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Biomedical subjects

A B Kay

Publications and source records attributed to A B Kay.

At least 289 records · Page 16Linked to original sources
PubMed1986

Enhanced granulocyte cytotoxicity by mediators derived from anti-IgE-stimulated human leucocytes.

Basophil-containing leucocyte fractions stimulated with an anti-human IgE, F(ab')2, generated histamine and the leukotrienes LTB4 and LTC4 with significant correlations between LTB4 and histamine (P less than 0.01; n = 26) and LTC4 and histamine release (P less than 0.001; n = 29) in the cell-free supernatants (SN). SN from these anti-IgE-treated cells enhanced the cytotoxicity of eosinophils and neutrophils (against complement-coated schistosomula of Schistosoma mansoni) in vitro. When SN were fractionated by reverse phase-high performance liquid chromatography (RP-HPLC), the enhancing activity for neutrophils was almost totally confined to fractions having LTB4 immunoreactivity (co-eluting as a single peak with the synthetic LTB4 marker). In contrast, the LTB4-containing fraction had minimal effects on eosinophil cytotoxicity, whereas synthetic histamine gave comparable enhancement to the unfractionated SN. The generation of LTs (but not histamine), as well as enhanced neutrophil cytotoxicity from basophil-containing leucocytes by anti-IgE treatment, was maximally inhibited by the 5-lipoxygenase inhibitors U-60, 257 and BW755C. Conversely, the cyclooxygenase inhibitor indomethacin did not significantly affect LT release, nor did it affect the subsequent cytotoxicity enhancing activity of SN from such cells. These results indicate that LTB4 and LTC4 are released from basophils, together with histamine, by IgE-dependent mechanisms, LTB4 enhances the cytotoxicity of bystander neutrophils, and histamine (and to a lesser extent, LTB4) augments eosinophil cytotoxicity.

Basophils↗
PubMed1986

The cells causing airway inflammation.

Inflammation is the response of living tissue to injury and serves to restore the affected area to its original function. To a large extent the nature of the injury (e.g. micro-organisms, parasites, trauma or allergy) will determine the pattern of cell infiltration, as will the chronicity (the balance between the persistence of the insult and repair). Neutrophils and macrophages are the principal cells of acute inflammation, with eosinophils also participating in special circumstances, e.g. allergic and helminthic parasitic processes. In chronic inflammation, macrophages, lymphocytes and plasma cells are present in large numbers; again, the predominance of one cell type or other depends on the nature of the injury. Large numbers of basophils are also observed in certain delayed-in-time chronic processes but their role in lung pathology is uncertain. Similarly, platelets have potential for lung injury and their role in certain inflammatory states is established, although their participation in lung injury is still debated. The mast cell must also be considered since it is the repository for mediators which cause increased vascular permeability and has the potential for eliciting, and possibly sustaining, some of the white cell mediated events associated with the inflammatory process. Inflammatory cells cause injury by secretion of inflammatory mediators derived from their membranes (principally prostaglandins, leukotrienes and PAF-acether) and by elaboration of their granule constituents. Neutrophils have primary and secondary granules which contain an array of proteases and other enzymes, whereas eosinophils possess large amounts of unique basic proteins which have potential for direct cytotoxicity, i.e. of mucosal epithelium.(ABSTRACT TRUNCATED AT 250 WORDS)

Basophils↗
PubMed1986

The effects of eosinophil activating factor on IgG-dependent sulphidopeptide leukotriene generation by human eosinophils.

Eosinophil activating factor (EAF) is a 40 kD protein released from cultured, unstimulated human monocytes which enhances the IgG-dependent eosinophil-mediated cytotoxicity of helminthic larvae. We have recently shown that eosinophils elaborate substantial quantities of leukotriene C4 (LTC4) during incubation with IgG-coated particles and now report that EAF, partially purified by sequential chromatography on Sephacryl S-200 and DEAE-cellulose, enhanced this IgG-dependent LTC4 production by human eosinophils in a dose- and time-dependent fashion. LTC4 production by normal density eosinophils, separated on discontinuous metrizamide gradients, was significantly increased after incubation with several dilutions of EAF (P less than 0.05), although an increase was not seen with low density cells. The enhancement was similar in degree to that seen when normal density eosinophils were activated with the bacterial analogue, f-met-leu-phe (fMLP). EAF produced a time-dependent increase in LTC4 which was significantly greater (P less than 0.01) than the control. Sulphidopeptide leukotriene (LT) generation was validated by reverse phase high pressure liquid chromatography (RP-HPLC). These results indicate that there is a firm association between monocytes, eosinophils and LTC4; an observation which may be of relevance to mechanisms in chronic asthma and related disorders, and in immune reactions against migrating helminthic larvae.

Dose-Response Relationship, Drug↗
PubMed1986

Binding of immunoglobulin classes and subclasses to human neutrophils and eosinophils.

A comparative study of membrane expression of immunoglobin (Fc) receptors on human eosinophils and neutrophils has been undertaken using human IgG-1, IgG-2, IgG-3, IgG-4, IgA-1, IgA-2, IgM, IgD and IgE myeloma proteins. Sheep erythrocytes (E) coated with either human IgG-1, IgG-2, IgG-3 or IgG-4 myeloma proteins formed rosettes with human neutrophils and eosinophils. Proportionally more (1 1/2-2 times) rosettes were observed with neutrophils compared to eosinophils. In contrast, E-IgE bound to eosinophils (but not to neutrophils) to a degree that was comparable to E-IgG-1. Although IgG and IgE rosettes were inhibited by aggregates prepared from their corresponding myeloma protein there was no evidence that eosinophils and neutrophils have distinct receptors for IgG subclasses. Cells from four patients with hypereosinophilia were separated on density (metrizamide) gradients. The percentages of E-IgG-1 and E-IgE rosettes with normal- and light-density eosinophils were similar. Neutrophils, but not eosinophils, also bound significantly more E-IgA-1 and E-IgA-2 than the E-human albumin (E-Alb) control. In contrast, neutrophil and eosinophil rosette formation with E-IgM and E-IgD was not significantly different from E-Alb or E alone. These experiments indicate that human neutrophils and eosinophils bind homologous IgG subclass myeloma proteins, eosinophils, but not neutrophils, bind E-IgE with a similar avidity to that observed with E-IgG1, neutrophils, but not eosinophils, readily express demonstrable receptors for IgA-1 and IgA-2 and neither neutrophils nor eosinophils form E-IgM or E-IgD rosettes in greater numbers than the E-Alb controls.

Dose-Response Relationship, Immunologic↗
PubMed1985

Nedocromil, a mucosal and connective tissue mast cell stabilizer, inhibits exercise-induced asthma.

Nedocromil, the disodium salt of a pyranoquinoline dicarboxylic acid, has a similar profile of activity to disodium cromoglycate (DSCG) but appears to be more active in stabilizing mucosal-type mast cells. In a double-blind placebo-controlled trial nedocromil (2 mg) was given by inhalation to eight asthmatic patients prior to a treadmill exercise task. There was a significant reduction in the fall in FEV1 (P less than 0.01) and FVC (P less than 0.05) after nedocromil when compared to placebo. This study indicates that nedocromil might be an effective anti-asthma agent and in addition may help define the role of the mucosal mast cell.

Adolescent↗
PubMed1985

Activation of neutrophils and monocytes after allergen- and histamine-induced bronchoconstriction.

To determine whether neutrophils and monocytes are activated after allergen-induced asthma, changes in the expression of complement (C3b) receptors were measured by use of the rosette technique. There was a time-dependent increase in the percentages of neutrophil and monocyte rosettes in 13 asthmatic patients for up to 60 min after allergen-inhalation challenge. This was preceded by elevations in the concentrations of serum neutrophil chemotactic activity and reductions in the FEV1. These changes were not observed in seven asthmatic patients who had histamine-induced bronchoconstriction. The present findings support the view that inflammatory cells are activated after allergen-induced asthma and that this may be the result of the release of mast cell-associated mediators rather than the consequence of bronchoconstriction per se.

Adult↗
PubMed1985

The effect of corticosteroids on monocyte and neutrophil activation in bronchial asthma.

The expression of IgG (Fc) receptor (FcR) and complement receptor (CR) on peripheral blood monocytes and neutrophils was determined by the rosette technique in patients with asthma receiving different forms of treatment. In 31 patients taking inhaled therapy (i.e., bronchodilators alone or in combination with inhaled corticosteroids), monocyte FcR (48.19 +/- 1.24%, mean +/- SEM) and complement (66.54 +/- 1.09%) rosettes were significantly higher (FcR p less than 0.001, CR p less than 0.001) than in the 17 healthy, normal control subjects (FcR 37.94 +/- 0.82%, CR 59.7 +/- 0.98%). These increases in the percent rosettes between the two groups were observed even when a wide concentration range of IgG or complement was used to coat the red cells. No significant differences in monocyte receptor expression were observed between those patients being treated with bronchodilators alone or patients being treated in combination with inhaled corticosteroids. In 19 patients with asthma receiving oral corticosteroids, the mean monocyte FcR (38.21 +/- 1.73%) and CR (52.78 +/- 2.09%) were significantly reduced when these patients were compared with those patients receiving inhaled therapy alone (FcR p less than 0.001, CR p less than 0.001), and there was a significant inverse correlation between the percent rosettes and the dose of prednisolone. Neutrophil CR (51.32 +/- 1.30%, p less than 0.05) but not FcR expression (24.7 +/- 0.80%) was significantly increased when these were compared with those of control subjects (FcR 24.7 +/- 0.60%, CR 47.11 +/- 0.86%), and both neutrophil FcR and CR expression was significantly reduced (FcR p less than 0.01, CR p less than 0.001) in those patients with asthma receiving oral corticosteroids. (ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1985

Inhibition of leukotriene C4 and B4 generation by human eosinophils and neutrophils with the lipoxygenase pathway inhibitors U60257 and BW755C.

Human eosinophils and neutrophils have the capacity to generate leukotriene C4 (LTC4) and leukotriene B4 (LTB4) respectively when stimulated by calcium ionophore A23187. Leukotriene production by mixtures of these cell types was measured by radioimmunoassay for LTC4 and LTB4, and the specificities of the assays determined by assessing cross-reactivities with a number of other arachidonic acid metabolites. The IC50S for LTC4 and LTB4 in their respective assays were 1.76 +/- 0.04 nmol and 3.00 +/- 0.08 nmol. Cross-reactivity for anti-LTC4 was shown by leukotriene D4 (LTD4) (70%) and leukotriene E4 (LTE4) (8%), when compared to LTC4, whereas in the radioimmunoassay for LTB4, only the 5(S), 12(R) 6-trans isomer of LTB4 showed appreciable interaction (12%). LTC4 production by eosinophil enriched cell fractions obtained from metrizamide gradients was inhibited in a dose-dependent fashion by the prostacyclin analogue, 6,9-deepoxy-6,9-phenylimino-delta 6,8-prostaglandin I, (U60257) and by 3-amino-1-(3-trifluoromethyl phenyl)-2-pyrazole (BW755C). The ID50 values for U60257 and BW755C were 2 X 10(-6) and 5 X 10(-6) M respectively. This demonstration of LTC4 production by human eosinophils, which are known to be important cells in clinical asthma, provides an in vitro model to assess 5-lipoxygenase inhibitors in human tissue.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1985

Eosinophils, bronchial hyperreactivity and late-phase asthmatic reactions.

We have measured airways reactivity (methacholine PC20) and blood eosinophils in eleven asthmatics with allergen-induced late-phase reactions. Before challenge there was a significant (P less than 0.05) inverse correlation between blood eosinophils and the methacholine PC20. After allergen inhalation eosinophil counts were significantly (P less than 0.01) elevated at 24 hr. These increases in blood eosinophil counts were not observed in patients who developed single early responses. The magnitude of the changes in eosinophil counts (24 hr minus pre-challenge values) also correlated with the baseline methacholine PC20 (P less than 0.01) in the late-phase responders. These observations suggest that there may be a direct association between eosinophils and airway reactivity in subjects who develop late-phase asthmatic reactions.

Allergens↗
PubMed1985

Evidence for haemoglobins as common allergenic determinants in IgE-mediated hypersensitivity to chironomids (non-biting midges).

Chironomids (non-biting midges) are known to cause IgE-mediated hypersensitivity in man. This study compares the cross-reactivity between the chironomid midge Cladotanytarsus lewisi ('green nimitti'), a widespread cause of allergy in the Sudan and Chironomus riparius (= thummi, CTT) where larvae are used as pet fish food and where haemoglobins were previously shown to be major allergens. As with C. riparius, immature forms of C. lewisi also contain allergenic material since skin test responses to larval, pupal and adult extracts were obtained in Sudanese individuals. Crossed radioimmunoelectrophoresis of the C. lewisi larval and pupal extracts indicate that they contain a higher proportion of the allergenic fractions than adults. Further evidence of common allergen determinants between C. lewisi and C. riparius were obtained by the demonstration of positive skin-prick tests, in Sudanese patients, to extracts of larval, adult and isolated haemoglobin extracts of C. riparius. Cross-reactivity between C. lewisi and C. riparius was also demonstrable by RAST inhibition studies. A dose-dependent inhibition was observed using both the C. lewisi adult midge RAST and the C. riparius haemoglobin RAST, the two respective antigens, and sera from individuals hypersensitive to either C. lewisi or C. riparius. Due to the immunological cross-reactivity found between these distantly related species, we conclude that chironomids should be seen as significant environmental and occupational allergens.

Allergens↗
PubMed1985

Allergen-induced release of sulphidopeptide leukotrienes (SRS-A) and LTB4 in allergic rhinitis.

Leukotrienes are a recently discovered group of arachidonic acid-derived lipid mediators. Using radioimmunoassay and high pressure liquid chromatography (HPLC), we have identified the SRS-A sulphidopeptide leukotrienes (LTC4, LTD4 and LTE4) in nasal washings from patients with allergic rhinitis who underwent nasal challenge with specific allergen. Smaller, but significant, amounts of LTB4 were also detected. The concentrations of nasal leukotrienes were directly related to the dose of allergen, and were recovered in washings in a time-dependent fashion after challenge. When the patients were subjected to methacholine nasal challenge on a control day, we found only negligible amounts of either the sulphidopeptide leukotrienes or LTB4. These findings support the view that LTC4, LTD4 and LTE4 might contribute to the pathogenesis of allergic rhinitis as a result of their recognized effects on mucous hypersecretion and vasopermeability, and that the potent chemoattractant LTB4 might be involved in the subsequent infiltration of inflammatory cells.

Adult↗
PubMed1985

Mediators of hypersensitivity and "fog"-induced asthma.

Seven asthmatic and five normal subjects inhaled increasing amounts of nebulized water ("fog"). Neutrophil chemotactic activity (NCA), histamine and FEV1 measurements were undertaken before and at time intervals after challenge. In asthmatics, the mean maximal reduction in FEV1 (+/- 1 SD) was 46.6% +/- 11.5; whereas, in normal subjects, the reductions were less than 20% of pre-challenge values after the inhalation of 33 ml of water. There were no significant differences in the pre-challenge values for NCA between the asthmatics and the normal controls. When the highest values for NCA during the 30 min after challenge in the asthmatics were compared with controls there was a significant increase (P less than 0.02). The percentage change in NCA was also significantly greater in the asthmatics compared with the controls at 10 min after challenge (P less than 0.05). Fog-induced NCA was shown to be associated with proteins with approximate molecular weight of 600,000 daltons (as assessed by gel filtration chromatography on Sephacryl-S400). There was an increase in plasma histamine in the asthmatics after challenge but this was not significantly greater than the controls. These findings support the view that mediators might be involved in fog-induced asthma, possibly as a result of mast cell degranulation by "osmotic shock".

Adult↗
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↗