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Murphy Hedwig S.; Warner, Roscoe L.; Bakopoulos, Natalie; Dame, Michael K.; Varani, James; Ward, Peter A.


Vascular endothelial cell injury plays an important role in the pathogenesis of inflammatory-mediated tissue injury. In the current study, we assessed injury in primary cultures of endothelial cells obtained from different sites within the same species, comparing rat dermal microvascular and rat lung microvascular endothelial cells. Dermal microvascular-derived endothelial cells were more sensitive to killing by PMA (phorbol myristate acetate)-activated human neutrophils than were endothelial cells derived from lung microvasculature. Lung endothelial cells stimulated with interferon-γ plus lipopolysaccharide (IFNγ + LPS) generated high levels of nitric oxide (*NO), while dermal endothelial cells stimulated with IFNγ + LPS generated significantly lower levels of *NO. Under conditions of *NO generation (IFNγ + LPS stimulation), or in the presence of the *NO donor, S-nitroso-N-acetyl penicillamine (SNAP), endothelial cell killing by PMA-activated neutrophils was reduced. Lung endothelial cells stimulated with PMA generated less superoxide (O2*-) than dermal endothelial cells. Under conditions of *NO generation (IFNγ + LPS stimulation), or in the presence of SNAP, O2*- release from endothelial cells was reduced. Endothelial cell-derived *NO appeared to play a significant role in attenuating the neutrophil-mediated killing. The differences in the ability of endothelial cells to generate *NO and O2*- underlies, at least in part, the differences in susceptibility of these cells to injury by activated neutrophils.

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