Effect of endothelins on human neutrophil activation by immune complexes

Neutrophils are important effector cells of tissue injury in several pathological conditions, among them, immune complexes (IC)-induced inflammation and tissue injury. There is evidence that endothelins modulate IC-induced tissue injury in experimental models in vivo. In the present study we investigated the effect of endothelins on neutrophil activation by IC in vitro. To this purpose, pre-formed insoluble immune complexes were used to stimulate human neutrophils and production of leukotriene B4 (LTB4) and hydrogen peroxyde (H2O2) were measured as indicative of phospholipase A2 and oxidative burst activation and myeloperoxidase (MPO) release as indicative of cell degranulation. The effect of endothelins (ETs) in these events induced by IC was then examined. We found that IC stimulated all three events in human neutrophils. Addition of ET-1 but not ET-2 or ET-3 to the IC-stimulated neutrophils potentiated LTB4 but not H2O2 production. The endothelins added to resting neutrophils did not induce LTB4 production but they were effective to stimulate H2O2 production. The increased MPO activity induced by IC was not affected by endothelins nor did they stimulate the release of this enzyme in resting cells. These results show that endothelins are able to activate some neutrophil functions and to upregulate the IC-induced production of the pro-inflammatory molecule LTB4. These data indicate that products of endothelial cells, such as endothelins, can be involved in the potentiation of neutrophil-dependent tissue injury.