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

Abstract

Neutrophils are thought to play a key role in tissue injury. We investigated the role of human neutrophils in the induction of injury to the human pulmonary artery endothelial cells and the effect of erythromycin on neutrophil-induced endothelial cell damage. Incubation of unstimulated neutrophils with endothelial cells increased the release of lactate dehydrogenase (LDH) activity and preloaded fura-2 from endothelial cells. When neutrophils were activated by phorbol myristate acetate, the release of LDH and fura-2 was enhanced further. Superoxide dismutase partially inhibited the release of LDH and fura-2 induced by neutrophils, whereas erythromycin markedly inhibited the release of endothelial cell LDH and fura-2 induced by neutrophils. These results suggest that endothelial cell injury is, at least in part, mediated by the action of superoxide and that erythromycin protects against neutrophil-induced endothelial cell injury.

Neutrophil-induced Endothelial Cell Damage: Inhibition by a 14-Membered Ring Macrolide Through the Action of Nitric Oxide

“…Erythromycin and roxithromycin ameliorated neutrophil-induced endothelial cell injury [6,7]. In con trast, clarithromycin did not reduce neutrophil-induced en-dothelial cell damage, which seems not to be due to only the effect by the 14-mcmbcred ring macrolides on 0 2 produc tion o f neutrophils because the drugs did not inhibit PMAinduced 0 2 production of neutrophils and erythromycin and roxithromycin, but not clarithromycin, ameliorated en dothelial cell damage induced by PMA-stimulated neutro phils [6,7]. The effects of erythromycin and clarithromycin on the other neutrophil functions might be different to each other.…”

“…Endothelial cell injury was evaluated as previously described [6,7], Neutrophils and the indicated agents or vehicle were added to confluent monolayers o f endothelial cells in 25-cm 2 flasks, and LDH activity in the medium was assayed. Total LDH activity was measured after exposure o f the cells to 0.1% Triton X-100.…”

“…Addition of human neutrophils to endothelial cell monolayers results in endothelial cell damage and LDH is re leased in the culture medium [7]. To investigate the effects of erythromycin and clarithromycin on endothelial cell in jury induced by neutrophils, we added erythromycin and clarithromycin to endothelial cell monolayers incubated with PMA-stimulated neutrophils, fMLP-stimulated neu trophils and unstimulated neutrophils.…”

“…Neutrophils are involved in the disease state of adult respi ratory distress syndrome [1] or diffuse panbronchiolitis and a 14-membered ring macrolide is useful in treating patients with chronic lower respiratory tract diseases [2][3][4][5]. We have previously reported that erythromycin and roxithromycin inhibited superoxide ( 0 2 ) production of neutrophils and Ca2 influx into neutrophils induced by AMormyl-methionyl-leucyl-phenylalanine (fMLP) and the drugs ameliorat ed neutrophil-induced endothelial cell damage probably through the activtion of cyclic AMP-dependent protein ki nase (PKA) [6,7], The present study was undertaken to ex amine whether clarithromycin, a 14-membered ring macrolide, has similar effects to erythromycin and roxithromycin on neutrophil function and the interaction between neutro phils and endothelium.…”

The Effects of Macrolides on Inflammatory Cells

“…Reports of the success of macrolide therapy in symptom reduction and improved survival spurred interest in the potential benefits of their long-term application in a variety of chronic inflammatory pulmonary diseases. 5,6 Several laboratories 7,8 have demonstrated that macrolides may reduce pulmonary tissue damage by impairing superoxide generation by activated neutrophils. However, no single theory has yet to define a unified process by which the macrolides exert their protean effects as biological response modifiers.…”