Mast cells

Synthesis. Histamine [51-45-6] 2-(4-imidazolyl)ethylarnine (1) is formed by decarboxylation of histidine by the enzyme L-histidine decarboxylase (Fig. 1). Most histamine is stored preformed in cytoplasmic granules of mast cells and basophils. In humans mast cells are found in the loose connective tissue of all organs, especially around blood and lymphatic vessels and nerves. These cells are most abundant in the organs expressing allergic diseases the skin, respiratory tract, and gastrointestinal tract. 

Histamine in the Cardiovascular System. It has been known for many years that histamine is present in sympathetic nerves and has a distribution within the heart that parallels that of norepinephrine (see Epinephrine and norepinephrine). A physiological role for cardiac histamine as a modulator of sympathetic responses is highly plausible (15). A pool of histamine in rat heart located neither in mast cells nor in sympathetic nerves has been demonstrated. The turnover of this metaboHcaHy active pool of histamine appears to be maintained by normal sympathetic activity. 

Histamine AND histamine antagonists). It is formed from histidine by the enzyme L-histidine decarboxylase. In the periphery, histamine is stored ia mast cells, basophils, cells of the gastric mucosa, and epidermal cells. In the CNS, histamine is released from nerve cells and acts as a neurotransmitter. The actions of histamine ate terrninated by methylation and subsequent oxidation via the enzymes histamine-/V-methyltransferase and monoamine oxidase. 

Elevation of cycHc AMP levels is also known to inhibit the release of inflammatory and contractile mediators from mast cells (42). The good clinical efficacy of P2" goiAsts may be related to this action because some members of this class of dmgs inhibit mediator release at the same concentrations at which they relax smooth muscle (43). In contrast to their effectiveness against immediate bronchoconstriction, P2" gonists do not inhibit the late asthmatic... 

There are other glycosaminoglycans. Hyaluronic acid [9004-61-9] occurs both free and in noncovalent association with proteoglycan molecules. Heparin [9005-49-6] and heparan sulfate [39403-40-2] also known as heparitin sulfate [9050-30-0] occur in mast cells and in the aorta, Hver, and lungs. 

A Sail, R Matsumoto, HP McNeil, M Karplus, RL Stevens. Three-dimensional models of four mouse mast cell chymases. Identification of proteoglycan-bmdmg regions and protease-specific antigenic epitopes. I Biol Chem 268 9023-9034, 1933. 

Chloro-oxazolo[4,5-/i]quinoline-2-carboxylic acid methyl ester was the most active compound in tests for inhibitors of antigen-induced release of histamine in vitro from rat peritoneal mast cells (IC50 of 0.3 p,M) and as inhibitors of IgE-mediated passive cutaneous anaphylaxis in the rat (ED50 (intraperitoneal) of 0.1 mg/kg in dose 0.5 mg/kg as an inhibitor of the test)—10 times and 60 times more potent, respectively, than the disodium salt of cromoglycic acid (85JMC1255). 

Adenosine is produced by many tissues, mainly as a byproduct of ATP breakdown. It is released from neurons, glia and other cells, possibly through the operation of the membrane transport system. Its rate of production varies with the functional state of the tissue and it may play a role as an autocrine or paracrine mediator (e.g. controlling blood flow). The uptake of adenosine is blocked by dipyridamole, which has vasodilatory effects. The effects of adenosine are mediated by a group of G protein-coupled receptors (the Gi/o-coupled Ai- and A3 receptors, and the Gs-coupled A2a-/A2B receptors). Ai receptors can mediate vasoconstriction, block of cardiac atrioventricular conduction and reduction of force of contraction, bronchoconstriction, and inhibition of neurotransmitter release. A2 receptors mediate vasodilatation and are involved in the stimulation of nociceptive afferent neurons. A3 receptors mediate the release of mediators from mast cells. Methylxanthines (e.g. caffeine) function as antagonists of Ai and A2 receptors. Adenosine itself is used to terminate supraventricular tachycardia by intravenous bolus injection. 

An allergen is usually an inert substance (e.g. pollen, house dust mite faeces) that in some individuals can trigger the generation of an (inappropriate) antigenic response. Mediated by TH2 lymphocytes, it causes B-Lymphocytes to produce lgE. Subsequent exposure of a sensitized individual to the allergen is therefore able to cross-link IgE antibodies on the surface of mast cells and trigger an immune response and histamine release. 

Allergy. Figure 1 Type I Anaphylactic Reaction IgE-bearing mast cells are activated by allergens to release mediators of acute allergic reactions. 

Cromones suppress the release of mediators from mast cells by a mechanism that is not known (Fig. 4). In order to achieve the complete suppressive effect, cromones have to be given prophytactically several days to weeks before exposure to seasonal allergens can be expected,... 

Allergy. Figure 4 Crotnones stabilize mast cells. 

The most serious acute Type I reaction is the generalized reaction, the anaphylactic shock. Anaphylactic shock results from a generalized release of mediators from mast cells and basophils. The clinical symptoms are manifested predominantly in... 

Allergy. Figure 6 Anti IgE antibodies prevent IgE from binding to their receptors on mast cells, and thus from releasing allergic mediators. 

The atherosclerotic plaque overexpresses another chemoattractant, eotaxin, that may mediate mast cell... 

Mast Cell Regulation. Recent experiments have elucidated the deleterious role of mast cell activation in atherosclerotic mice. Atheromata from mast cell... 

Given the routine use of mast cell stabilizers in the clinic, for example in the setting of asthma treatment, these preclinical results may stimulate clinical evaluation in humans. 

Bradykinin is also released from mast cells within damaged tissues. It produces inflammation and activates nociceptors via bradykinin B1 and B2 receptors. 

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