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Biomedical subjects

M K Church

Publications and source records attributed to M K Church.

At least 181 records · Page 10Linked to original sources
PubMed1985

Adenoid histamine and its possible relationship to secretory otitis media.

We have shown that adenoid tissue contains large amounts of the inflammatory mediator histamine. Children with fluid present in both ears at operation were found to have increased amounts of histamine in their adenoid tissue compared to a group with no signs or symptoms of SOM. Also mouth breathing and nasal obstruction were associated with adenoid histamine content whereas other signs and symptoms were not. No significant differences in adenoid weight were seen between SOM and non SOM patients. Histamine, both free and cell-associated, was found in nasopharyngeal secretions and middle-ear fluid although the source and mechanism of release has not yet been identified. We suggest that the benefits of adenoidectomy in children with SOM may possibly come from removing a potential source of inflammatory mediators in the vicinity of the Eustachian tube.

Adenoidectomy↗
PubMed1985

Inhibition of histamine release from dispersed human lung and tonsillar mast cells by nicardipine and nifedipine.

Calcium entry blocking drugs attenuate antigen-induced bronchoconstriction in asthma which is mast cell mediated. We have investigated the effects of two calcium uptake blockers, nicardipine and nifedipine on histamine secretion from human mast cells dispersed from lung and tonsillar tissue. Mast cells were activated for secretion with anti-human IgE or calcium ionophore, A23187. Nicardipine and nifedipine caused a concentration-related inhibition of IgE-dependent histamine release from both lung (IC30 10 microM and 4.4 microM) and tonsillar (IC30 21 microM and 47 microM) mast cells. Nicardipine and nifedipine also inhibited mast cell histamine release induced by A23187 with IC30 values of 14 microM and 67 microM for lung and 15 microM and 30 microM for tonsillar mast cells. In the absence of drugs, increasing the extracellular calcium concentrations from 0.2 to 5 mM caused a concentration related increase in IgE-dependent histamine release from tonsillar mast cells. Both nicardipine and nifedipine (50 microM) displaced the concentration-effect curve to the right. Nicardipine (0.01-100 microM) caused a concentration related inhibition of rat kidney histamine methyltransferase activity used in the radioenzymatic assay of histamine (ki of 7.5-12 microM) whereas nifedipine was only a weak inhibitor. Nicardipine also interfered with the spectrofluorimetric assay after exposure to ultraviolet light. These observations demonstrate that nicardipine and nifedipine inhibit IgE-dependent and ionophore stimulated mediator secretion from human mast cells. The lack of stimulus-related specificity and the high drug concentrations required suggest that classical calcium channel blockade is not responsible for inhibition of mast cell mediator release. Furthermore, we suggest that inhibition of mast cell mediator release is unlikely to be the mechanism by which these drugs alleviate asthma.

Calcimycin↗
PubMed1985

Histamine secretion from human skin slices induced by anti-IgE and artificial secretagogues and the effects of sodium cromoglycate and salbutamol.

Human cutaneous mast cells show functional differences from their counterparts in other tissues. Following passive sensitization with 1% atopic serum for 30 min at 37 degrees C human skin slices released histamine after challenge with anti-human IgE in a concentration dependent manner. Maximum release of 14 +/- 2% was achieved with a 1/10 dilution of anti-IgE. Passive sensitization with 10% atopic serum increased the secretory response to anti-IgE but histamine release was only concentration related over the entire 1/1000 to 1/10 dilution range in half of the specimens studied, the remainder showing high dose tolerance to anti-IgE. Negligible histamine release occurred with anti-IgE challenge of slices which had not been passively sensitized. The histamine releasing ability of A23187 in human skin slices was similar to that observed in lung and adenoidal mast cells being concentration dependent over the range 0.1-3 microM with a maximum release of 25 +/- 3%. In contrast to human lung and adenoidal mast cells, poly-L-lysine and compound 48/80 induced histamine release from skin slices. Poly-L-lysine induced a concentration-dependent release of histamine over the range 0.01-10 microM with a maximum of 27 +/- 3%. The response to compound 48/80 was variable, releasing in some but not all specimens. Histamine release caused by anti-IgE, A23187 and poly-L-lysine was shown to be dependent upon extracellular calcium while release stimulated by compound 48/80 was calcium independent. The chemotactic peptide, formyl-methionyl-leucyl-phenylalanine, over the range 0.01-10 microM failed to release histamine from skin slices.(ABSTRACT TRUNCATED AT 250 WORDS)

Albuterol↗
PubMed1985

Adenosine potentiates immunological histamine release from rat mast cells by a novel cyclic AMP-independent cell-surface action.

Adenosine enhanced histamine release and prolonged the adenosine 3':5'-cyclic monophosphate (cyclic AMP) response in purified rat peritoneal mast cells following immunological challenge. The effect on the cyclic AMP response, which was blocked by 8-phenyltheophylline, probably results from an interaction with A2-purinoceptors. Enhancement of histamine release showed different characteristics. It was not inhibited by dipyridamole or hexobendine, thereby indicating an action at the cell surface. However, the relative potencies of adenosine analogues and nucleotides, together with the observation that this effect was not antagonized by 8-phenyltheophylline or theophylline, suggest that it is not mediated by a previously recognised purinoceptor. Thus, enhancement of histamine release may represent a novel cell surface action of adenosine which is independent of its effects on adenylate cyclase.

Adenosine↗
PubMed1985

Relationship between mediator release from human lung mast cells in vitro and in vivo.

There is now compelling evidence to incriminate bronchial mast cells in the pathogenesis of bronchoconstriction of allergic asthma. Human mast cells isolated from lung tissue or bronchoalveolar lavage release histamine and generate eicosanoids upon IgE-dependent activation. In this paper we present data that raise doubts about the significance of phospholipid methylation in IgE-dependent activation-secretion coupling and provide evidence that drugs such as 3-deazaadenosine inhibit mediator secretion by inhibiting phosphodiesterase, in addition to inhibiting putative methylation pathways. Activation of human mast cells and basophils also stimulates adenylate cyclase to increase levels of cyclic AMP, which, on the basis of pharmacological manipulation with purine nucleosides, we believe is involved in the progression of the secretory response. Human lung cells also generate both cyclo- and lipoxygenase products of arachidonate upon Ca++-dependent stimulation with complex interactions occurring between these pathways in the presence of the leukotriene inhibitor, Piriprost. The role of mast cells in the immediate airway response to inhaled allergens in asthma was demonstrated by showing an interaction between nonspecific bronchial reactivity and mast cell reactivity in predicting the airway response upon antigen inhalation. Further confirmation of this concept was obtained by showing an inverse relationship between the release of histamine and neutrophil chemotactic factor (NCF) into the circulation induced by antigen challenge, and nonspecific airway reactivity. The identification of significant increases in circulating mediators following antigen provocation of patients with seasonal asthma enabled the effects of drugs used in the treatment of asthma to be compared on airway calibre and mast cell mediator release. Sodium cromoglycate partially inhibited the airway and plasma histamine responses with antigen, but totally inhibited the increases in NCF. Salbutamol completely inhibited all responses, while ipratropium bromide, which produced the same bronchoconstriction as achieved with salbutamol, had no effect. The potent H1-antagonist astemizole partially inhibited bronchoconstriction without affecting histamine release. Antigen provocation produced a significant increase in circulating levels of the 13,14-dihydro-15-keto metabolite of PGF2 alpha which could originate from mast cell-derived PGD2. In both retrospective and prospective studies, a close relationship was shown between nonspecific bronchial reactivity and resting airway calibre in asthma.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1985

Influence of albuterol, cromolyn sodium and ipratropium bromide on the airway and circulating mediator responses to allergen bronchial provocation in asthma.

The effect of pharmacologic agents on mast cell mediator release was investigated in vivo. Eight atopic asthmatic subjects with airways relatively unreactive to nonspecific stimuli (geometric mean PC20 methacholine, 4.0 mg/ml) underwent single-concentration allergen challenge before (control) or after inhaling albuterol 200 micrograms, cromolyn sodium 20 mg, or 0.9% sodium chloride placebo. Six of the same subjects also underwent allergen challenge after pretreatment with ipratropium bromide, 1 mg. Airway responses to pharmacologic agents and bronchial challenge were measured by change in both specific airway conductance (SGaw) and FEV1. Mast cell mediator release was monitored by serial change in plasma histamine and, in addition, serum neutrophil chemotactic factor (NCF) on the placebo, albuterol, and cromolyn sodium challenge days. Control and placebo allergen challenges were associated with repeatable mean maximal falls in SGaw (48.5 versus 49.6%) and FEV1 (25.7 versus 25.5%). The mean increments in plasma histamine were not significantly different on the control (0.17 to 0.44 ng/ml) or placebo challenge days (0.18 to 0.64 ng/ml), with maximal levels occurring 5 min after challenge. A sustained increase in NCF was identified on the placebo challenge day (155.0% above baseline). Pretreatment with albuterol abolished any significant bronchoconstriction, with mean maximal falls in SGaw and FEV1 after challenge of 7.5 and 1.4%, respectively. These changes in airway caliber were not associated with any significant increment in mean plasma histamine (0.17 to 0.22 ng/ml) or serum NCF (4.1% increase). Cromolyn sodium pretreatment, while attenuating the airway response, was still associated with significant falls in SGaw (22.7%) and FEV1 (7.3%) and increases in plasma histamine (0.18 to 0.27 ng/ml).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1984

Adenosine inhibits and potentiates IgE-dependent histamine release from human lung mast cells by an A2-purinoceptor mediated mechanism.

Adenosine, at physiological concentrations, may modulate histamine release from mechanically dispersed human lung mast cells. Addition of adenosine to the dispersed mast cells at times up to 5 min before immunological challenge with anti-human IgE inhibited histamine release. When added after this time adenosine caused a small potentiation of immunological histamine release, maximum potentiation occurring with addition of adenosine 5 min after challenge, coincidental with the end of the rapid phase of histamine release. Both inhibition and potentiation of histamine release were more pronounced with low levels of immunological challenge. Theophylline, 8-phenyltheophylline, dipyridamole and analogues of adenosine were used to determine the site of action of adenosine on mast cell mediator release. Theophylline and 8-phenyltheophylline displaced the concentration-response lines for both inhibition and potentiation of mediator release by adenosine to the right whilst dipyridamole, 1 microM, was without significant effect. This suggests that both effects result from interaction of adenosine with cell surface receptors. This was confirmed by demonstrating that the P-site agonist 2',5'-dideoxyadenosine produced only inhibition of histamine release, an effect which was inhibited by dipyridamole but not by theophylline. The rank potency order of adenosine analogues, NECA much greater than adenosine greater than or equal to L-PIA greater than or equal to D-PIA in both inhibiting and potentiating immunological histamine release suggests that both effects are mediated through activation of cell surface A2-purinoceptors. Since adenosine is released into the circulation of asthmatic subjects following bronchial provocation with antigen, causes bronchoconstriction and has the ability to modulate mast cell histamine release, this nucleoside should be considered as an additional inflammatory mediator of allergic reactions.

Adenosine↗
PubMed1984

The effect of methyltransferase inhibitors on histamine release from human dispersed lung mast cells activated with anti-human IgE and calcium ionophore A23187.

Inhibitors of adenosylmethionine (AdoMet)-dependent methyltransferases reduce histamine release from enzymatically dispersed human lung mast cells activated with either anti-human IgE or calcium ionophore A23187. The IC25 values for adenosine and 3-deazaadenosine (DZA) inhibiting anti-IgE-induced histamine release were 395 microM and 301 microM respectively. The addition of homocysteine thiolactone (Hcy) potentiated the effects of adenosine and DZA, reducing their IC25 values to 32 microM and 10.5 microM respectively. The adenosine deaminase (adenosine aminohydrolase EC 3.5.4.4) inhibitors erythro-9-(2-hydroxy-3-nonyl)-adenine (EHNA) inhibited anti-IgE-induced histamine release with an IC50 of 162 microM. This inhibition was not potentiated by Hcy. The combination of DZA and Hcy effectively inhibited histamine release induced by concentrations of A23187 which released a similar amount of histamine to anti-IgE. However the combination was 17 times less potent against A23187-compared with anti-IgE-induced release. These observations suggest that AdoMet-dependent methyltransferases play an important role in IgE-dependent histamine release from human lung mast cells but their role in A23187-induced release is less clear.

Adenine↗
PubMed1984

Exercise and isocapnic hyperventilation-induced bronchoconstriction in asthma: relevance of circulating basophils to measurements of plasma histamine.

The relationship of airway cooling during exercise to changes in airway caliber, plasma histamine levels, and circulating basophils was investigated in eight allergic asthmatic and eight normal subjects. In asthma matched RHE during exercise and ICH produced almost identical bronchoconstriction with maximum falls in SGaw of 61.0 +/- 4.5% and 57.9 +/- 5.2%, respectively. A similar RHE in normal subjects was associated with a 7.9 +/- 3.3% fall in SGaw. The resting plasma-histamine levels were higher in the asthmatic (0.52 +/- 0.06 ng/ml) than in the normal (0.31 +/- 0.07 ng/ml, p less than 0.05) subjects. No significant change in plasma histamine occurred after exercise in either group nor in the asthmatic subjects with ICH. In contrast, exercise but not ICH stimulated an increase in leukocytes, basophils, and total blood histamine in parallel with the airway response that reached a maximum at 2 to 5 min in both normal and asthmatic subjects. There was a positive correlation between basal plasma and total blood-histamine levels (r = 0.67, p less than 0.01) in normal and asthmatic subjects suggesting that basophils contribute significantly to plasma histamine. The spontaneous basophil release of histamine was greater in asthmatic (13.4 +/- 2%) than in normal subjects (6.46 +/- 7%, p less than 0.005), which is consistent with the higher resting plasma-histamine levels in the asthmatic subjects. These findings suggest that plasma-histamine changes with exercise in asthma but not ICH may be related to the associated basophilia and sample handling rather than intrapulmonary mast cell degranulation.

Adult↗
PubMed1984

Histamine and secretory otitis media.

Histamine, both free and cell associated, has been demonstrated in middle ear fluid from patients with secretory otitis media (SOM). Histamine, mainly free in solution, has also been shown to be present in nasopharyngeal secretions taken from close to the Eustachian tube openings into the nasopharynx. The adenoids from patients with middle ear effusion contained significantly (P less than 0.05) more histamine than those with no effusion. However, in preliminary experiments, we could demonstrate no differences in the histamine secretory response of adenoids from SOM and non-SOM patients to anti-immunoglobulin E (anti-IgE), house dust mite antigen and calcium inophore A23187 in vitro. These results support the hypothesis of an inflammatory basis for SOM.

Adenoids↗
PubMed1984

Anaphylactic- and calcium-dependent generation of prostaglandin D2 (PGD2), thromboxane B2, and other cyclooxygenase products of arachidonic acid by dispersed human lung cells and relationship to histamine release.

Proteolytic digestion of human lung tissue dispersed a population of cells (HDLC) containing 1 to 8% mast cells but which were free from bronchial and vascular smooth muscle. Incubation of HDLC with anti-human IgE, which released a net 24.8 + 4.3% of mast cell-derived histamine, stimulated a 14-fold increase in the generation of PGD2, a seven-fold increase in TXB2, and less than a twofold increase in PGF2 alpha, immunoreactive PGE, (i-PGE) and 6-keto-PGF1 alpha. A similar profile of prostanoid release was observed when cells were challenged with epsilon-specific anti-IgE, indicating that the response was specific to the coupling of IgE Fc receptors. The calcium ionophore A23187 also released prostanoids from HDLC in approximately the same proportions as anti-IgE. This stimulus, however, released only 50% as much PGD2 per nanogram histamine than did IgE-dependent activation, thereby showing a fundamental difference in the mechanisms by which the two agents activate mast cells and liberate arachidonic acid for oxidative metabolism. In concentration-response and time course experiments, both secretory stimuli released prostanoids and histamine in parallel. After separation of lung cells by isopyknic centrifugation, challenge with anti-IgE or A23187 released PGD2 only from those fractions containing mast cells, the amount released corresponding closely to both the mast cell concentration and net histamine release. On pooling data from all experiments, the closest correlation was found between release of PGD2 and histamine when cells were stimulated with either anti-IgE (r = 0.813, p less than 0.001) or A23187 (r = 0.763, p less than 0.001), supporting a mast cell origin for PGD2. The release of other prostanoids in fractions not containing mast cells demonstrates that macrophages, monocytes, and lymphocytes have the capacity to generate TXB2, PGF2 alpha, and i-PGE both in the absence and presence of mast cells. Thus, although mast cells are likely to be the major source of PGD2 generated upon IgE-dependent stimulation of HDLC, other cells dispersed from lung tissue have the capacity to generate prostanoids directly after activation of their IgE-Fc receptors and, indirectly after the secretion of mast cell mediators.

Anaphylaxis↗
PubMed1983

The relationship between cyclic AMP changes and histamine release from basophil-rich human leucocytes.

Histamine release and changes in cyclic AMP levels induced by a variety of stimuli have been measured in isolated human leucocytes from a patient with 40-70% basophilia. Adenosine and sodium fluoride induced early monophasic rises in cyclic AMP which peaked at 1 min, but they did not release histamine. 2',5'-Dideoxyadenosine (DDA) caused a transient fall in cyclic AMP levels. Anti-IgE, polylysine and calcium ionophore A23187 induced a slow release of histamine commencing 2-5 min after addition of secretagogue. With polylysine and A23187, release was still proceeding 45 min after challenge. In contrast, the chemotactic peptide formyl-methionyl-leucyl-phenylalanine (f-met-leu-phe) induced a rapid secretion of histamine which was complete within 2 min. Anti-IgE induced a rapid monophasic rise in cyclic AMP which reached a maximum at 45 sec and was inhibited by pretreatment with DDA. Cyclic AMP rises induced by polylysine and f-met-leu-phe were kinetically similar but smaller in magnitude. A23187 caused a later rise in cyclic AMP which peaked 3 min after challenge. A high concentration (50 microM) of compound 48/80 induced a slow cytotoxic release of histamine which was not accompanied by changes in cyclic AMP levels. The inconsistent quantitative and kinetic relationships of histamine release and cyclic AMP production suggest that changes in cyclic AMP levels may not play a key role in the biochemical events leading to mediator secretion from human basophil leucocytes.

Adenosine↗
PubMed1983

The characteristics of inhibition of histamine release from human lung fragments by sodium cromoglycate, salbutamol and chlorpromazine.

1 Three drugs have been tested for activity against antigen-induced histamine release from passively sensitized human lung fragments after increasing periods of pre-incubation before challenge.2 After 30 s pre-incubation, sodium cromoglycate inhibited histamine release in the concentration range 0.2-200 muM, producing a maximum inhibition of 33.0%. As the pretreatment period was extended, tolerance developed in a dose-related manner, resulting in a 48.3% and 82.8% loss of activity of the 200 muM dose after 60 min and 19 h pre-incubation, respectively. Tolerance was independent of extracellular calcium and was poorly reversible. Lung tissue desensitized to cromoglycate was cross-tolerant to the related drug, bufrolin, but not to salbutamol or chlorpromazine.3 In acute studies, salbutamol (0.03-3.0 muM) produced dose-related inhibition of histamine release, with a maximum inhibition of 72.2%. The effect was blocked stereoselectively by 1 muM propranolol, suggesting that it occurred through an interaction with lung beta-adrenoceptors. Increasing the pre-incubation time with salbutamol from 30 s to 19 h did not produce tolerance. Inhibition produced by incubation with salbutamol for 19 h was totally prevented when propranolol was added at the beginning of the pre-incubation period, indicating that it resulted from stimulation of beta-receptors and not from a non-specific or toxic effect. However, studies of reversibility of effect through washing or late addition of propranolol did indicate some change in the nature of salbutamol inhibition with time.4 Chlorpromazine was a weak inhibitor of immunological histamine release. A 100 muM concentration was ineffective after 30 s pre-incubation but its activity increased with time. Pre-incubation of lung fragments with this concentration for 1 h or longer, or with a 1 mM dose for a shorter period, provoked histamine release in the absence of antigen. Effects of chlorpromazine were not reversed by washing.5 The different characteristics shown by sodium cromoglycate, salbutamol and chlorpromazine indicate that these drugs inhibit histamine release by interfering with the secretory mechanisms in different ways.

Albuterol↗
PubMed1983

Adenosine inhibits and potentiates IgE-dependent histamine release from human basophils by an A2-receptor mediated mechanism.

Adenosine added to human basophils before anti-IgE challenge inhibited histamine release, whereas addition after challenge potentiated release. Peak responses for the two effects occurred 15 min before and after challenge respectively. The effects of adenosine on histamine secretion were dose-related over concentration ranges of 1-100 microM for inhibition and 0.01-1 microM for potentiation. The capacity of adenosine to inhibit and potentiate histamine secretion was inversely related to the strength of immunological challenge. The ability of theophylline (50 microM) to inhibit and dipyridamole (1 microM) to enhance slightly adenosine-induced responses, and the differing pharmacological effect of 2',5'-dideoxyadenosine suggested that adenosine's effects on basophil histamine secretion were mediated by stimulation of cell surface adenosine receptors. The order of potency of adenosine and its analogues L- and D- N6-phenylisopropyladenosine (PIA) and 5'-N-ethylcarboxamideadenosine (NECA) in inhibiting and potentiating IgE-dependent histamine release from basophils indicated that both responses were mediated by stimulation of the adenosine A2-receptor subtype. The capacity of adenosine to cause a transient increase of cyclic AMP levels in 40-70% basophil-enriched leucocytes confirmed the association between stimulation of A2-receptors and activation of adenylate cyclase.

Adenosine↗
PubMed1983

Passive anaphylaxis in human lung fragments as a model for testing anti-allergic drugs: its variability and constraints.

Histamine release from human lung fragments, passively sensitized and challenged with antigen under standardized experimental conditions, varied between 0 and 41.2% (mean +/- SD 15.6 +/- 10.0%) in 89 experiments. Over 41 lungs, the mean coefficient of variation for release from 10 to 28 tissue replicates was 21.4% (range 7-44%). Sodium cromoglycate and chlorpromazine were both partial antagonists of histamine release producing, at best, 30-40% inhibition. The cromoglycate analogue, bufrolin, showed similar activity. There was considerable variation in the effects of these drugs both within and between experiments. Salbutamol was a more potent and more effective inhibitor of release but it, too, showed variability. Although theoretically a very appropriate model of allergic asthma, passive anaphylaxis in human lung fragments is quantitatively inconsistent and gives only a gross indication of drug efficacy.

Albuterol↗
PubMed1983

The effect of an anti-allergic, nasal decongestant combination ('Dimotapp') and sodium cromoglycate nose drops on the histamine content of adenoids, middle ear fluid and nasopharyngeal secretions of children with secretory otitis media.

Twenty-four children with secretory otitis media awaiting operation for removal of adenoids were studied to investigate the effects of an antihistamine/nasal decongestant combination ('Dimotapp') and sodium cromoglycate nasal drops on the histamine content of adenoids, middle ear fluid and nasopharyngeal secretions. The children were divided into three age and sex matched groups, one of which acted as a control, and received recommended therapeutic doses of either drug for 7 days immediately prior to operation. The results showed that total adenoid histamine content of both drug groups was significantly raised (p less than 0.05) when compared to the control group. Where present, neither 'Dimotapp' nor sodium cromoglycate had any effect on the mean free histamine in the middle ear fluid. In the sodium cromoglycate group the mean free histamine content of the nasopharyngeal secretions was significantly higher than in the control or 'Dimotapp' groups.

Adenoids↗