation.
- Interferons (IFN). Activate macrophages and NK cells, enhance antigen presentation and HLA antigen expression. They exhibit pronounced antiviral activity.
- Tumor necrosis factor (TNF). Activates leukocytes, stimulates angiogenesis (new blood vessel formation) and fibrogenesis, and triggers proteolysis and lipolysis.
- Lysosomal hydrolytic enzymes and cationic proteins. Released by phagocytes and destroyed cells. They exert a powerful bactericidal effect, but at the same time destroy the extracellular matrix, collagen, and elastin, increasing cell membrane permeability.
Arachidonic acid derivatives
Acidic lipid derivatives are formed from phospholipids upon cell membrane injury.
- Prostaglandins. Synthesized in leukocyte, platelet, and endothelial membranes. Their effects depend on the type: $PGE_2$ causes pain, fever, vasodilation, and bronchodilation; $PGF_{2\alpha}$ provokes vasospasm and bronchospasm while suppressing leukocyte migration; and prostacyclin ($PGI_2$) dilates microvessels and decreases platelet aggregation.
- Thromboxane $A_2$. A potent stimulator of platelet aggregation and adhesion, causes vasospasm and bronchospasm, enhances chemotaxis.
- Leukotrienes. Formed under the influence of the enzyme lipoxygenase. Leukotriene $B_4$ enhances leukocyte margination and chemotaxis. Leukotrienes $C_4, D_4, E_4$ sharply increase vascular wall permeability and cause smooth muscle spasm (vessels, bronchi, intestine).
Briefly: answers to topical questions
Which inflammatory mediators cause pain?
Pain in inflammation is caused by biogenic amines, peptides, and arachidonic acid derivatives. The main pain mediators include:
- Histamine — causes pain and increases vascular permeability.
- Serotonin — independently causes pain sensations and vasospasm.
- Bradykinin — activates vanilloid receptors, acting as a chemical irritant.
- Substance P — acts in complex with other mediators.
- Prostaglandins (specifically, prostaglandin E₂) — cause pain and increase the sensitivity of pain nociceptors to algesics (histamine, bradykinin).
Protons (H+) and ATP are also involved in pain perception.
What plasma (humoral) inflammatory mediators exist?
Plasma (humoral) inflammatory mediators represent components of three blood systems functioning via a cascade principle. They include:
- Kallikrein-kinin system mediators — kinins (e.g., bradykinin).
- Complement system mediators — biologically active components such as opsonin C3b, chemotactic factors (C5), anaphylatoxins (C3a, C5a), and the membrane attack complex C5b-9.
- Hemostasis system mediators — cleavage products of blood clotting factors and fibrinolysis (thrombin, fibrin), as well as Hageman factor, which initiates the clotting process.
Which enzymes are involved in arachidonic acid metabolism during inflammation?
Arachidonic acid metabolism during inflammation involves a cascade of enzymes ensuring substrate release and its further conversion. The main enzymes are:
- Phospholipases (phospholipase A2 and C) — release arachidonic acid from cell membrane phospholipids.
- Cyclooxygenase (including COX-1) — a key enzyme of the cyclooxygenase pathway that synthesizes prostaglandins and cyclic endoperoxides.
- Thromboxane synthase — forms thromboxane A2 from cyclic endoperoxides.
- Lipoxygenase (specifically, 5-lipoxygenase) — a key enzyme of the lipoxygenase pathway responsible for leukotriene synthesis.
Which cells synthesize tumor necrosis factor (TNF)?
Tumor necrosis factor (TNF) is synthesized by various cells involved in the immune response and inflammatory reactions. The main producers of this cytokine are:
- Macrophages — actively secrete TNF-α upon interaction with infectious agents or in response to inflammation.
- Lymphocytes — participate in TNF production in the lesion.
- Endothelial cells — also serve as a source of synthesis for this cellular mediator.
Which mediators ensure leukocyte chemotaxis to the inflammation focus?
Leukocyte chemotaxis to the inflammation focus is provided by various endogenous and exogenous mediators (chemoattractants). The main groups include:
- Cytokines and chemokines — interleukins (IL-1, IL-8), TNF-α, α-chemokines (GRO factors), and β-chemokines (MCP, MIP).
- Complement components — anaphylatoxins C3a and C5a.
- Lipid mediators — leukotrienes (specifically, leukotriene B4 and D4), thromboxane A2, platelet-activating factor (PAF).
- Peptides and proteins — cationic proteins, bradykinin, C-reactive protein, immunoglobulins, and immune complexes.
- Degradation products — fragments of fibrin and collagen.
- Bacterial factors — microorganisms, their toxins, and bacterial peptides (e.g., fMLP).
Effects of histamine: Pain, Edema (due to permeability), Mucus, Vessels (dilation). Histamine is the BOSS of the early stage of inflammation.
Class and exam questions
How does primary alteration differ from secondary alteration?
Primary alteration is the tissue damage itself caused by a pathogenic factor. Secondary alteration occurs later when hydrolytic lysosomal enzymes released by phagocytes begin to destroy the body's own tissues within the inflammation focus.
Which cells are the main source of histamine?
The main source of histamine is mast cells, as well as basophils and platelets.
How are leukotrienes formed?
Leukotrienes are synthesized in the membranes of leukocytes, mast cells, and the endothelium from arachidonic acid under the action of the enzyme lipoxygenase.
What is the role of tumor necrosis factor (TNF) in inflammation?
TNF activates leukocytes, stimulates the synthesis of acute-phase proteins, and triggers angiogenesis and fibrogenesis processes for subsequent tissue repair.
What else to study on this topic
- Plasma inflammatory mediators (complement system, kinins)
- Mechanisms of leukocyte chemotaxis and margination
- The role of reactive oxygen species in bactericidal action
- Platelet-activating factor (PAF) and its effects
- Eosinophil chemotactic factor A
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