Activation of neutrophils (PMN) within the airways results in the secretion of a number of products such as reduced oxygen metabolites that could contribute to the inflammatory response associated with asthma. However, mediators of allergy, such as histamine, prostaglandin E2 (PGE2), isoproterenol, and adenosine, may serve to mitigate this inflammation through feedback inhibition of neutrophil function. To test the hypothesis that PMN activation and feedback inhibition mechanisms may be abnormal in asthmatics, we compared both superoxide production and adenosine-induced suppression of superoxide production in 12 matched pairs of asthmatics and control subjects. PMN obtained from asthmatic patients generated significantly more superoxide in response to f-met-leu-phe (fMLP) than controls (2.94 ± 55 nmol/5 × 105 PMN/5 min versus 1.38 ± 0.35 at 2 × 10−8 M fMLP and 3.81 ± 0.68 nmol versus 2.04 ± 0.45 nmol at 10−7 M; p < 0.01 for both). In contrast, the respiratory burst generated by two receptor-independent stimuli, the calcium ionophore A23187 and phorbol myristate actetate, was equivalent between control and asthmatic subjects. At 10−6 M, 2-chloroadenosine induced a 19.5 ± 5.1% inhibition of fMLP-stimulated superoxide production in PMN from patients with asthma as compared to 55.6 ± 24.6% inhibition in PMN from control subjects (p < 0.01). Decreased responsiveness to adenosine reflects both a shift in the dose-response curve (IC50 shift from 1.98 × 10−6 M in normal subjects to 5.96 × 10−6 M in asthmatics; p < 0.02) and a decline in the maximal suppression observed with adenosine (52.9 ± 6.1% in asthmatic versus 64.5 ± 5.8 with normal subjects). A smaller defect in PMN suppression was observed in the presence of PGE2, which was significant only at 10−7 M PGE2 (26.0 ± 7.6% inhibition with asthmatics versus 35.2 ± 9.7%; p < 0.05). There were no significant differences observed with the suppression mediated by isoproterenol. The failure to respond to adenosine did not reflect a generalized decreased suppressibility of primed neutrophils. Priming of PMN with either cytochalasin B or endotoxin resulted in no differences in the amount of suppression observed after exposure to adenosine. Finally, adenosine deaminase produced a significantly greater enhancement of the fMLP-mediated respiratory burst in normal subjects (95.4%) as compared to asthmatics (60.5%) (p < 0.05). In summary, there is a priming of PMN obtained from asthmatics to fMLP and decreased responsiveness to regulatory signals provided by adenosine. Activation of PMN and a failure to respond to negative signals may be responsible, in part, for the severity and persistence of inflammation in the airways of asthmatics.
