Chemical Mediators of Inflammation

Chemical Mediators of Inflammation

• These substances initiate and regulate inflammatory reactions.
• Understanding the principal mediators, their source, and actions is crucial.

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, particularly around blood vessels and vascular channels.
• It is released early during inflammation, leading to vascular permeability.
• Rapid response mediator that starts acting within seconds.
• Stimuli for release: tissue injury, allergens, complement proteins (C3a, C5a), neuropeptides, and cytokines.
• Platelets take up and store histamine from the plasma via histamine transporters, without synthesizing it themselves.
• Platelets release stored histamine through granule exocytosis, contributing to vascular changes during injury repair, hemostasis, and inflammation.
• Contributes to fibrin deposition, wound healing, and revascularization.

Prostaglandins

• Source: mast cells and leukocytes.
• Actions: vasodilation, pain, and fever.
• Increased levels contribute to menstrual pain.
• Blockers 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 helps immune cells reach sites of injury or infection and contributes to redness and warmth at the affected site.
• PGE2 sensitizes pain receptors, contributing to hyperalgesia, while also acting on the hypothalamus to increase the body’s temperature set point, leading to fever.
• Stimuli for release: cyclooxygenase (COX-1 & COX-2) activation by mechanical or chemical injury, infection, hypoxia, inflammation, and cytokines (TNF, IL-1).
• Enable bacteria to enter the lungs
• Macrophages TLRs recognize bacterial components , releasing IL-1, TNF, IL-6 (cytokines) into circulation and signal the hypothalamus to increase prostaglandin (PGE2) production → Fever.
• Vasodilation → Redness and warmth.
• Sensitization of pain receptors → Body aches.

Leukotrienes

• Source: mast cells and leukocytes.
• Actions: increased vascular permeability, chemotaxis, leukocyte adhesion, and activation.
• Increased vascular permeability leads to mucosal edema and airway narrowing.
• LTB4 is a potent chemoattractant for neutrophils, eosinophils, and monocytes.
• Increased expression of adhesion molecules on blood vessel walls by white blood cells, priming and improving their ability to phagocytose pathogens.
• Triggered by allergen exposure, infections, and cytokine stimulation (TNF, IL-4, IL-13).
• Derived from arachidonic acid through the action of the 5-lipoxygenase (5-LOX) enzyme.
• Play a key role in inflammation, allergic reactions, and immune cell recruitment.
• Cysteinyl leukotrienes cause contraction of endothelial cells lining blood vessels, creating small gaps that allows plasma proteins, immune cells, and fluid to exit the bloodstream and enter tissues.
• Stimulates mast cells → Histamine and PAF are released.
• Effects of Leukotrienes: Bronchoconstriction , increased Mucus Secretion, and Eosinophil recruitment which lead to prolonged inflammation.

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

• Source: macrophages, endothelial cells, and mast cells.
• Local action: endothelial activation.
• Systemic actions: fever, metabolic abnormalities, hypotension (may lead to shock).
• TNF attracts leukocytes to areas of inflammation
• Medications that block TNF are used in inflammatory bowel disease because they prevent neutrophils from entering the mucosa of the colon in Ulcerative Colitis and Crohn’s Disease.
• TNF-α, IL-1, and IL-6 key pro-inflammatory cytokines released during injury, infection, or immune activation, leading to inflammation, fever, metabolic changes, and septic shock.
• Promote neutrophil recruitment and macrophage activation, intensifying inflammation.
• Excessive levels causes chronic inflammation and is seen in diseases like rheumatoid arthritis and inflammatory bowel disease (IBD)
• Act on the hypothalamus, increasing production of prostaglandin E2 (PGE2) which raises the body's set point for temperature, causing fever.
• TNF-α and IL-6 increase muscle and fat breakdown to provide energy for immune cells which suppresses appetite by acting on the brain

Chemokines

• Source: leukocytes and activated macrophages.
• Actions: chemotaxis and leukocyte activation.
• Act primarily as chemoattractants for specific types of leukocytes.

Platelet-Activating Factor (PAF)

• Source: leukocytes and mast cells.
• Actions: vasodilation, increased vascular permeability, leukocyte activation, chemotaxis, and degranulation.
• Factors cause attraction of leukocytes, increased vascular permeability, and systemic effects like fever and hypotension.
• Stronger vasodilation & vascular permeability than histamine which leads to Leukocyte chemotaxis and activation.
• Stimulates platelet aggregation and degranulation, whilst also inducing bronchoconstriction.
• Released by: inflammation & injury, IgE-mediated reactions, bacterial endotoxins and complement activation.
• Contributes to bronchoconstriction and vasodilation in allergic conditions and is being investigated as potential treatments for asthma and allergic rhinitis to block.
• Involved in platelet aggregation and the formation of atherosclerotic plaques, contributing to the development of cardiovascular diseases
• Actions on vasodilation, increased vascular permeability, and leukocyte activation contribute to the hypotension and organ dysfunction seen in septic shock.
• Enhances the delivery of immune cells, increases oxygen and nutrient supply to tissues during inflammation or infection.
• Interacts with PAF receptors on leukocytes, triggering their activation and leads to directed movement toward higher concentrations of PAF near the site of injury
• Stimulates the degranulation of various immune cells, including mast cells and platelets, leading to the release of pre-stored mediators which increases vascular permeability, recruits immune cells, and further enhances the inflammatory response.

Complement System

• Source: Plasma proteins produced in the liver.
• Actions: leukocyte chemotaxis and activation.
• Complement complex: provides direct killing for microbes and other invaders.
• Functions in 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.
• High-molecular-weight kininogen activates prekallikrein and Factor IX.
• Kallikrein activates Hageman Factor (Factor XII).
• Bradykinin is produced by activated endothelial cells via the Kinin-Kallikrein system.
• Strongly increases vascular permeability , causes pain and induces smooth muscle contraction in some tissues.
• Vasodilator via nitric oxide and prostacyclin.
• Activated by: Hageman factor and tissue damage, clotting, or complement activation.
• HMWK is crucial in activating prekallikrein and Factor XI
• Tissue Injury or Activation of Factor XII increases Kallikrein which cleaves HMWK → leading to the release of bradykinin, which is a potent vasodilator, that contributes to inflammation vascular permeability and pain.

Clotting System (Factor XII / Hageman Factor)

• Hageman Factor (Factor XII) plays a role in the clotting cascade.

Mediator Action Timings

• 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.