Modulation of eicosanoid metabolism in endothelial cells in a xenograft model. Role of cyclooxygenase-2.
Lipid inflammatory mediators are thought to play a critical role in the pathogenesis of vascular injury. Among the events which might cause the synthesis of eicosanoids in blood vessels is activation of the complement. To evaluate how complement might influence eicosanoid metabolism, we investigated endothelial cells exposed to xenoreactive antibodies and complement, as might occur in rejecting xenografts where severe vascular injury is a typical feature. While resting porcine aortic endothelial cells released only prostaglandin (PG) I2, endothelial cells stimulated with xenoreactive antibodies and complement released PGE2 and thromboxane A2 (TXA2), in addition to increased amounts of PGI2. This alteration in eicosanoid metabolism was associated with induction of cyclooxygenase (Cox)-2 and thromboxane synthase, but not Cox-1. Unlike results seen in other systems, the upregulation of Cox-2 and the subsequent release of eicosanoids by endothelial cells was not directly induced by complement but rather required production of IL-1alpha, which acted on endothelial cells as an autocrine factor. Since eicosanoids have a potent effect on inflammation, vascular tone and platelet aggregation, we postulated that the abnormalities in eicosanoid release induced by xenoreactive antibodies and complement might provide one explanation for the vascular injury, focal ischemia, and thrombosis observed in acute vascular rejection and other vasculitides mediated by complement.
Bustos
M
M
Department of Surgery, Duke University, Durham, North Carolina 27710, USA.
Coffman
T M
TM
Saadi
S
S
Platt
J L
JL
D000818:Animals; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D015777:Eicosanoids / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism*; D006084:Graft Rejection; D007375:Interleukin-1 / Q000502:physiology; D007527:Isoenzymes / Q000032:analysis / Q000502:physiology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000032:analysis / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis; D013552:Swine; D013930:Thromboxane-A Synthase / Q000032:analysis; D014183:Transplantation, Heterologous / Q000276:immunology*
D015777:Eicosanoids; D007375:Interleukin-1; D007527:Isoenzymes; D012333:RNA, Messenger; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D013930:Thromboxane-A Synthase