Mediator mast-cell

Mast cells express high-affinity IgE Fc receptors (FceRI) on their surface, contain cytoplasmic granules which are major sources of histamine and other inflammatory mediators, and are activated to release and generate these mediators by IgE-dependent and non-IgE-dependent mechanisms [1]. Disturbances either in the release of mast cell mediators or in mast cell proliferation are associated with clonal mast cell disorders including monoclonal mast cell activation syndrome (MMAS) and mastocytosis respectively, which are in turn associated with some cases of anaphylaxis [2], Molecular mechanisms have been identified which may link increased releasability of mast cell mediators and conditions leading to increased mast cell numbers [3]. Patients with mastocytosis have an increased risk to develop anaphylaxis [4, 5] and those with anaphylaxis may suffer from unrecognized mastocytosis or may display incomplete features of the disease [6-8]. 

Table 4. Triggers for mast cell mediator release ... 

Therapy of Mast Cell Mediator-Induced Symptoms... 

No increase of plasma leukotrienes after RCM administration Mast cell mediator release correlates with severity of reaction, positive basophil activation test to RCM in patients... 

Cromolyn and nedocromil are inhaled anti-inflammatory agents that block both the early- and late-phase response. Both agents are considered alternative therapies to inhaled corticosteroids for the treatment of mild persistent asthma however, both are less effective than low doses of inhaled corticosteroids.2,30 The exact mechanism of action of these agents is not understood, but they appear to inhibit mast cell mediator release as well as modulate other inflammatory responses.3... 

Corticosteroids (e.g., beclomethazone, flunisolide, triamcinolone) have anti-inflammatory and immunosuppressant actions. These drugs are used prophylactically to prevent the occurrence of asthma in patients with frequent attacks. Because they are not useful during an acute attack, corticosteroids are prescribed along with maintenance bronchodilators. These drugs are also administered by inhalation. Cromolyn is another anti-inflammatory agent used prophylactically to prevent an asthmatic attack. The exact mechanism of action of cromolyn is not fully understood however, it is likely to involve the stabilization of mast cells. This prevents the release of the inflammatory mast cell mediators involved in inducing an asthmatic attack. Cromolyn has proven effective in patients with exercise-induced asthma. 

Fig. 11.4. Model for cholinergic signalling in the intestinal mucosa, providing a possible rationale for AChE secretion by parasitic nematodes. ACh released from enteric cholinergic motor neurons stimulates chloride secretion, mucus secretion and Paneth cell exocytosis through muscarinic receptors. Secretory responses may be modulated by mast cell mediators, either directly or via the induction of neural reflex programmes. The role of muscarinic receptor-positive cells in the lamina propria of rats infected with N. brasiliensis is undetermined, as are potential mechanisms of trans-epithelial transport of the enzymes. Adapted from Cooke (1984).

Intranasal corticosteroids effectively relieve sneezing, rhinorrhea, pruritus, and nasal congestion with minimal side effects (Table 79-4). They reduce inflammation by blocking mediator release, suppressing neutrophil che-motaxis, causing mild vasoconstriction, and inhibiting mast cell-mediated, late-phase reactions. 

Theophylline appears to produce bronchodilation by inhibiting phosphodiesterases, which may also result in antiinflammatory and other nonbronchodilator activity through decreased mast cell mediator release, decreased eosinophil basic protein release, decreased T-lymphocyte proliferation, decreased T-cell cytokine release, and decreased plasma exudation. 

Inhibitors of histamine release One of the effects of the so-called mast cell stabilizers cromoglycate (cromolyn) and nedocromil is to decrease the release of histamine from mast cells (p. 72, 326). Both agents are applied topically. Release of mast cell mediators can also be inhibited by some Hi antihistamines, e.g., oxatomide and ketotifen, which are used systemically. 

Albeturol sulfate 32.5 (1.5) 41.7 (1.5) 40.0(1.7) A selective beta-2 agonist broncbodilator that inhibits the release of mast cell mediators and increases clearance of the mucus membranes. 

Neither APNEA nor compound 48/80 induced cardiovascular effects in animals depleted of their mast cell mediators by repeated dosing with compound 48/80. 

In both cases the response to adenosine is mainly mast cell mediated. Indeed, at the doses of adenosine used the contribution of the Aj receptor (which is not mast cell mediated) to the bronchoconstrictor response in vivo is minimal (Hannon et al. 2002b). The pharmacological analysis gave generally similar results although... 

Feoktistov I, Ryzhov S, Goldstein AE, Biaggioni I (2003) Mast cell-mediated stimulation of angiogenesis cooperative interaction between A2B and A3 adenosine receptors. Circ Res 92(5) 485 192... 

Murine mast cells Degranulation and mast cell-mediated increase in cutaneous vasopermeability Ramkumar et al. 1993 Ali et al. 1990 Fozard et al. 1996 Reeves et al. 1997 Tilley et al. 2000, 2003 Zhong et al. 2003... 

Theoharides, T.C. and Bielory, L. Mast cells and mast cell mediators as targets of dietary supplements. Ann Allergy Asthma Immunol, 93(2 Suppl 1), S24-34, 2004. 

Tang L, Jennings TA, Eaton JW. Mast cells mediate acute inflammatory responses to implanted biomaterials. Proceedings of the National Academy of Sciences of the United States of America 1998, 95, 8841-8846. 

Stabilization of mast cells. Cromolyn prevents IgE-mediated release of mast cell mediators, although only after chronic treatment. It is applied locally to conjunctiva, nasal mucosa, the bronchial tree (inhalation), and intestinal mucosa (absorption is almost nil with oral intake). Indications prophylaxis of hay-fever, allergic asthma, and food allergies. Nedocromil acts similarly. 

Nedocromil was developed as a result of research for compounds to control asthma. Its activity has been studied in vitro in a variety of inflammatory cells, including mast cells, eosinophils, and polymorphonuclear leukocytes. Nedocromil appears to be more potent than cromolyn in its ability to inhibit immimologic release of mast cell mediators. It can also modify the actions of eosinophils, neutrophils, monocytes, macrophages, and platelets. Pharmacokinetic studies indicate that ocular penetration of nedocromil is slow, and clearance from the eye is relatively rapid. Nedocromil differs from the other mast cell stabilizers in that it is effective within 15 to 30 minutes. 

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