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Asthmatic patients have neutrophils that exhibit diminished responsiveness to adenosine
A M Sustiel1, B Joseph, R E Rocklin
1Department of Medicine, New England Medical Center Hospital, Tufts Medical School, Boston, Massachusetts.
Abstract:
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 x 10(5) PMN/5 min versus 1.38 +/- 0.35 at 2 x 10(-8) M fMLP and 3.81 +/- 0.68 nmol versus 2.04 +/- 0.45 nmol at 10(-7) M; p less than 0.01 for both). In contrast, the respiratory burst generated by two receptor-independent stimuli, the calcium ionophore A23187 and phorbol myristate acetate, 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 less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
Asthma patients show heightened neutrophil activation and impaired adenosine-induced suppression of superoxide production, suggesting abnormal inflammatory feedback mechanisms in asthma. This impacts neutrophil function and airway inflammation.
Area of Science:
- Immunology
- Respiratory Medicine
- Cell Biology
Background:
- Neutrophil activation in airways releases products contributing to asthma inflammation.
- Allergic mediators like adenosine may inhibit neutrophil function via feedback.
- Potential abnormalities in neutrophil activation and feedback exist in asthmatics.
Purpose of the Study:
- To test if neutrophil (PMN) activation and adenosine-induced feedback inhibition are abnormal in asthma.
- To compare superoxide production and adenosine's suppressive effects in asthmatics versus controls.
Main Methods:
- Matched pairs of 12 asthmatics and 12 controls were studied.
- Superoxide production by neutrophils stimulated with fMLP, A23187, and PMA was measured.
- Adenosine-induced suppression of fMLP-stimulated superoxide production was assessed.
Main Results:
- Asthmatic neutrophils produced significantly more superoxide in response to fMLP than controls.
- Superoxide production stimulated by A23187 and PMA was similar in both groups.
- 2-chloroadenosine inhibited fMLP-stimulated superoxide production less effectively in asthmatics (19.5%) compared to controls (55.6%).
Conclusions:
- Neutrophil activation by fMLP is enhanced in asthma.
- Adenosine-mediated feedback inhibition of neutrophil superoxide production is impaired in asthma.
- These findings suggest abnormal inflammatory feedback mechanisms in asthmatic airways.
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