Effect of theophylline and adenosine on eosinophil function.
Eosinophils may play a critical role in asthma and bronchial hyperresponsiveness, yet the effect of theophylline on their function is not certain. We have examined the effects of theophylline on opsonized zymosan-induced superoxide anion (O2-) release from guinea pig eosinophils harvested from the peritoneal cavity and from human eosinophils obtained by differential centrifugation of blood from patients with peripheral eosinophilia. Theophylline at high concentration (10(-3) M) inhibited O2- release by 27.6 +/- 9.4% (mean +/- SEM, p less than 0.05), whereas at clinically relevant concentrations (10(-6) and 10(-5) M), it significantly potentiated this by 26.8 +/- 9.9% (p less than 0.05) and 36.9 +/- 6.3% (p less than 0.01), respectively. 8-phenyltheophylline (10(-7) to 10(-3) M), which like theophylline inhibits adenosine receptors but does not inhibit phosphodiesterase activity, produced potentiation at all concentrations. Preincubation of eosinophils with adenosine deaminase (0.1 U/ml) enhanced O2- release by 72.4 +/- 15.2% (p less than 0.01), whereas addition of adenosine (3 x 10(-8) to 10(-6) M) reversed the potentiation induced by theophylline (10(-5) M) in a concentration-dependent manner. Inhibition was greater with the A2-selective analog N-ethylcarboxamide adenosine than the A1-selective analog phenylisopropyladenosine, suggesting that A2-receptors are involved. In human eosinophils we have demonstrated a similar effect of theophylline and adenosine on O2- release. Our results indicate that therapeutic concentrations of theophylline may potentiate eosinophil activation in vivo by competing with circulating adenosine for eosinophil A2-receptors. This would be consistent with the lack of effect of theophylline on bronchial hyperresponsiveness, which may be related to eosinophilic inflammation.
Yukawa
T
T
Department of Thoracic Medicine, Brompton Hospital, London, UK.
Kroegel
C
C
Chanez
P
P
Dent
G
G
Ukena
D
D
Chung
K F
KF
Barnes
P J
PJ
D000241:Adenosine / Q000494:pharmacology*; D000243:Adenosine Deaminase / Q000494:pharmacology; D000818:Animals; D000838:Anions; D004802:Eosinophilia / Q000503:physiopathology; D004804:Eosinophils / Q000187:drug effects* / Q000502:physiology / Q000503:physiopathology; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D009895:Opsonin Proteins; D011983:Receptors, Purinergic / Q000502:physiology; D013268:Stimulation, Chemical; D013481:Superoxides / Q000378:metabolism; D013806:Theophylline / Q000031:analogs & derivatives / Q000494:pharmacology*; D015054:Zymosan / Q000494:pharmacology
D000838:Anions; D009895:Opsonin Proteins; D011983:Receptors, Purinergic; D013481:Superoxides; D015054:Zymosan; D013806:Theophylline; C028322:8-phenyltheophylline; D000243:Adenosine Deaminase; D000241:Adenosine