RESUMEN
OBJECTIVES AND DESIGN: The effects of the mucolytic agents ambroxol and N-acetylcystein (NAC) were studied on the release of histamine, leukotrienes, cytokines and superoxide anions from a variety of cells involved in the pathogenesis of allergic inflammation. SUBJECTS: Mast cells were isolated from human adenoids and skin (n = 5-6). Basophils, monocytes and granulocytes were obtained from Buffy-coat blood obtained from healthy blood donors (n = 4-7) and enriched by density centrifugation. TREATMENT AND METHODS: Ambroxol or NAC were added to the cells for different periods before stimulation with various immunological and non-immunological secretagogues. Histamine release from mast cells, basophils and monocytes was assayed either by radioimmunoassay or spectrofluorometrically. LTC4 (basophils), LTB4 (neutrophil/eosinophil granulocytes or monocytes), IL-4 and IL-13 (basophils) were measured by ELISA. RESULTS: Ambroxol inhibited histamine release by more than 50% from human adenoidal mast cells (1000 microM ambroxol) and skin mast cells (100 microM ambroxol) stimulated by Con A and compound 48/80, respectively. Ambroxol (100 microM) strikingly inhibited anti-IgE induced release of both histamine, LTC4, IL-4 and IL-13 from basophils and reduced both histamine and LTB4 release induced by C5a or Zymosan in monocytes. The drug also reduced LTB4 and superoxide anion production in granulocytes stimulated by zymosan or fMLP. In all cell types studied, ambroxol was more efficacious following a short preincubation (5-15 min) of the drug with the cells before stimulation. In contrast, NAC produced no clear effects on any of the different cell types studied, regardless of the preincubation period, the concentration or the stimulus employed. CONCLUSIONS: Unlike NAC, ambroxol is able to not only inhibit acute mediator release from mast cells and leukocytes but also reduce immunomodulatory cytokine generation from basophils and may have beneficial effects in the treatment of allergic respiratory diseases.
Asunto(s)
Ambroxol/farmacología , Antiinflamatorios/farmacología , Citocinas/metabolismo , Liberación de Histamina/efectos de los fármacos , Leucocitos/efectos de los fármacos , Leucotrienos/metabolismo , Mastocitos/efectos de los fármacos , Humanos , Leucocitos/metabolismo , Mastocitos/metabolismoAsunto(s)
Tonsila Faríngea/efectos de los fármacos , Ambroxol/farmacología , Antialérgicos/farmacología , Expectorantes/farmacología , Liberación de Histamina/efectos de los fármacos , Mastocitos/efectos de los fármacos , Tonsila Faríngea/citología , Relación Dosis-Respuesta a Droga , Granulocitos/efectos de los fármacos , Granulocitos/metabolismo , Humanos , Leucotrieno B4/metabolismo , Mastocitos/metabolismo , Monocitos/efectos de los fármacos , Monocitos/metabolismo , Piel/efectos de los fármacos , Superóxidos/metabolismo , Zimosan , p-Metoxi-N-metilfenetilamina/toxicidadAsunto(s)
Liberación de Histamina/efectos de los fármacos , Mastocitos/efectos de los fármacos , Monocitos/efectos de los fármacos , Agonistas Adrenérgicos beta/farmacología , Antiinflamatorios no Esteroideos/farmacología , Antioxidantes/farmacología , Carotenoides/farmacología , Relación Dosis-Respuesta a Droga , Combinación de Medicamentos , Etretinato/farmacología , Antagonistas de los Receptores Histamínicos H1/farmacología , Humanos , Isotretinoína/farmacología , Queratolíticos/farmacología , Mastocitos/metabolismo , Metaproterenol/análogos & derivados , Metaproterenol/farmacología , Monocitos/metabolismo , Ftalazinas/farmacología , Quinolinas/farmacología , Superóxido Dismutasa/farmacología , Teofilina/análogos & derivados , Teofilina/farmacología , beta CarotenoRESUMEN
Some recent observations have indicated that cells other than mast cells, notably macrophages, may contain significant amounts of histamine. Using a histamine-specific radioimmunoassay, we found that human blood monocytes and lymphocytes contain about 0.05 pg histamine/cell. Various other cells, e.g. fibroblasts, colorectal tumor, kidney and ovarian cells, and murine bone marrow derived macrophages contained markedly less histamine (< 0.008 pg/cell). Ionophore A23187 (1 microM) released up to 50% of the total histamine from monocytes and lymphocytes. C5a caused a dose-dependent histamine release of up to 40% in monocytes and up to 20% in lymphocytes. Substance P induced a release only in cells of certain donors. Lipopolysaccharide, concanavalin A, and compound 48/80 had no effect. Culturing of the cells caused a loss of cellular histamine and its releasability. In view of the huge numbers of monocytes and lymphocytes in the blood, the histamine in these cells has to be taken into account under both physiological and pathophysiological conditions.
Asunto(s)
Histamina/metabolismo , Linfocitos/metabolismo , Macrófagos/metabolismo , Células Cultivadas , Liberación de Histamina/efectos de los fármacos , Humanos , Técnicas In Vitro , Monocitos/metabolismo , RadioinmunoensayoRESUMEN
The effects of the H3-agonist R-alpha-methylhistamine (R-alpha-MeHA) and the H3-antagonist thioperamide on the spontaneous and concanavalin A (ConA) induced histamine release from human mast cells were tested and compared with the effect of some H1- and H2-receptor active substances. R-alpha-MeHA (10(-9)-10(-7) M) exerted no effect on histamine release whereas thioperamide increased the spontaneous release at 10(-6)-10(-4) M but inhibited the ConA induced release in a narrow concentration range (10(-6)-10(-5) M). This enhancement might be taken as an indication of the existence of H3-receptor dependent autoregulation although presently other mechanism cannot be excluded.
Asunto(s)
Tonsila Faríngea/citología , Concanavalina A/farmacología , Mastocitos/fisiología , Receptores Histamínicos/fisiología , Cimetidina/farmacología , Guanidinas/farmacología , Antagonistas de los Receptores Histamínicos , Humanos , Hidroxizina/farmacología , Imidazoles/farmacología , Impromidina , Mastocitos/efectos de los fármacos , Meclizina/farmacología , Metilhistaminas/farmacología , Piperidinas/farmacología , Receptores Histamínicos/efectos de los fármacos , Receptores Histamínicos H1/efectos de los fármacos , Receptores Histamínicos H1/fisiología , Receptores Histamínicos H2/efectos de los fármacos , Receptores Histamínicos H2/fisiología , Receptores Histamínicos H3RESUMEN
N-(6-aminohexyl)-1-naphthalenesulfonamide (W5), N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W7) and Triflupromazine (TFPr) are substances with calmodulin antagonistic properties. All of these compounds inhibited the Con A-induced histamine release from human adenoidal mast cells. Maximal inhibition for W5 was observed at 200 microM, for W7 at 50 microM and for TFPr at 20 microM. Higher concentrations of each substance induced a marked histamine release. The kinetics of the mediator release were found to be different for Con A and W7 only after 5 mins incubation. The kinetics of TFPr were found to be biphasic: a slow onset was followed by a fast release reaction.
Asunto(s)
Calmodulina/antagonistas & inhibidores , Liberación de Histamina/efectos de los fármacos , Mastocitos/metabolismo , Tonsila Faríngea/citología , Concanavalina A/farmacología , Humanos , Técnicas In Vitro , Cinética , Mastocitos/efectos de los fármacos , Sulfonamidas/farmacología , Triflupromazina/farmacologíaRESUMEN
Cloxacepride is an amide of the dopamine antagonist metoclopramide and has been reported to possess oral antiallergic properties in the rat PCA model. Both substances have now been tested in isolated mast cell preparations from human adenoidal tissues to determine whether any therapeutic antiallergic potential in man could be expected. Metoclopramide at concentrations 10(-5)-10(-3) M had no inhibitory effect but instead enhanced Con A-induced histamine release at concentrations greater than 10(-4) M. Cloxacepride at concentrations 10(-5)-10(-4) M significantly inhibited Con A-induced histamine release. This inhibitory effect was not diminished by increasing the preincubation time for up to 30 min. In contrast, cloxacepride concentrations greater than 4 x 10(-5) M caused a substantial histamine release. This effect could not be alleviated by an increase in the number of mast cells per sample. These results then suggest a very narrow range of therapeutic potential for cloxacepride.
Asunto(s)
Benzamidas/farmacología , Mastocitos/efectos de los fármacos , Metoclopramida/farmacología , Tonsila Faríngea/efectos de los fármacos , Tonsila Faríngea/inmunología , Tonsila Faríngea/metabolismo , Concanavalina A/farmacología , Liberación de Histamina/efectos de los fármacos , Humanos , Técnicas In Vitro , Mastocitos/inmunología , Mastocitos/metabolismoRESUMEN
The histamine-releasing effect of human C5a was compared with that of concanavalin A in blood basophils and isolated adenoidal mast cells from the same donors. In basophils, C5a (10 ng/ml) induced a significant histamine release (7.5 +/- 2.1%, corrected value). In isolated adenoidal mast cells C5a had only a marginal effect (2% histamine release), although the cells responded markedly to concanavalin A stimulation (about 13% release). The results support the view that the heterogeneity of mast cells and basophils is also reflected in the expression of anaphylatoxin receptors on their surface.
Asunto(s)
Basófilos/metabolismo , Complemento C5/farmacología , Liberación de Histamina , Mastocitos/metabolismo , Tonsila Faríngea/citología , Niño , Preescolar , Complemento C5a , Concanavalina A/farmacología , Humanos , RadioinmunoensayoRESUMEN
The number of mast cells which can be recovered from human adenoid tissues varies characteristically in the course of the year. The yield was found to be highest in May and lowest in July. The average histamine content was above average in April, June, July and September. Although the spontaneous histamine release remained relatively constant, the concanavalin A-stimulated histamine release was significantly reduced from June to September.