Inhibition by Erythromycin of Superoxide Anion Production by Human Polymorphonuclear Leukocytes through the Action of Cyclic AMP-Dependent Protein Kinase

Abstract

The long-term low-dose administration of erythromycin is effective in treating chronic inflammatory diseases of the lower respiratory tract. The aim of this study was to clarify the mechanism for this therapeutic effect of erythromycin. We measured its effect on the production of superoxide anion (O₂^-) by polymorphonuclear leukocytes (PMN) that was induced by N-formyl-methionyl-leucyl-phenylalanine (fMLP) or by phorbol myristate acetate (PMA). 25 μM erythromycin inhibited fMLP-induced O₂^- production by about 50%, but not PMA-induced O₂^- production. Moreover, this inhibition was overcome by adding an inhibitor of cyclic AMP-dependent protein kinase (PKA), H-89. The fMLP-induced O₂^- production was also inhibited by isoproterenol, a β-adrenergic agonist, and by dibutyryl cyclic AMP, a cell membrane permeating analogue of cyclic AMP. The inhibition was also overcome by the addition of H-89. Therefore, the effect of erythromycin seemed to be, in part, mediated through the activation of PKA. The inhibition by erythromycin of O₂^- generation by PMN may contribute to the beneficial effect of this drug in treating chronic respiratory diseases.

Hemorrhage increases cytokine expression in lung mononuclear cells in mice: involvement of catecholamines in nuclear factor-kappaB regulation and cytokine expression.

“…In addition, during anaerobic conditions such as occur in ischemic tissues catecholamines can release iron from ferritin, and then can react with the released iron and xanthine oxidase to produce reactive hydroxyl radicals (65). Furthermore, NADPH oxidase-dependent hydroxyl radical production is increased in activated macrophages and polymorphonuclear leukocytes by PKC activation and elevation in intracellular Ca 2ϩ (67)(68)(69). Both of these conditions occur after ␣-adrenergic stimulation (56).…”

Interference of Antibacterial Agents with Phagocyte Functions: Immunomodulation or "Immuno-Fairy Tales"?

“…These studies suggest that macrolide-induced inhibition is linked to the cellular accumulation of these drugs. In vitro conditions which modify cellular uptake can thus interfere with the inhibitory effect of these drugs: for instance, PKA inhibitors, which impair macrolide uptake, also decrease the inhibitory effect of these drugs (256). In contrast, Kadota et al (166) observed marked suppression of superoxide anion generation by G-CSF-primed neutrophils by therapeutic concentrations of erythromycin A, but the uptake of this drug was not investigated.…”

Inhibition by Erythromycin of Human Pulmonary Artery Endothelial Cell Injury Induced by Human Neutrophils

“…We have previously reported that neutrophil 05 produc tion by fMLP but not by PMA was inhibited by the incuba tion with erythromycin above 25 jxM for more than 60 min and the effect of erythromycin was mediated through the action of PKA [14]. Thus, one possible mechanism for the protective effect of erythromycin may be that the drug acti vates PKA and reduces neutrophil 05 production.…”