Methylxanthine bronchodilators potentiate multiple human neutrophil functions.

Area of Science:

• Immunology
• Pharmacology

Background:

• Methylxanthines, such as theophylline and aminophylline, are bronchodilators with dual mechanisms of action.
• At high concentrations (>10⁻⁴ M), they inhibit phosphodiesterase activity.
• At lower, clinically relevant concentrations (10⁻⁵ to 10⁻⁴ M), they act as adenosine receptor antagonists.

Purpose of the Study:

• To investigate the effect of therapeutic methylxanthine concentrations on human neutrophil functions.
• To examine the impact of methylxanthines on neutrophil aggregation, lysosomal enzyme release, and superoxide anion formation stimulated by N-formyl-methionyl-leucyl-phenylalanine (FMLP).

Main Methods:

• Human neutrophils were treated with cytochalasin B and preincubated with varying concentrations of methylxanthines.
• Neutrophil aggregation, lysosomal enzyme release, and superoxide anion formation were measured.
• The role of adenosine receptors was assessed using adenosine deaminase and exogenous adenosine.

Main Results:

• Methylxanthines exhibited a biphasic, concentration-dependent effect on neutrophil functions.
• Low concentrations (10⁻⁵ to 10⁻⁴ M) potentiated neutrophil aggregation, lysosomal enzyme release, and superoxide anion formation.
• Higher concentrations (>10⁻⁴ M) inhibited these responses.
• 8-Phenyltheophylline, a non-phosphodiesterase inhibitor, only caused potentiation.
• Adenosine deaminase mimicked potentiation, while adenosine reversed it.

Conclusions:

• Therapeutic concentrations of methylxanthines may enhance neutrophil activation in vivo.
• This potentiation is likely mediated by antagonism of neutrophil adenosine receptors.
• The findings suggest a complex interaction between methylxanthines, adenosine, and immune cell function.