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Biomedical subjects

A B Kay

Publications and source records attributed to A B Kay.

At least 343 records · Page 19Linked to original sources
PubMed1983

Mediators of hypersensitivity and inflammatory cells in the pathogenesis of bronchial asthma.

The events which lead to airway narrowing in bronchial asthma are complex. There is little doubt that mast cell-derived pharmacological agents are involved, at least in part, in the initiation of the asthmatic response. However, the inflammatory response which follows mast cell activation might have more relevance to the daily pattern of asthma than the direct effects of mediators on bronchial tissue. Although the IgE mediated release of mediators from sensitized mast cells seems to play a role in pathogenesis in some individuals for some of the time, there is now increasing awareness that mast cells are also triggered by a number of non-immunological stimuli such as exercise/cold air, infection and agents which activate the complement system. Mast cell mediators are either pre-formed within granules or generated from membrane-bound phospholipids. The pre-formed mediators include histamine, various chemotactic peptides including ECF-A and the high molecular weight neutrophil chemotactic factor (NCF), proteases, glycosidases, and the heparin proteoglycan. The membrane-derived agents include the lipoxygenase products (e.g. LTB4 and the "SRS-A" leukotrienes-LTC4/D4/E4), prostaglandins and thromboxane in addition to the PAF-ace-tether (AGEPC). The mediators are diverse both in chemical composition and modes of actions. However, many of the pathological features of bronchial asthma can be explained on the basis of their recognised actions. These can be summarised as follows. Bronchial smooth muscle constriction (histamine, LTC4, LTD4, LTE4, PGF2 alfa, PGD2 and PAF); mucosal oedema (increased permeability--histamine, LTC4, LTD4 and PAF; vasodilation--PGD2, PGE2); mucous plugging (histamine, mono-HETEs and LTC4); inflammatory cell infiltrate (NCF, ECF-A peptides, HETEs, LTB4 and PAF); desquamation of epithelium (proteases, glycosidases, together with lysosomal enzymes, and basic proteins derived from neutrophils and eosinophils). It is likely that mild, easily reversible, episodic asthma is due largely to bronchial smooth muscle contraction whereas the late sustained response is more indicative of an inflammatory response, and dependent on the infiltration of neutrophils and eosinophils as the result of mediators which recruit and activate leucocytes. Much of the evidence for this is based on the demonstration that NCF concentrations in the serum are elevated during early and late phase, antigen- and exercise-induced asthma. Moderate to severe asthma is likely to be largely dependent on a subacute/chronic inflammation of the bronchi with eosinophils and mononuclear cells being prominent.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1982

Neutrophil chemotactic activity in antigen-induced late asthmatic reactions.

Nine patients with bronchial asthma who had early and late falls in forced expiratory volume in one second (FEV1)(10 minutes and six hours, respectively) after inhalational challenge with specific antigens were studied for the presence of circulating neutrophil chemotactic activity (NCA). NCA was detected during both the early and the late asthmatic responses; the time course of appearance of NCA in the circulation paralleled that of the falls in FEV1. In contrast, five patients with asthma who had early reactions had only a single early peak of NCA, with no further rise for up to 24 hours. The NCA detected during early and late reactions eluted with macromolecules of an estimated molecular weight greater than 500,000 daltons when applied separately to columns of Sephadex G-200. Since high-molecular-weight NCA is believed to be associated with mast cells, these observations support the view that mediators of hypersensitivity are released in both the late and the early asthmatic responses.

Adult↗
PubMed1982

Exercise-induced release of histamine and neutrophil chemotactic factor in atopic asthmatics.

Concentrations of plasma histamine and serum neutrophil chemotactic factor (NCF) were measured in seven atopic asthmatics who developed exercise-induced asthma (EIA) after a treadmill task. The results were compared with those obtained after inhalation of specific antigen or methacholine. Plasma histamine concentrations were measured with a novel double-isotope radiometric assay, and NCF was identified by its elution in the void volume fractions of Sephadex G-200 and as a single peak of activity at approximately 0.20 molar NaCl after anion exchange chromatography on diethylaminoethyl-Sephacel (pH 7.8). After exercise or antigen challenge, the time courses of appearance of both mediators were virtually identical and accompanied the increase in airways obstruction. There was a statistically significant correlation between the concentrations of histamine or NCF and the magnitude of airflow obstruction after exercise and antigen challenge. This suggested that there may be a direct association between mediator release and EIA or antigen-induced bronchoconstriction. In contrast, there were no significant elevations in circulating histamine and NCF after inhalation of methacholine, at concentrations giving a fall in FEV1 comparable to that induced by exercise or antigen. The prior administration of cromolyn to three asthmatics inhibited both their EIA and the release of histamine and NCF. When four asthmatics were exercised for periods of 1, 3, and 6 min, the release of NCF and fall in peak expiratory flow rate were directly related to the duration of the exercise. The rise of NCF activity in subjects with EIA was fivefold greater than that observed in asthmatics who did not experience airways obstruction when subjected to the same exercise task. These results provide further evidence that mediators of hypersensitivity are released during EIA.

Adolescent↗
PubMed1982

Bronchial asthma and the neutrophil chemotactic factor.

Neutrophil chemotactic factor (NCF) is a slight acidic macromolecule which is released into the circulation of asthmatic individuals following antigen provocation and an exercise task. It also appears in late asthmatic reactions with a time course of appearance which precedes the second fall in FEV1. The release of NCF was inhibited by prior administration of disodium cromoglycate (DSCG) suggesting its possible mast cell origin.

Airway Obstruction↗
PubMed1982

Identification and partial characterization of an exercise-induced neutrophil chemotactic factor in bronchial asthma.

A heat-stable neutrophil chemotactic factor (NCF) has been identified in the serum of 13 atopic asthmatic subjects after treadmill exercise. Peak activity was detected at 10 min and returned to prechallenge values by 1 h. No NCF activity was detected in the sera of three nonasthmatic atopic or four normal nonatopic individuals performing the same task. NCF produced by exercise (NCFEX) had a similar time-course of release to NCF provoked by specific antigen (NCFAG). The appearance of circulating NCFEX and NCFAG closely paralleled the fall in peak expiratory flow rate/forced expiratory volume in 1 s (PEFR/FEV1). Histamine challenge in atopic asthmatics at concentrations giving a comparable change in PEFR/FEV1 to that evoked by exercise or inhaled antigen was not associated with the appearance of circulating NCF. In seven subjects NCFEX release was inhibited by prior administration of disodium cromoglycate. NCFEX and NCFAG eluted as single peaks of activity when applied separately to columns of Sephadex G-200, and both were an estimated 750,000 daltons. NCFEX and NCFAG also eluted as single peaks of activity, at between 0.15 and 0.30 M NaCl, following anion exchange chromatography on DEAE-Sephacel (pH 7.8). The isoelectric points of NCFEX and NCFAG were virtually identical (between pH 6.0 and 6.5) as determined by chromatofocusing on Polybuffer Exchanger 94. The activities of NCFEX and NCFAG were substantially reduced, in both a time- and dose-dependent fashion, after incubation with trypsin and chymotrypsin. Partially purified NCFEX and NCFAG promoted both stimulated random migration (chemokinesis) as well as directional migration (chemotaxis). These experiments indicate that NCFEX and NCFAG might be identical substances and raise the possibility that mediators by hypersensitivity are released during exercise-induced asthma in atopic subjects.

Adolescent↗
PubMed1982

Complement receptor enhancement and chemotaxis of human neutrophils and eosinophils by leukotrienes and other lipoxygenase products.

The lipoxygenase products of arachidonic acid, 5-HPETE, 5-HETE, LTB4, LTC4 and LTD4, were examined for their capacity to enhance the expression of complement (C3b) receptors and to evoke chemotaxis of human neutrophils and eosinophils. With the exception of LTD4 all gave enhancement of C3b receptors. LTB4 and LTC4 enhanced over the concentration range 10(-7) to 10(-11) moles/l, and 5-HETE and 5-HPETE from 5 X 10(-6) to 5 X 10(-10) moles/l. The rank order of activity, as assessed by the magnitude of enhancement, was LTB4 (concentration for maximal effect = 10(-7) moles/l) greater than 5-HETE (5 X 10(-7)) greater than 5-HPETE (5 X 10(-6)) greater than LTC4 (10(-9)). High dose inhibition was observed with LTC4 and 5-HETE. Chemotaxis experiments performed in parallel over the same concentration ranges indicated that neither neutrophils nor eosinophils migrated towards LTC4 or LTD4. However, LTB4 evoked chemotaxis with a linear dose response from 10(-9) to 10(-7) moles/l and 5-HPETE and 5-HETE from 5 X 10(-8) to 5 X 10(-6) moles/l. At 10(-7) moles/l LTB4 was approximately 6 and 8 X more potent in chemotaxis than 5-HPETE and 5-HETE respectively. In general, complement receptor enhancement and chemotaxis of eosinophils were similar to that observed with neutrophils and did not vary with the patient source.

Arachidonate Lipoxygenases↗
PubMed1982

Identification of leukotrienes in the sputum of patients with cystic fibrosis.

Sputum extracts from 16 of 25 adult patients with CF produced a slow, sustained contraction of isolated guinea pig ileum which was partially inhibitable by the SRS-A antagonist FPL 55712. Following progressive purification and HPLC, the major ileum-contracting substance was identified as LTD4. LTC4 was also present but in smaller amounts. The sputum contained other SRS-A-like activity which was not inhibited by FPL 55712; this substance was of a smaller molecular size than LTD4. The presence of LTB4 was also established using HPLC and an assay of neutrophil chemotaxis. These studies raise the possibility that leukotrienes and other lipoxygenase products may contribute to the progressive lung disease characteristics of CF.

Adolescent↗
PubMed1981

Corticosteroid resistance in chronic asthma.

Fifty-eight patients with chronic asthma in whom airflow obstruction was relieved by bronchodilator aerosols but not by oral corticosteroids were compared with 58 other chronic asthmatics who responded equally well to both treatments. The two groups were matched for age and sex. The only significant clinical differences between the two groups were that in the "corticosteroid-resistant" patients there was a more frequent family history of asthma and a longer duration of symptoms. Resistant patients also had a relatively lower peak expiratory flow rate in the morning than later in the day and a greater degree of bronchial reactivity to methacholine. Such features, however, may not be specific criteria of corticosteroid resistance since they were also observed in untreated asthmatics who subsequently responded well to corticosteroids. The failure of prednisolone to inhibit a monocyte-mediated bronchial reaction may explain why some chronic asthmatics do not respond to corticosteroids. Patients with corticosteroid-resistant asthma should be recognised at an early stage so that regular treatment with oral corticosteroids may be withdrawn. Failure to do this results in needless exposure to the risk of developing serious side effects.

Adrenal Cortex Hormones↗