UNIVERSITY COLLEGE LONDON Department of Pharmacology PHAR2002/2005 General and Systematic Pharmacology Dr Dean Willis
HISTAMINE AND OTHER MEDIATORS OF INFLAMMATION Learning objectives: 1. 2. 3. 4. To understand the concept of local hormones or autacoids as mediators of inflammation. To understand the components of the inflammatory response. To understand the process of IgE-mediated mast-cell activation and its role in allergy. To know the other major mediators of inflammation.
Learning tasks: (a) Draw a diagram to show the sequence of events in which an allergen (antigen) causes the release of mediators of inflammation from mast cells.
Inflammation Inflammatory reactions are characterized by:Increased blood flow (may be detected as redness and heat) Increased vascular permeability (tissue swelling) Pain Cellular infiltration (contributes to tissue swelling) Loss of function Inflammation is caused by the release of 'mediators' from cells. These mediators act on tissues to produce the signs of inflammation listed above. The mediators of inflammation are often produced locally around the site of the stimulus to inflammation hence the term local hormone or autacoid.
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Local hormones include: histamine, 5-hydroxytryptamine, eicosanoids, kinins, platelet activating factor, cytokines (e.g. interleukins, tumour necrosis factor, interferon). Histamine and Histamine receptors I. HISTAMINE A Formation C = C-CH2.CH.NH2.COOH HN N C H Histidine decarboxylase HC = C-CH2,CH2.NH2 HN N C H Histamine is 4(2-aminoethyl) imidazole
Enzyme inhibitor - α methyl histidine cf - α methyl tyrosine B Location Blood: Tissues: basophil leucocytes present in all connective tissue within the MAST CELLS. Skin, lung, especially rich. Connective tissue mast cells located around blood vessels. Also mast cells in mucosal surfaces. G.I. tract especially rich. Stomach: large amounts in mast cells. Histaminergic neurones - Hypothalamus. Projections into cortex, thalamus, striatum and hippocampus.
C.N.S.:
C Storage Contained in the granules of mast cells or basophils as a complex with protein and proteoglycan: heparin or chondroitin. Protein has enzyme activity which activates Hageman factor and initiates kinin formation. Not all mast cells are structurally and functionally identical. They may be subclassified on the basis of their protease content (tryptase or chymase) or on the basis of their proteoglycan content (heparin or chrondroitin). D Release Antigen-antibody (IgE class) reaction on the mast cell membrane. Antigens e.g. pollen, house dust mite, bee venom proteins. All people make IgE. Allergy is determined by the capacity to bind that IgE to specific receptors on mast cells or basophils and the capacity of these cells to release histamine and other substances in response to antigen-IgE interaction. Antigen (allergen) + IgE reaction cross links membrane proteins (IgE receptors). Cross-linking induces increased membrane permeabilitiy to calcium. Calcium entry or release of calcium from intracellular stores initiates exocytotic release of granules. Agents which increase intracellular cyclic AMP - β2 agonists reduce histamine release. The complement fragments C5a and C3a (anaphylatoxins) also release histamine from mast cells. Some peptides such as substance P and vasoactive intestinal polypeptide release
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histamine. Compound 48/80 is a polybasic molecule that releases histamine from mast cells in some tissues. Drugs that release histamine: tubocurarine, morphine. E Metabolism OXIDATION; Diamine oxidase (histaminase) N-METHYLATION; N-methyltransferase ACETYLATION; Gut flora Oral dose is acetylated and oxidised (diamine oxidase in gut and liver) Other mediators of inflammation 1. Kinins. The principle kinins are bradykinin (arg-pro-pro-gly-phe-ser-pro-phe-arg) and kallidin (lys-brdykinin). Kinins are formed from plasma protein precursors called kininogens by the action of enzymes: plasma and tissue kallikreins, which split the active kinins from the precursors. Once formed the kinins are destroyed by carboxypeptidase N and angiotensin converting enzyme. Plasma half-life about 20 min. Kinins are vasodilators, increase venular permeability, cause pain and contract smooth muscle. Actions mediated mostly by β2 receptors but β1 receptors also exist. Some actions are indirectly mediated by histamine or prostaglandin release. Icatibant is an experimental β2 antagonist. 2. Platelet-activating factor (PAF) PAF is acetyl-glyceryl-ether-phosphorylcholine. It is formed when the membrane precursor, acyl-PAF is released by phospholipase A2 (see also role of PLA2 in eicosanoid formation). Acyl-PAF is acted on by PLA2 to produce lyso-PAF which is acetylated to yield PAF. PAF aggregates platelets but it is also a vasodilator and increases vascular permeability. It causes hyperalgesia and leucocyte accumulation. There are several PAF antagonists but none have yielded a clinical useful drug. Eicosanoids (see later lecture) Cytokines. Cytokines comprise interleukins, tumour necrosis factor and interferons. There are many interleukins They are local hormones and many are involved in activation of the immune system, inflammation, tissue repair and regeneration. Interleukin-1 (IL-1) has many properties which make it a likely mediator of chronic inflammation. IL1 is necessary for response of B & T lumphocytes to antigen mediates fever stimulates fibroblasts induces eicosanoid formation stimulates the production of other cytokines – IL-1, IL-3, IL-6 activates endothelial cells to express receptors e.g. adhesion molecules promotes muscle degradation, bone resorption, cartilage degradation
3. 4.
There is naturally occurring IL-1 inhibitor and synthetic antagonists have been produced.
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