THE EFFECTS OF BETA(2)-AGONISTS AND METHYLXANTHINES ON NEUTROPHIL FUNCTION IN-VITRO

Therapeutic agents which affect polymorphonuclear neutrophil (PMN) fun ctions have the potential to reduce or increase PMN activation and, he nce, influence the progression of lung inflammation. We have assessed the effects of the beta(2)-agonist, terbutaline, and the methylxanthin e, aminophylline, on PMN functions in vitro at both therapeutic and hi gher concentrations, At therapeutic levels, both agents increased PMN chemotaxis to formyl-methionyl-leucyl-phenylalanine (FMLP) in a dose-d ependent manner from a control value of 22.5+/-3.58 cells.field(-1) to 26.1+/-4.73 cells.field(-1) with 4 mg.l(-1) terbutaline, and to 26.3/-4.49 cells.field(-1) with 20 mg.l(-1) aminophylline. When the cells were preincubated with higher doses of the agents in separate experime nts there was inhibition of chemotaxis from a control value of 31.1+/- 2.06 cells.field(-1) to 18.3+/-0.82 cells.field(-1) at 160 mg.l(-1) te rbutaline, and to 16.1+/-0.77 cells.field(-1) at 400 mg.l(-1) aminophy lline. A similar effect was seen when the PMNs were preincubated with terbutaline and aminophylline prior to assessment of superoxide anion generation, with stimulation of superoxide release at therapeutic leve ls of the drugs and inhibition at higher doses (19% increase from rest ing control cells at terbutaline 4 mg.l(-1) and 53% reduction at 160 m g.l(-1); 28% increase with aminophylline 20 mg.l(-1) and 22% reduction at 400 mg.l(-1)). Both terbutaline and aminophylline had no effect on PMN degranulation, as assessed by the degradation of fibronectin. The se data suggest that terbutaline and aminophylline exert a biphasic ef fect on PMN functions in vitro, and may have detrimental effects on lu ng tissues at therapeutic levels through potentiation of PMN recruitme nt and activation. However, the observed effects of therapeutic doses of these agents on in vitro PMN functions were relatively small and, t herefore, the clinical relevance of these results is, as yet, uncertai n.