Mechanisms Involved in the Induction of Human Endothelial Cell Necrosis

The effects of the inflammatory mediators lipopolysaccharide (LPS) and tumor necrosis factor-α (TNF) and unstimulated and activated neutrophils (PMNs) on endothelial cell (EC) necrosis were studied using the cultured human EC line (ECV-304) and human PMNsin vitro.LPS and TNF alone or their combinati...

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Bibliographic Details
Published in:Cellular immunology 1996-02, Vol.168 (1), p.91-99
Main Authors: Wang, Jiang Huai, Redmond, H.Paul, Watson, R.William G., Duggan, Susan, McCarthy, Julie, Barry, Mary, Bouchier-Hayes, David
Format: Article
Language:English
Subjects:
Adult
Aprotinin - pharmacology
Cell Adhesion - drug effects
Cell Line
Drug Synergism
Endothelium, Vascular - drug effects
Endothelium, Vascular - pathology
Humans
Intercellular Adhesion Molecule-1 - biosynthesis
Lipopolysaccharides - toxicity
Necrosis
Neutrophil Activation
Tumor Necrosis Factor-alpha - toxicity
Umbilical Veins
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Summary:The effects of the inflammatory mediators lipopolysaccharide (LPS) and tumor necrosis factor-α (TNF) and unstimulated and activated neutrophils (PMNs) on endothelial cell (EC) necrosis were studied using the cultured human EC line (ECV-304) and human PMNsin vitro.LPS and TNF alone or their combination failed to induce EC necrosis. Activated PMNs, as evidenced by augmentations in CD11b expression and respiratory burst, induced significant EC necrosis commencing at 12 hr of coculture, which was strongly dependent on the ratio of PMN:ECs and the duration of PMN:EC coculture. In contrast, unstimulated PMNs induced no significant increases in EC necrosis. To examine the mechanisms of activated PMN-mediated EC necrosis, the oxygen radical scavengers superoxide dismutase (SOD) and catalase, as well as the protease inhibitors phenylmethysulfonyl fluoride (PMSF), α1-antitrypsin (α1-AT), soybean trypsin–chymotrypsin inhibitor (TCI), and aprotinin, were studied in coculture experiments. EC necrosis induced by activated PMNs could be markedly attenuated by SOD, PMSF, α1-AT, TCI, aprotinin, or their combinations. Although aprotinin enhanced respiratory burst, this agent inhibited necrosis by downregulating PMN CD11b and PMN–EC adhesion. These results demonstrate that the inflammatory mediators LPS and TNF and quiescent PMNs fail to induce EC necrosis. However, PMNs activated by inflammatory mediators can induce EC necrosis through oxidative and nonoxidative mechanisms and this process is dependent on PMN–EC adhesion.
ISSN:0008-8749
1090-2163
DOI:10.1006/cimm.1996.0053