A Combination of Budesonide and the SH-Metabolite I of Erdosteine Acts Synergistically in Reducing Chemiluminescence during Human Neutrophil Respiratory Burst

Abstract

Activated neutrophils can release superoxide anion and nitric oxide (NO), which subsequently combine with each other to yield peroxynitrite anions, powerful and harmful oxidants that preferentially mediate the oxidation of the thiol groups in proteins and non-protein molecules. These oxidants play a direct role in the inflammatory process in chronic obstructive pulmonary disease and asthma by increasing the number of neutrophils and macrophages that induce a self-sustaining phlogogenic loop. Budesonide (BUD) and erdosteine (a muco-active drug which, after metabolization, produces an active metabolite (Met I) with a sulfhydryl group) are both active in reducing the release of superoxide anion, NO and peroxynitrite, and can be administered to patients with respiratory diseases. The aim of this study was to investigate the possible synergistic in vitro effect of BUD and Met I on chemiluminescence generation during fMLP-stimulated respiratory bursts of human neutrophils with the NO donor L-arginine, added to the incubating medium. The investigated BUD concentrations ranged from 6 x 10(-8) to 1 x 10(-6) mol/l in logarithmic scale and a significant and progressive reduction in luminol-amplified chemiluminescence (LACL) was observed at concentrations ranging from 2.5 x 10(-7) to 1 x 10(-6) mol/l. The investigated concentrations of Met I varied from 0.62 to 10 microg/ml. No significant changes were observed at 0.62, 1.25, and 2.5 microg/ml, but a significant decrease in LACL was observed at 5 and 10 microg/ml. When the two drugs were combined, there was a greater significant decrease in LACL versus the single drugs with the combinations of BUD 1 x 10(-6) mol/l plus Met I 10 microg/ml, BUD 5 x 10(-7) mol/l plus Met I 5 microg/ml, BUD 2.5 x 10(-7) mol/l plus Met I 2.5 microg/ml, and BUD 1.25 x 10(-7) mol/l plus Met I 1.25 microg/ml. A further interesting finding was that the combination of BUD 2.5 x 10(-7) mol/l plus Met I 2.5 microg/ml and BUD 1.25 x 10(-7) mol/l plus Met I 1.25 microg/ml significantly decreased LACL, whereas the single concentrations had no significant effect, thus indicating the possibility of extending the duration of the effect. Our findings indicate a synergistic antioxidant effect when BUD and Met I are given together, which is of interest for counteracting the airway phlogosis involved in many respiratory diseases.