title: Endothelial cell determinants of susceptibility to neutrophil-mediated killing.
abstract: 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-gamma plus lipopolysaccharide (IFNgamma + LPS) generated high levels of nitric oxide (*NO), while dermal endothelial cells stimulated with IFNgamma + LPS generated significantly lower levels of *NO. Under conditions of *NO generation (IFNgamma + 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 (02*-) than dermal endothelial cells. Under conditions of *NO generation (IFNgamma + 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 02*- underlies, at least in part, the differences in susceptibility of these cells to injury by activated neutrophils.
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor 48109, USA.
authors.forename: H S
authors.initials: HS
authors.lastname: Murphy
authors.forename: R L
authors.initials: RL
authors.lastname: Warner
authors.forename: N
authors.initials: N
authors.lastname: Bakopoulos
authors.forename: M K
authors.initials: MK
authors.lastname: Dame
authors.forename: J
authors.initials: J
authors.lastname: Varani
authors.forename: P A
authors.initials: PA
authors.lastname: Ward
mesh_terms: D000818:Animals; D002374:Catalase / Q000494:pharmacology; D002478:Cells, Cultured; D019040:E-Selectin / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005456:Fluorescent Dyes / Q000378:metabolism; D016166:Free Radical Scavengers / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000276:immunology*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000378:metabolism; D008168:Lung / Q000098:blood supply / Q000166:cytology / Q000378:metabolism; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D009569:Nitric Oxide / Q000378:metabolism*; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D020318:Rats, Long-Evans; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012867:Skin / Q000098:blood supply / Q000166:cytology / Q000378:metabolism; D013481:Superoxides / Q000037:antagonists & inhibitors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology
chemical_list: D019040:E-Selectin; D005456:Fluorescent Dyes; D016166:Free Radical Scavengers; D008070:Lipopolysaccharides; D017382:Reactive Oxygen Species; C110881:S-nitro-N-acetylpenicillamine; D014409:Tumor Necrosis Factor-alpha; D013481:Superoxides; D018799:Intercellular Adhesion Molecule-1; D009569:Nitric Oxide; D007371:Interferon-gamma; D002374:Catalase; D010396:Penicillamine