title: Effect of theophylline and adenosine on eosinophil function.
abstract: 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.
authors.affiliation: Department of Thoracic Medicine, Brompton Hospital, London, UK.
authors.forename: T
authors.initials: T
authors.lastname: Yukawa
authors.forename: C
authors.initials: C
authors.lastname: Kroegel
authors.forename: P
authors.initials: P
authors.lastname: Chanez
authors.forename: G
authors.initials: G
authors.lastname: Dent
authors.forename: D
authors.initials: D
authors.lastname: Ukena
authors.forename: K F
authors.initials: KF
authors.lastname: Chung
authors.forename: P J
authors.initials: PJ
authors.lastname: Barnes
mesh_terms: 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
chemical_list: D000838:Anions; D009895:Opsonin Proteins; D011983:Receptors, Purinergic; D013481:Superoxides; D015054:Zymosan; D013806:Theophylline; C028322:8-phenyltheophylline; D000243:Adenosine Deaminase; D000241:Adenosine