Cellular inflammatory mediators are biologically active substances released by cells in response to tissue injury. They provide chemical communication between reactions at the site of injury, regulate vascular permeability, recruit leukocytes, and trigger the immune response. The release of these molecules transitions primary alteration into a full-blown local inflammatory reaction.
Core MechanismProvide chemical communication between all reactions at the site of inflammation.
Secondary AlterationPhagocytic enzymes destroy host tissues, worsening the initial damage.
OriginSynthesized within cell membranes or released from preformed granules.
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 focus.
These substances act as chemical couriers, altering metabolism in the damaged zone. Their main tasks include:
Regulating phagocytosis and recruiting new leukocytes.
Altering vascular tone and sharply increasing microvascular permeability.
Exerting bactericidal activity to destroy pathogens.
Destroying damaged tissues at the focus (secondary alteration).
Activating systemic immune mechanisms.
Regulating cell proliferation and maturation during the healing phase.
Biogenic Amines
Biogenic amines are the first to engage in the vascular response, driving the early signs of inflammation.
Histamine. Released by mast cells, basophils, and platelets. It causes acute dilation of arterioles and microvessels, sharply increasing their permeability, which leads to edema. Additionally, histamine stimulates mucus secretion, induces pain, causes smooth muscle contraction, and increases endothelial adhesiveness for leukocyte adhesion.
Serotonin. Produced by platelets and eosinophils. It also increases vascular permeability and causes pain. Its distinct feature is the ability to induce spasm in damaged vessels while dilating undamaged ones, and stimulating platelet aggregation.
Epinephrine and Norepinephrine. Released by sympathetic nerve fibers and the adrenal glands. They cause vasoconstriction, activate glycolysis, lipolysis, and lipid peroxidation.
Acetylcholine. A parasympathetic neurotransmitter. It dilates microvessels, stimulates phagocytosis, and promotes cellular 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 drive directed leukocyte movement (chemotaxis), leukocytosis, acute-phase protein synthesis, and lymphocyte differentiation.
Interferons (IFN). Activate macrophages and NK cells, enhance antigen presentation and HLA antigen expression. They possess 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 damaged cells. They exert powerful bactericidal activity, but simultaneously degrade 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 subtype: $PGE_2$ causes pain, fever, vasodilation, and bronchodilation; $PGF_{2\alpha}$ provokes vasoconstriction and bronchoconstriction while inhibiting leukocyte migration; prostacyclin ($PGI_2$) dilates microvessels and inhibits platelet aggregation.
Thromboxane $A_2$. A potent stimulator of platelet aggregation and adhesion, causing vasoconstriction, bronchoconstriction, and enhanced chemotaxis.
Leukotrienes. Formed under the action of the enzyme lipoxygenase. Leukotriene $B_4$ enhances leukocyte margination and chemotaxis. Leukotrienes $C_4, D_4,$ and $E_4$ sharply increase vascular wall permeability and cause smooth muscle spasms (vessels, bronchi, intestines).
Mnemonic
Histamine effects: Pain, Edema (due to permeability), Mucus, Vessels (dilation). Histamine is the PEMV (boss) of early inflammation.
Frequently asked questions
Which inflammatory mediators cause pain?
Pain during inflammation is caused by biogenic amines, peptides, and arachidonic acid derivatives. The main pain mediators include:
Histamine — induces pain and increases vascular permeability.
Serotonin — directly causes pain sensations and vasoconstriction.
Bradykinin — activates vanilloid receptors, acting as a chemical irritant.
Substance P — acts in synergy with other mediators.
Prostaglandins (specifically prostaglandin E₂) — cause pain and lower the threshold of pain nociceptors to algogens (histamine, bradykinin).
Protons (H+) and ATP are also involved in pain perception.
What are the plasma (humoral) inflammatory mediators?
Plasma inflammatory mediators consist of components from three cascading blood systems. They include:
Kallikrein-kinin system mediators — kinins (e.g., bradykinin).
Complement system mediators — biologically active components such as the opsonin C3b, chemotactic factors (C5a), anaphylatoxins (C3a, C5a), and the membrane attack complex (C5b-9).
Hemostasis system mediators — cleavage products of clotting factors and fibrinolysis (thrombin, fibrin), as well as Hageman factor, which initiates coagulation.
Which enzymes are involved in arachidonic acid metabolism during inflammation?
Arachidonic acid metabolism involves a cascade of enzymes ensuring substrate release and subsequent conversion. Key enzymes include:
Phospholipases (phospholipase A2 and C) — release arachidonic acid from cell membrane phospholipids.
Cyclooxygenase (including COX-1) — the key enzyme of the cyclooxygenase pathway that synthesizes prostaglandins and cyclic endoperoxides.
Thromboxane synthase — generates thromboxane A2 from cyclic endoperoxides.
Lipoxygenase (specifically 5-lipoxygenase) — the key enzyme of the lipoxygenase pathway responsible for leukotriene synthesis.
Which cells synthesize tumor necrosis factor (TNF)?
Tumor necrosis factor is synthesized by various cells involved in immune responses and inflammation. The main producers of this cytokine are:
Macrophages — actively release TNF-α when interacting with pathogens or in response to inflammation.
Lymphocytes — participate in TNF production at the injury site.
Endothelial cells — also serve as a source of this cellular mediator.
Which mediators provide leukocyte chemotaxis to the inflammatory focus?
Leukocyte chemotaxis to the inflammatory focus is mediated by diverse endogenous and exogenous chemoattractants. Major 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.
Peptides and proteins — cationic proteins, bradykinin, C-reactive protein, immunoglobulins, and immune complexes.
Degradation products — fibrin and collagen fragments.
Bacterial factors — microorganisms, their toxins, and bacterial peptides (e.g., fMLP).
How does primary alteration differ from secondary alteration?
Primary alteration is the direct tissue damage caused by a pathogenic factor. Secondary alteration occurs later when lysosomal hydrolytic enzymes released by phagocytes begin to destroy the host's own tissues at the inflammatory site.
Which cells are the primary source of histamine?
The main source of histamine is mast cells, along with basophils and platelets.
How are leukotrienes formed?
Leukotrienes are synthesized in the membranes of leukocytes, mast cells, and endothelium from arachidonic acid via the lipoxygenase pathway.
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 for subsequent tissue repair.