DEMO DEMOBradykinin
Major source: via activation of plasma kinins pathway. Receptors: B1 + B2. The B1 receptor is inducible (note oedema is inhibited by B2 antagonist HOE 140, but not by the B1 antagonist desArg9[Leu8]Bk in normal non-inflamed skin). Pathological role: under study, evidence for role in allergy and pain . Metabolism: Captropril by inhibiting angiotensin converting enzyme, which is a kininase, prevents the loss of the terminal two amino acids from bradykinin. This prolongs the activity of bradykinin and is observed as a potentiation of oedema formation.
C5a
Major source: via activation of plasma complement pathway. A potent neutrophil chemoattractant agent. Pathological role: under study, evidence for presence in inflammatory diseases including rheumatoid arthritis.
Captopril
An orally active inhibitor of angiotensin I-converting enzyme (ACE). It reduces elevated blood pressure by inhibiting the renin-angiotensin system and also inhibits pressure responses to exogenous angiotensin I. It also potentiates the presence and thus the activity of bradykinin, which is normally metabolised by ACE.
Cimetidine
An anti-ulcer medication which work through the inhibition of basal and nocturnal gastric acid secretion by competitive inhibition of the action of histamine at histamine H2 receptor sites on the parietal cells. It also blocks H2 receptor sites in vascular tissue.
N-formyl-methionyl-leucine-phenylalanine (FMLP)
Major source: bacterial cell walls. A potent chemotactic agent.
Histamine
Major source: mast cells and basophils. Receptors: H1 (note oedema is inhibited by the H1 antagonist mepyramine, but not by the H2 antagonist cimetidine). Pathological role: Released from mast cells in IgE-dependent allergy; the non sedative antihistamines (e.g. terfenadine) are beneficial in hayfever and acute skin conditions.
HOE 140
A bradykinin B2 receptor antagonist. It inhibits oedema formation induced by bradykinin. Kinin antagonists are under study for use in allergic and painful conditions.
Interleukin-1, (IL-1)
Major source: inflammatory cells, especially macrophages. Pathological role: under study, evidence for role in chronic inflammatory disease. Effects dependent on de novo protein synthesis and thus slow in onset (1-2h) and inhibited by protein synthesis inhibitors (eg cycloheximide). Activates endothelial cells to stimulate glycoprotein expression (selectius and ICAM expression).
Interleukin-8, (IL-8)
Major source: inflammatory cells that include endothelial cells. Pathological role: under study. A potent neutrophil chemoattractant.
Leukotriene (LT) B4, LTB4
Major source: inflammatory cells especially neutrophils. Pathological role: under study. A potent neutrophil chemoattractant. A product of metabolism via the arachiclonate 5-lipoxygenose pathway. Inhibition: Steroids induce synthesis of lipocortin which acts to inhibit phospholipase A2. There are also inhibitors of the 5-lipoxygenase enzyme available.
Leukotrienes (LT) C4 and D4, LTD4
Product of metabolism of arachidonic acid via the5-lipoxygenose pathway. Major source: inflammatory cells e.g. mast cells and eosinophils. Pathological role: Allergy, evidence for role in asthma. A potent bronchoconstrictor. Inhibition: Steroids induce synthesis of lipocortin which acts to inhibit phospholipase A2. There are also inhibitors of the 5-lipoxygenase enzyme available which are currently in use for various forms of asthma.
Mediator
A chemical substance (transmitter substance) that induces activity in an excitable tissue, such as nerve or muscle.
Mepyramine
A histamine H2 receptor antagonist. Inhibits oedema formation induced by histamine. Not used clinically but an established experimental tool.
Neutrophil
A granulocyte, a white blood cell that normally acts to defend the body (for example against bacterial invasion). In inflammatory disease neutrophils can accumulate in large numbers at inflammatory sites and act in a pro-inflammatory manner.
Neutrophil depletion
Nitrogen mustard acts to prevent maturation of neutrophils in the bone marrow. It acts selectively in the rabbit leaving normal circulating levels of other cell types whilst circulating levels of neutrophils are reduced to about 5%. Methotrexate is sometimes used in the rat. Anti-neutrophil antiserum is also used.
Non-steroidal anti-inflammatory drugs, NSAIDs
There is a wide range of non-steroidal anti-inflammatory drugs which act to inhibit the synthesis of prostaglandins and thromboxanes via inhibition of the cyclo-oxygenase enzyme. Arachidonic acid is converted into vasodilator prostaglandins when injected into rabbit skin and thus potentiates oedema formation. In the experiments shown indomethacin and ibuprofen inhibit the ability of arachidonic acid but not PGE2 to potentiate oedema formation. NSAIDs also have other effects and it is also shown that ibuprofen, when given systemically in the rabbit, can inhibit neutrophil accumulation.
Oedema
The presence of abnormally large amounts of fluid in the intercellular tissue spaces of the body, usually applied to demonstrable accumulation of excessive fluid in the subcutaneous tissues.
Oedema may be localised, due to venous or lymphatic obstruction or to increased vascular permeability or it may be systemic due to heart failure or renal disease.
Collections of oedema fluid are designated according to the site, for example ascites (peritoneal cavity), hydrothorax (pleural cavity) and hydropericardium (pericardial sac).
Platelet Activating Factor, PAF
Major source: Several inflammatory cell types. Receptors: Specific PAF receptors, effect antagonised by PAF antagonists such as WEB 2086. Path. role: Under study.
Prostaglandin, PGE
A cylcoygenase product of arachidonic acid which increases blood flow at inflammatory sites. This can, in turn, lead to a potentiation of the inflammatory response. Also involved in the pain process.
Protein synthesis inhibition
The use of agents such as cylcohexamide leads to an inhibition of protein synthesis. This can inhibit the de novo synthesis inflammatory dependent actions of some mediators such as interleukin-1.
Substance P (also the related peptide neurokinin A)
Major source: sensory nerves. Receptors: Neurokinin NK-1, NK-2 and NK-3; NK-1 receptors on endothelial cells are active in mediating an increase in microvascular permeability in rat, guinea-pig and human skin, but not rabbit skin. Thus no activity of substance P is observed in rabbit skin (NB 5-HT is likewise weak in the rabbit, but potent in other species). Substance P can also activate mast cells. Pathological role: Under study, evidence from animal studies of a role in inflammation and pain.
Steroidal anti-inflammatory drugs
The effects of the anti-inflammatory steroids are dependent on de novo protein synthesis, thus a pretreatment (2h is ideal) is necessary before an inhibition of oedema is observed in the rabbit. Steroids inhibit arachidonic acid metabolism via production of lipocortin which inhibits phospholipase A2. It is suggested that another protein, vasocortin, is produced which acts to inhibit oedema formation. Steroids can suppress the inflammatory response via a variety of mechanisms Steroids have little effect on the vasodilator component of the inflammatory component, however they do inhibition expression of adhesive glycoproteins on endothelial cells.
Tumour Necrosis Factor (TNF)
Major source: inflammatory cells, especially macrophages Pathological role: under study, evidence for role in chronic inflammatory disease, mechanisms similar to those of IL-1.