NEUTROPHIL-INDUCED ENDOTHELIAL-CELL DAMAGE - INHIBITION BY A 14-MEMBERED RING MACROLIDE THROUGH THE ACTION OF NITRIC-OXIDE

Macrolide antibiotics have been used worldwide for about 40 years. The clinical effectiveness of oral erythromycin for diffuse panbronchioli tis has been established and erythromycin seems to act not only as an antibacterial but also as an anti-inflammatory agent, We investigated the effect of 14-membered ring macrolides, erythromycin and clarithrom ycin, on human neutrophil functions and endothelial cell damage induce d by neutrophils. The superoxide production of neutrophils and Ca2+ in flux into neutrophils induced by N-formyl-methionyl-leucyl-phenylalani ne was inhibited by treatment with erythromycin but not by treatment w ith clarithromycin, When endothelial cells were cocultured with neutro phils, nitric oxide (NO) presumably released from endothelial cells we re enhanced by treatment with erythromycin but not by treatment with c larithromycin and endothelial cell injury induced by neutrophils was a meliorated by addition of erythromycin but not by clarithromycin. The reduction of neutrophil-induced endothelial cell injury by erythromyci n was abolished by treatment with carboxy-PTIO which traps NO in the m edium. Moreover nitrite in the medium in which endothelial cells were incubated with neutrophils was enhanced by treatment with erythromycin and the enhancement of nitrite by erythromycin was partially canceled by addition of H-89, an inhibitor of cyclic AMP-dependent protein kin ase (PKA), Erythromycin seems to ameliorate neutrophil-induced endothe lial cell injury by affecting not only neutrophil functions but the re lease of NO from endothelial cells through the action of PKA. The usef ulness for the treatment of diseases worsened by the interaction betwe en neutrophils and endothelium might be different among 14-membered ri ng macrolides.