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Neutrophil-induced endothelial cell damage: inhibition by a 14-membered ring macrolide through the action of nitric
T Mitsuyama1, K Hidaka, T Furuno
1Research Institute for Diseases of the Chest, Faculty of Medicine, Kyushu University, Fukuoka, Japan.
Abstract:
Macrolide antibiotics have been used worldwide for about 40 years. The clinical effectiveness of oral erythromycin for diffuse panbronchiolitis 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 clarithromycin, on human neutrophil functions and endothelial cell damage induced by neutrophils. The superoxide production of neutrophils and Ca2+ influx into neutrophils induced by N-formyl-methionyl-leucyl-phenylalanine was inhibited by treatment with erythromycin but not by treatment with clarithromycin. When endothelial cells were cocultured with neutrophils, nitric oxide (NO) presumably released from endothelial cells were enhanced by treatment with erythromycin but not by treatment with clarithromycin and endothelial cell injury induced by neutrophils was ameliorated by addition of erythromycin but not by clarithromycin. The reduction of neutrophil-induced endothelial cell injury by erythromycin was abolished by treatment with carboxy-PTIO which traps NO in the medium. 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 cancelled by addition of H-89, an inhibitor of cyclic AMP-dependent protein kinase (PKA). Erythromycin seems to ameliorate neutrophil-induced endothelial cell injury by affecting not only neutrophil functions but the release of NO from endothelial cells through the action of PKA. The usefulness for the treatment of diseases worsened by the interaction between neutrophils and endothelium might be different among 14-membered ring macrolides.
Insights
Erythromycin, a macrolide antibiotic, reduces neutrophil activity and protects endothelial cells by increasing nitric oxide release. Clarithromycin did not show these anti-inflammatory effects, suggesting macrolide differences in treating inflammatory diseases.
Area of Science:
- Pharmacology
- Immunology
- Cell Biology
Background:
- Macrolide antibiotics, like erythromycin, are used for their antibacterial and anti-inflammatory properties.
- Erythromycin's effectiveness in diffuse panbronchiolitis suggests broader mechanisms beyond simple bacterial inhibition.
Purpose of the Study:
- To investigate the differential effects of 14-membered ring macrolides (erythromycin and clarithromycin) on human neutrophil function and neutrophil-induced endothelial cell damage.
- To elucidate the mechanisms underlying erythromycin's protective effects on endothelial cells.
Main Methods:
- Assessing neutrophil superoxide production and calcium (Ca2+) influx in response to N-formyl-methionyl-leucyl-phenylalanine (fMLP).
- Co-culturing endothelial cells with neutrophils to evaluate nitric oxide (NO) release and endothelial cell injury.
- Utilizing carboxy-PTIO to scavenge NO and H-89 to inhibit protein kinase A (PKA) to investigate mechanisms.
Main Results:
- Erythromycin inhibited neutrophil superoxide production and Ca2+ influx, while clarithromycin did not.
- Erythromycin enhanced nitric oxide (NO) release from endothelial cells and reduced neutrophil-induced endothelial cell injury, effects not observed with clarithromycin.
- Erythromycin's protective effect was linked to NO release and involved the cyclic AMP-dependent protein kinase (PKA) pathway.
Conclusions:
- Erythromycin exhibits anti-inflammatory effects by modulating neutrophil function and enhancing endothelial NO production via PKA.
- Clarithromycin lacks these specific anti-inflammatory actions on neutrophils and endothelial cells.
- The therapeutic utility of 14-membered macrolides may vary depending on their impact on neutrophil-endothelial interactions.