Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P15088 (mast cell)
 14,925 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Assays based on reporter gene technology represent today an important tool in the pharmaceutical industry for discovering novel compound classes interfering with the activation and signaling of target cells after stimulation. Here we describe a reporter gene assay targeting mast cell activation of IgE plus antigen, established in an attempt to identify substances preventing type I allergy (allergic rhinitis, allergic conjunctivitis, allergic asthma, and acute and chronic urticaria). The assay is based on a murine mast cell line designated CPII, stimulation by IgE plus antigen, and a reporter gene construct with the TNF alpha promoter linked to luciferase as a read-out system. Via screening about 50,000 substances, compound 2 was found to inhibit the reporter gene induction in the submicromolar range in this assay. Analogues of compound 2 of the 2,3,4-trihydropyrimidino[2,1-a]isoquinoline type were synthesized starting from 2-alkyl-substituted benzonitriles via aminolysis with 1,3-diaminopropane, dimetalation of 2-substituted 2-phenyl-1,4,5,6-tetrahydropyrimidines with n- and sec-butylithium, reaction with carboxylic acid methyl esters, and finally acidic dehydration. From about 50 derivatives, compound 41 was selected as a lead structure with an IC50 of 0.2 microM and a TC50 of 2.7 microM. In a first profiling in secondary assays, it effectively interfered with the production of mediators such as TNF alpha, IL-4, IL-6, IL-13, and leukotriene synthesis as measured by the corresponding ELISAs. In addition, a passive cutaneous anaphylaxis in mice (a typical type I reaction) is inhibited to more than 90% by compound 41, when administered intradermally 90 min before challenge.
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PMID:Inhibition of Fc epsilon RI-mediated activation of mast cells by 2,3,4-trihydropyrimidino[2,1-a]isoquinolines. 954 5

The present studies demonstrate that histamine induces the secretion of IL-6, IL-8 and GM-CSF from human conjunctival epithelial cells in a dose- and time-dependent manner. The histamine antagonists emedastine (H1), ranitidine (H2) and thioperamide (H3) were evaluated for their ability to inhibit secretion of these cytokines. Emedastine potently inhibited histamine-induced IL-6, IL-8 and GM-CSF secretion with mean IC50 values of 2.23, 3.42 and 1.50 nM, respectively. Ranitidine and thioperamide failed to inhibit cytokine secretion over a wide dose range. These data suggest that mast cell derived histamine may stimulate inflammatory cytokine production in allergic conjunctivitis via activation of epithelial cell H1 receptors. The histamine H1 antagonist emedastine potently inhibits this response.
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PMID:Histamine-stimulated cytokine secretion from human conjunctival epithelial cells: inhibition by the histamine H1 antagonist emedastine. 956 51

Recent reports describe the beneficial use of lodoxamide, an anti-allergic compound, for the treatment of asthma and allergic conjunctivitis. Lodoxamide is known as a mast cell stabilizer, however, the association of a significant clinical improvement with a specific decrease in eosinophil infiltrate suggested possible direct effects of lodoxamide on eosinophils. The chemotactic response of eosinophils to fMLP as well as to IL-5, in vitro, was very significantly and dose-dependently inhibited by Lodoxamide. Lodoxamide was also able to strongly inhibit the release of eosinophil peroxidase after IgA-dependent activation and, to a lesser extent, the release of eosinophil cationic protein and eosinophil-derived neurotoxin. Moreover, the release of cytotoxic mediators evaluated in an antibody-dependent cytotoxicity assay against parasitic targets was also significantly reduced, not only in the case of human eosinophils but also in a rat eosinophil-mast cell model of cytotoxicity. Taken together, these results indicate that lodoxamide can exert potent inhibitory effects on eosinophil activation in vitro combined with a strong inhibition of eosinophil attraction, leading therefore to a reduction in their pathological potential in vivo.
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PMID:Inhibitory effects of lodoxamide on eosinophil activation. 965 7

Prostaglandins likewise leukotriens are proinflammatory mediators resulting from metabolic degradation of the arachidonic acid originating from membrane phospholipids. The most important products of enzyme cyclooxygenation of arachidonic acid are prostaglandins D2, E2, F2a, tromboxane A2 and prostacyclin. Prostaglandins express their tissue effects via the five basic receptor types. Within the allergic inflammation activated mast cell synthesizes prostaglandin D2 (first lipid mediator) which has bronchoconstrictive and vasodilating effects and attracts neutrophilic leukocytes. Moreover, it also participates in the late phase reactions, six hours subsequent to the exposure to the allergen. This mediator is also important in pathogenesis of urticaria, allergic rhinitis and allergic bronchial asthma. In addition to prostaglandin D2, prostaglandin F2a and tromboxane A2 also have bronchoconstrictive actions, while prostacyclin and prostaglandin E have bronchodilating effects. Inhalation of prostaglandin E prevents asthmatic attacks caused by allergens, strain, metabisulfite and ameliorates attacks of aspirin asthma, which confirms the hypothesis that aspirin asthma is based on cyclooxigenase inhibition and increased leukotriene production. In patients with atopic dermatitis, prostaglandin E has suppressive effects on Interferon gamma production by Th1 helper cells and increases production of Interleukin 4 by the Th2 cells. Tromboxane A2 plays a certain role in the development of bronchial hyperreactivity and late asthmatic response. Prostaglandins are also important mediators in the pathogenesis of allergic conjunctivitis. Most of nonsteroidal antiinflammatory drugs inhibit the enzyme cyclooxygenase and thus also prostaglandin biosynthesis and release.
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PMID:[The role of prostaglandins in allergic inflammation]. 986 13

Stem cell factor (SCF) is a major cytokine regulator of mast cell growth and function. The present study demonstrates that human mast cells are able to produce SCF. Constitutive synthesis of SCF mRNA was seen in the mast cells isolated from human lung and skin by RT-PCR. This was confirmed by in situ hybridization in conjunctival mast cells of both tryptase-only (MCT) and tryptase/chymase (MCTC) subsets. SCF protein product was found in conjunctival MCT and MCTC mast cells by immunohistochemistry. Soluble SCF protein was detected in the culture supernatant of isolated lung mast cells by ELISA, and cross-linkage of IgE receptor (Fc epsilon-RI) on the lung mast cells in culture did not alter SCF mRNA expression, or the secreted soluble SCF protein. This was consistent with the finding that levels of SCF mRNA expression in conjunctival mast cells were similar between normal subjects and patients with seasonal allergic conjunctivitis (SAC). This study shows that human mast cells themselves are a cellular source of SCF, as well as being target cells for this growth factor. SCF may regulate mast cell growth and function via both paracrine and autocrine mechanisms. The production of SCF by mast cells may be regulated via mechanisms other than IgE receptor-mediated pathways.
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PMID:Human mast cells express stem cell factor. 987 41

Two important realizations about pathophysiological mechanisms involved in allergic conjunctivitis have led to novel drug discovery efforts and new topical ocular medications for prevention and treatment of this prevent allergic disease. The first of these, interspecies and intraspecies mast cell heterogeneity, was established in the mid-1980's by investigators working in the field of asthma. It is now appreciated that secretory responses as well as effects of pharmacological agents differ depending upon the mast cell population studied. Two types of human mast cells, the tryptase containing (T) and the tryptase/chymase containing (TC) mast cells, have been characterized in a variety of tissues. Significantly, Irani et al. (1) demonstrated by immunohistochemical staining that the mast cells present in conjunctival tissues from patients with allergic conjunctivitis were 100% TC. Functional responses of human conjunctival mast cells to a variety of secretagogues (2) were consistent with their classification as TC or connective tissue type mast cells. Importantly, the studies by Miller et al. mentioned above allowed the harvesting and preparation of human conjunctival mast cells for use in drug screening studies. Utilization of these cells has led to the identification of Patanol, the most effective human conjunctival mast cell stabilizer available for topical use in allergic conjunctivitis (3). These same studies demonstrated the lack of mast cell stabilizing activity for cromolyn and nedocromil in these connective tissue type, TC containing, human conjunctival mast cells. Similar lack of effect was noted with these drugs on human skin mast cell degranulation (4). The second important discovery in the area of allergic conjunctivitis has been the demonstration that conjunctival epithelial cells may contribute to the perpetuation of the allergic response. A report from Gamache et al. (5) identified cytokines produced by human conjunctival epithelial cells following treatment with a number of stimuli. Significantly, Sharif et al. (6) subsequently identified functional histamine H1 receptors on these same cell types. Recently, Weimer et al. (7) have shown that exposure of human conjunctival epithelial cells to histamine leads to the production of pro-inflammatory cytokines IL-6 and IL-8. Importantly, treatment of the epithelial cells with drugs that possess histamine H1 antagonist properties prevents cytokine production. It is noteworthy that first generation anti-histamines antazoline and pheniramine are not potent inhibitors of histamine-stimulated cytokine synthesis in intact epithelial cells, while newer anti-histamines Emadine and levocabastine are more potent. Surprisingly, Patanol was more potent as an inhibitor of histamine-stimulated cytokine production by the epithelial cells than would be predicted from its histamine H1 antagonist affinity. These inhibitory effects on conjunctival epithelial cell production of pro-inflammatory cytokines may contribute to enhanced clinical activity noted with these recently approved drugs.
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PMID:A current appreciation of sites for pharmacological intervention in allergic conjunctivitis: effects of new topical ocular drugs. 1033 30

A wealth of antiallergic drugs is available for ocular allergy, and many new drugs will soon be approved. Pharmaceutical companies frequently seek approval of anti-inflammatory drugs for allergic indications, because it is relatively easy to perform clinical trials for ocular allergy. Extremely safe drugs for mild to moderate degrees of allergic conjunctivitis include antihistamines, mast cell stabilizers, and nonsteroidal anti-inflammatory agents. Topical corticosteroids, preferably those with reduced side effects, are available for more severe forms of ocular allergy. The choice of an antiallergic drug may be guided by the indication for which the drug was approved. The ultimate selection will be made based on the patient's symptoms, the drug's availability, and its cost.
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PMID:The current and future therapy of allergic conjunctivitis. 1038 70

Seasonal allergic conjunctivitis is rarely associated with permanent vision impairment; however, it is a relatively common condition that may compromise the quality of life. It may, in extreme cases, impair daily activities, including work. Numerous treatment options have become available for the relief of acute symptoms. Avoidance should always be the first line in therapy but, in most cases, is not practical, especially with pollen allergies. The use of saline eyedrops is simple and nontoxic, and it is effective in up to 30% to 35% of cases. It can and should be added to all other remedies to reduce adverse effects and cost by decreasing the need for other therapeutic options. Antihistamines and decongestants are useful treatment choices for the majority of cases. Ketorolac tromethamine may be helpful in relieving pruritus, but it offers little advantage over topical antihistamines. Corticosteroids may be used for severe cases for a limited time. If topical corticosteroids are being considered, an ophthalmologist should be consulted. Cromolyn sodium and lodoxamide ophthalmic solution may be helpful in the prophylaxis of symptoms during the allergy season, but these agents require frequent dosing. Olopatadine hydrochloride is a mast cell stabilizer and antihistamine that can be dosed twice a day. Immunotherapy is effective and should be offered to those who are intolerant or have allergic conjunctivitis refractory to medications.
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PMID:Seasonal allergic conjunctivitis: overview and treatment update. 1047 15

The effects of intravenous administration of nedocromil sodium were investigated in active and passive models of conjunctival immediate hypersensitivity in rats. In the active sensitization model, animals were immunized with ovalbumin 21 days prior to ocular instillation of a solution containing ovalbumin. Nedocromil sodium administered prior to antigen challenge significantly inhibited emergence of conjunctival edema and erythema (P < .05) and reduced mast cell degranulation (P < .02). In the passive-sensitization model, the conjunctiva in one eye was injected with ovalbumin antiserum 48 hours prior to intravenous administration of ovalbumin. Nedocromil sodium administered prior to antigen challenge significantly and dose-dependently reduced appearance of the signs of conjunctivitis (P < .01) as well as vascular leakage (P < .05). These data indicate that intravenous nedocromil sodium is effective in animal models of allergic conjunctivitis and may have potential for wider therapeutic application. These data are also consistent with results of clinical studies in which nedocromil sodium relieved symptoms of allergic conjunctivitis and further support a role for nedocromil sodium in the prevention of allergic conjunctivitis.
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PMID:Nedocromil sodium in two models of conjunctival immediate hypersensitivity. 1091 4

Among the several eye diseases (or diseases involving the eye) based on hypersensitivity reactions, the most frequent is allergic conjunctivitis. Recently six types of allergic conjunctivitis/keratoconjunctivitis are distinguished: 1. seasonal, 2. perennial, 3. vernal, 4. giant papillary, 5. atopic and 6. of contact origin. Their treatment is generally local. In the most frequent seasonal ("hay fever") and perennial forms the elimination of the allergen or when it is impossible antihistamines (with or without vasoconstrictors), "weak" steroids or hyposensitisation are offered. In vernal and atopic keratoconjunctivitis mast cell stabilizers are the most effective, with special effect of lodoxamide in the vernal type. In giant papillary and contact allergic inflammations the elimination of the causative agent is the first method of choice. In resistant cases "strong" steroids, in extreme forms immunosuppressive, cytostatic and systemic treatment may become necessary. The paper gives a review of currently applied medicines (mainly eyedrops) and other methods of treatment, and includes therapeutic principles applying to various forms of allergic conjunctivitis.
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PMID:[Therapy of allergic conjunctivitis]. 1100 10


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