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Circulating concentrations of the mast cell-associated mediators, histamine and neutrophil chemotactic factor (NCF) of high molecular weight, were measured in atopic and nonatopic asthmatics after treadmill exercise. Elevations in the concentrations of both mediators accompanied the development of exercise-induced asthma (EIA). Normal individuals did not release mediators or develop bronchoconstriction after an identical exercise. The elaboration of mediators was not due to the onset of airflow obstruction, the postexercise basophilia, or the exercise task per se. A treadmill exercise undertaken while inhaling fully conditioned air inhibited EIA and NCF release; in contrast the same exercise undertaken while breathing cold, dry air elicited EIA and the production of mediators. This suggests that the stimulus for EIA and mediator release may be identical. Late-phase asthmatic reactions occur 3 to 9 hr after exercise in some asthmatics and are accompanied by the appearance of circulating NCF, as previously reported in allergen-induced late responses. In addition to the contribution of mediators to the spasmogenic reaction in EIA, mediators may contribute to bronchial inflammation by activating circulating leukocytes. There was a kinetic increase in the expression of neutrophil C3b receptors in EIA (+) asthmatics for up to 60 min after treadmill exercise. The enhancement of C3b receptors, as evidence of neutrophil activation, was preceded by release of NCF and reductions in peak expiratory flow rates. The prior administration of cromolyn inhibited EIA, NCF release, and enhancement of C3b receptors. These changes were not observed in EIA (−) asthmatics after an identical exercise task. These findings support the view that mediators are released in EIA and may play an important role in its pathogenesis.

To determine whether neutrophils are activated after exercise-induced asthma, increases in neutrophil complement receptor numbers (complement receptor enhancement) were measured by the rosette technique. In twelve asthmatic patients there was a time-dependent rise in complement receptor numbers for up to 60 min after treadmill exercise. This enhancement of complement receptors was preceded by a rise in plasma neutrophil chemotactic activity and a reduction in the peak expiratory flow rate. These changes could be inhibited by prior administration of disodium cromoglycate. The changes were not observed in seven asthmatic patients in whom asthma was not induced by an identical exercise task. Complement receptor enhancement was also observed in vitro when partially purified neutrophil chemotactic activity from a patient with exercise-induced asthma was incubated with normal neutrophils. These findings suggest that inflammatory cells are activated after exercise-induced asthma, possibly as a result of the release of neutrophil chemotactic activity and other mast-cell-associated mediators.

Two adults and 13 children with exercise-induced asthma had both immediate and late reductions in forced expiratory volume in one second (FEV1) after treadmill exercise. The late reactions developed 4 to 10 hours after exercise and in each instance were associated with wheezing or chest tightness (or both). Increases in neutrophil chemotactic activity, measured in the 2 adults and in 11 of the children, accompanied the reductions in FEV1 in all these subjects. In contrast, four other adults with only an immediate fall in FEV1 after exercise had only an initial elevation in neutrophil chemotactic activity, with no subsequent increase for the remaining 24-hour period. The agent responsible for the neutrophil chemotactic activity released during exercise-induced late reactions appeared to be identical to that released during immediate reactions. These observations suggest that some patients with exercise-induced asthma have late reactions that, as in the case of antigen-induced bronchoconstriction, are accompanied by the release of neutrophil chemotactic activity.

Four subjects with clinical histories of milk-induced asthma were studied (three allergic to cow's milk; one to soya milk). In each instance, skin prick tests, RAST (IgE and IgG4), the basophil histamine release, and serum precipitins, using appropriate milk extracts, were negative. After the ingestion of milk all the subjects developed a reproducible and dose-dependent increase in airflow limitation. Three patients (two allergic to cow's milk; one to soya milk) gave a characteristic immediate-type reaction, which was maximal at 30 min after challenge. The fourth individual developed an isolated late-phase response, with maximal airways obstruction 3 hr after ingesting milk. In the three subjects who gave an early reaction, wheezing was accompanied by an elevation in circulating neutrophil chemotactic activity (NCA). This was not observed in the individual with the isolated late reaction. By Sephacryl S-400 gel-filtration chromatography it was shown that NCA of the early reactions eluted with proteins having an estimated molecular weight of 600,000 daltons. The immediate asthmatic response in peak expiratory flow rate and the elevation in NCA were inhibited by the prior oral administration of either disodium cromoglycate (DSCG) or oral beclomethasone dipropionate (BDP). In contrast, DSCG had no effect on airways obstruction in the subject with the isolated late asthmatic response, although inhibition was achieved by BDP.