Endothelial cell determinants of susceptibility to neutrophil-mediated killing

Vascular endothelial cell injury plays an important role in the pathogenesi s of inflammatory-mediated tissue injury. In the current study, we assessed injury in primary cultures of endothelial cells obtained from different si tes within the same species, comparing rat dermal microvascular and rat lun g microvascular endothelial cells. Dermal microvascular-derived endothelial cells were more sensitive to killing by PMA (phorbol myristate acetate)-ac tivated human neutrophils than were endothelial cells derived from lung mic rovasculature. Lung endothelial cells stimulated with interferon-gamma plus lipopolysaccharide (IFN gamma + LPS) generated high levels of nitric oxide ((NO)-N-.), while dermal endothelial cells stimulated with IFN gamma + LPS generated significantly lower levels of (NO)-N-.. Under conditions of (NO) -N-. generation (IFN gamma + LPS stimulation), or in the presence of the (N O)-N-. donor, S-nitroso-N-acetyl penicillamine (SNAP), endothelial cell kil ling by PMA-activated neutrophils was reduced. Lung endothelial cells stimu lated with PMA generated less superoxide (O2(.-)) than dermal endothelial c ells. Under conditions of (NO)-N-. generation (IFN gamma + LPS stimulation) , or in the presence of SNAP, O-2(.-) release from endothelial cells was re duced. Endothelial cell-derived (NO)-N-. appeared to play a significant rol e in attenuating the neutrophil-mediated killing. The differences in the ab ility of endothelial cells to generate (NO)-N-. and O-2(.-) underlies, at l east in part, the differences in susceptibility of these cells to injury by activated neutrophils.