Inflammation Mediators: Histamine

Principal Mediators of Inflammation

• Inflammatory chemical mediators initiate and regulate inflammatory reactions.
• Principal mediators, their source, and action are key to understanding their roles.

Histamine

• Source: mast cells, basophils, and platelets.
• Actions: Vasodilation, increased vascular permeability, and endothelial activation.
• Clinical relevance: Seen in asthma and allergies.
• Stored in granules within mast cells around blood vessels and vascular channels.
• One of the first mediators released during inflammation, leading to vascular permeability.
• Acts within seconds, causing vasodilation, increased vascular permeability, and endothelial activation.
• Key player in allergic reactions (e.g., anaphylaxis, asthma).
• Released due to tissue injury (physical or chemical damage).
• Allergens (IgE cross-linking on mast cells and basophils) stimulate its release.
• Complement proteins (C3a, C5a) cause mast cell degranulation, leading to histamine release.
• Neuropeptides (substance P) and cytokines stimulate histamine release.
• Platelets take up and store histamine from the plasma via histamine transporters.
• Platelets release stored histamine through granule exocytosis when activated.
• Platelet-derived histamine promotes vascular permeability and vasodilation.
• It helps recruit immune cells like neutrophils to sites of injury or infection.
• It modulates endothelial function, contributing to clot formation or resolution.
• Mast cells and basophils release histamine in response to allergic reactions, parasitic infections, and immune signaling.
• Platelets release histamine mainly in the context of injury repair, hemostasis, and inflammation.
• Histamine promotes vasodilation and increases vascular permeability, contributing to fibrin deposition, wound healing, and revascularization.

Prostaglandins

• Source: mast cells and leukocytes.
• Actions: Vasodilation, pain, and fever.
• Certain prostaglandins (PGE2, PGI2) cause relaxation of vascular smooth muscle, leading to increased blood flow.
• PGE2 sensitizes pain receptors (nociceptors).
• PGE2 acts on the hypothalamus to increase the body’s set-point for temperature.
• Increased prostaglandins contribute to menstrual pain.
• Blockers of prostaglandins exist and will be covered in pharmacology.
• Generated by the action of COX-1 and COX-2 enzymes in local tissues.
• Blocking COX-1 and COX-2 reduces pain and inflammation.
• Vasodilation (especially PGE2, PGI2).
• Fever (PGE2 acts on the hypothalamus).
• Pain (sensitizes nociceptors).
• Menstrual cramps & uterine contraction (PGF2α).
• Regulation of platelet aggregation (TXA2 promotes; PGI2 inhibits).
• Generated in response to injury, infection, or immune activation.
• Generated by the action of COX-1 and COX-2 enzymes in local tissues.
• Cyclooxygenase (COX) enzymes—COX-1 (constitutive) and COX-2 (inducible)—convert arachidonic acid into prostaglandin precursors.
• Bacterial pneumonia: Streptococcus pneumoniae enters the lungs and TLRs recognize bacterial components (e.g., LPS, peptidoglycan).
• Bacterial pneumonia: Release of IL-1, TNF, IL-6 (cytokines) into circulation.
• Fever induction: IL-1 & TNF signal the hypothalamus to increase prostaglandin (PGE2) production, raising body temperature set point.
• Additional prostaglandin effects: Vasodilation, resulting in redness and warmth and sensitization of pain receptors, causing body aches.

Leukotrienes

• Source: mast cells and leukocytes.
• Actions: Increased vascular permeability, chemotaxis, leukocyte adhesion, and activation.
• Increased vascular permeability (LTB4, LTC4, LTD4).
• Bronchoconstriction (LTD4, LTE4 → asthma).
• Leukocyte chemotaxis & activation (LTB4).
• Released due to Lipoxygenase pathway activation (LOX) triggered by allergen exposure (IgE cross-linking).
• Infections (bacteria, viruses) trigger release.
• Cytokine stimulation (TNF, IL-4, IL-13) triggers release.
• Act on the 5-lipoxygenase (5-LOX) enzyme, playing a key role in inflammation, allergic reactions, and immune cell recruitment.
• Leukotrienes C4, D4, and E4 (cysteinyl leukotrienes) cause contraction of endothelial cells lining blood vessels, creating small gaps.
• Leukotriene B4 (LTB4) is a potent chemoattractant for neutrophils, eosinophils, and monocytes.
• Leukotrienes increase the expression of adhesion molecules (like ICAM-1 and VCAM-1) on blood vessel walls.
• Ensures white blood cells actively migrate to sites of inflammation and activates neutrophils and macrophages, improving their ability to phagocytose pathogens.
• Cold air or exertion stimulates mast cells in the airways, leading to degranulation. Simultaneously, leukotrienes (LTC4, LTD4, LTE4) are synthesized via 5-LOX pathway.
• Asthma attack: Triggered by cold air or exertion stimulating mast cells; effects of leukotrienes include bronchoconstriction, increased mucus secretion, and eosinophil recruitment (via IL-5).

Cytokines (TNF, IL-1, IL-6)

• Source: macrophages, endothelial cells, and mast cells.
• Actions: Local endothelial activation; systemic fever, metabolic abnormalities, hypotension (may lead to shock).
• TNF attracts leukocytes to inflammation. Medications that block TNF are used in inflammatory bowel disease (e.g., Ulcerative Colitis, Crohn’s Disease).
• TNF-α, IL-1, and IL-6 are key pro-inflammatory cytokines released during injury, infection, or immune activation.
• Stimulate endothelial cells to express adhesion molecules (e.g., E-selectin, ICAM-1, VCAM-1) that help leukocytes stick to blood vessel walls.
• Disrupt endothelial barriers, allowing plasma proteins and immune cells to enter inflamed tissues.
• IL-1, IL-6, and TNF-α act on the hypothalamus, increasing production of prostaglandin E2 (PGE2).
• Increase muscle and fat breakdown (catabolism) to provide energy for immune cells, and suppress appetite by acting on the brain.
• Dilate blood vessels, leading to a drop in blood pressure.
• Anti-TNF drugs like infliximab (Remicade) and adalimumab (Humira) block TNF-α, reducing inflammation, particularly in IBD.

Chemokines

• Source: leukocytes and activated macrophages.
• Actions: Chemotaxis and leukocyte activation.
• A family of small proteins.
• Act as chemoattractants for leukocytes.

Platelet-Activating Factor (PAF)

• Source: leukocytes and mast cells.
• Actions: Vasodilation, increased vascular permeability, leukocyte activation, chemotaxis, and degranulation.
• Many mediators attract leukocytes, increase vascular permeability, and cause systemic effects like fever and hypotension.
• Stronger vasodilation & vascular permeability than histamine.
• Stimulates platelet aggregation and degranulation, and can induce bronchoconstriction (like leukotrienes).
• PAF causes smooth muscle relaxation, aiding in increased flow of immune cells and plasma proteins.
• Increases the permeability of endothelial cells, allowing larger molecules to move into affected tissues.
• Interacts with specific receptors (PAF receptors) on leukocytes, triggering their activation.
• Is a potent chemotactic factor.
• Stimulates the degranulation of various immune cells, including mast cells and platelets.
• Contributes to bronchoconstriction and vasodilation in allergic conditions, and is involved in platelet aggregation and the formation of atherosclerotic plaques.
• Acts on vasodilation, increased vascular permeability, and leukocyte activation contribute to the hypotension and organ dysfunction seen in septic shock.

Complement System

• Source: plasma proteins produced in the liver.
• Actions: leukocyte chemotaxis and activation.
• Has a complex that directly kills microbes and other invaders.
• Part of host defense mechanisms against microbes.
• Involved in pathological inflammatory reactions.

Kinin System (Bradykinin)

• Source: plasma proteins produced in the liver.
• Actions: increased vascular permeability, smooth muscle contraction, vasodilation, and pain.
• Bradykinin is produced by activated endothelial cells via the Kinin-Kallikrein system.
• High-molecular-weight kininogen activates prekallikrein and Factor IX.
• Kallikrein activates Hageman Factor (Factor XII), which is part of the clotting system.
• Strongly increases vascular permeability and causes pain (stimulates nerve endings).
• Is a vasodilator (via nitric oxide and prostacyclin).
• Activation of HMWK begins with the activation of HMWK and the conversion of prekallikrein to kallikrein, and HMWK is cleaved by kallikrein.
• Activation of Prekallikrein: Kallikrein cleaves prekallikrein to form kallikrein.
• Kallikrein Cleaves HMWK to Produce Bradykinin: Once kallikrein is activated, it cleaves HMWK to produce bradykinin.
• Hereditary Angioedema (HAE) is caused by a deficiency in C1 inhibitor (C1INH).
• ACE inhibitors (used for hypertension and heart failure) block the degradation of bradykinin, leading to its accumulation.

Clotting System (Factor XII / Hageman Factor)

• Plays a role in the clotting cascade.
• Some congenital deficiencies of Factor XII exist.
• Thermal injury activates Hageman factor (Factor XII), activating the Kinin-Kallikrein System.
• Kallikrein converts high molecular weight kininogen to bradykinin, and cytokines (TNF, IL-6) contribute to local inflammation.

Key Patterns Across Mediators

• Histamine and PAF act first in acute allergic/inflammatory reactions.
• Bradykinin and Prostaglandins are key for pain and vasodilation in tissue injury.
• Leukotrienes are major players in bronchoconstriction (asthma).
• PAF links inflammation and clotting, seen in sepsis.
• Cytokines sustain chronic inflammation in autoimmune diseases.