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.

[1]  A. Wardlaw,et al.  Eosinophils and mast cells in bronchoalveolar lavage in subjects with mild asthma. Relationship to bronchial hyperreactivity. , 1988, The American review of respiratory disease.

[2]  C. Salome,et al.  Inhaled corticosteroids reduce the severity of bronchial hyperresponsiveness in asthma but oral theophylline does not. , 1987, The American review of respiratory disease.

[3]  J. Daly,et al.  Definition of subclasses of adenosine receptors associated with adenylate cyclase: interaction of adenosine analogs with inhibitory A1 receptors and stimulatory A2 receptors. , 1987, Canadian journal of physiology and pharmacology.

[4]  G. Gleich,et al.  The eosinophil and the pathophysiology of asthma. , 1986, The Journal of allergy and clinical immunology.

[5]  M. Peters,et al.  Increased numbers of hypodense eosinophils in the blood of patients with bronchial asthma. , 1985, The American review of respiratory disease.

[6]  R. Pauwels,et al.  The effect of theophylline and enprofylline on allergen-induced bronchoconstriction. , 1985, The Journal of allergy and clinical immunology.

[7]  S. Durham,et al.  Eosinophils, bronchial hyperreactivity and late‐phase asthmatic reactions , 1985, Clinical allergy.

[8]  S. B. Kramer,et al.  Adenosine; a physiologic modulator of superoxide anion generation by human neutrophils. Adenosine acts via an A2 receptor on human neutrophils. , 1985, Journal of immunology.

[9]  H. Sluiter,et al.  Bronchoalveolar eosinophilia during allergen-induced late asthmatic reactions. , 1985, The American review of respiratory disease.

[10]  K. Masuyama,et al.  Direct interaction of guinea pig eosinophils and adrenergic agents. , 1985, International archives of allergy and applied immunology.

[11]  A. Jesaitis,et al.  Membrane‐cytoskeleton interactions and the regulation of chemotactic peptide‐induced activation of human granulocytes: The effects of dihydrocytochalasin B , 1985, Journal of cellular biochemistry.

[12]  S. B. Kramer,et al.  Adenosine: a physiological modulator of superoxide anion generation by human neutrophils , 1983, The Journal of experimental medicine.

[13]  C. Brown,et al.  Adenosine A1 receptor mediated inhibition of nerve stimulation-induced contractions of the rabbit portal vein. , 1983, European journal of pharmacology.

[14]  R. F. Bruns,et al.  Adenosine receptor binding: structure-activity analysis generates extremely potent xanthine antagonists. , 1983, Proceedings of the National Academy of Sciences of the United States of America.

[15]  R. Berne,et al.  Extracellular Action of Adenosine and the Antagonism by Aminophylline on the Atrioventricular Conduction of Isolated Perfused Guinea Pig and Rat Hearts , 1982, Circulation research.

[16]  R. Snyderman,et al.  Transmethylation reactions regulate affinity and functional activity of chemotactic factor receptors on macrophages , 1982, Cell.

[17]  J. Whitin,et al.  Opsonized Zymosan-Stimulated Granulocytes-Activation and Activity of the Superoxide-Generating System and Membrane Potential Changes , 1981 .

[18]  C. Londos,et al.  Independent mechanisms of adenosine activation and inhibition of the turkey erythrocyte adenylate cyclase system. , 1980, The Journal of biological chemistry.

[19]  S. Klebanoff.  Oxygen metabolism and the toxic properties of phagocytes. , 1980, Annals of internal medicine.

[20]  I. Gärtner.  Separation of human eosinophils in density gradients of polyvinylpyrrolidone-coated silica gel (Percoll). , 1980, Immunology.

[21]  J. Daly,et al.  Alkylxanthines: inhibition of adenosine-elicited accumulation of cyclic AMP in brain slices and of brain phosphodiesterase activity. , 1979, Life sciences.

[22]  S. Pincus.  Production of eosinophil-rich guinea pig peritoneal exudates. , 1978, Blood.

[23]  E D Robin,et al.  Total eosinophil counts in the management of bronchial asthma. , 1975, The New England journal of medicine.

[24]  G. Weissmann,et al.  Mechanisms of lysosomal enzyme release from human leukocytes. II. Effects of cAMP and cGMP, autonomic agonists, and agents which affect microtubule function. , 1974, The Journal of clinical investigation.

[25]  Y. Tanizaki,et al.  Basophils in bronchial asthma with reference to reagin‐type allergy , 1973, Clinical allergy.

[26]  B. Babior,et al.  Biological defense mechanisms. The production by leukocytes of superoxide, a potential bactericidal agent. , 1973, The Journal of clinical investigation.

[27]  R. Butcher,et al.  Adenosine 3',5'-phosphate in biological materials. I. Purification and properties of cyclic 3',5'-nucleotide phosphodiesterase and use of this enzyme to characterize adenosine 3',5'-phosphate in human urine. , 1962, The Journal of biological chemistry.

[28]  M. Dunnill.  THE PATHOLOGY OF ASTHMA, WITH SPECIAL REFERENCE TO CHANGES IN THE BRONCHIAL MUCOSA , 1960, Journal of clinical pathology.

[29]  F. Wróblewski,et al.  Lactic Dehydrogenase Activity in Blood.∗ , 1955, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.