Bacterial lipopolysaccharide induces endothelial cells to synthesize a degranulating factor for neutrophils

^a Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah School of Medicine, Salt Lake City, Utah 84112–5000, USA
^b Eccles Program in Human Molecular Biology and Genetics, University of Utah School of Medicine, Salt Lake City, Utah 84112–5000, USA
^c Department of Medicine, University of Utah School of Medicine, Salt Lake City, Utah 84112–5000, USA
^d Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, Utah 84112–5000, USA
^e Department of Pathology, University of Utah School of Medicine, Salt Lake City, Utah 84112–5000, USA

Enzymes and other factors secreted by degranulating neutrophils (polymorphonuclear leukocytes, PMNs) mediate endothelial injury, thrombosis, and vascular remodeling. In bacteremia and sepsis syndrome and their consequent complications (including acute respiratory distress syndrome and systemic ischemia-reperfusion resulting from septic shock), neutrophil degranulation is an important mechanism of injury. In related studies, we found that human endothelial cells regulate neutrophil degranulation and that inflammatory cytokines induce synthesis of degranulating factors by human endothelial cells. Here we show that lipopolysaccharides (LPS) from gram-negative bacteria were the most potent agonists for release of degranulating activity by endothelial cells when compared to several cytokines and stimulatory factors. LPS also induced the release of degranulating signals for PMNs from a human endothelial cell line, EA.hy 926. Interleukin 8 (IL-8) is synthesized by endothelial and EA.hy 926 cells in response to LPS and induces neutrophil degranulation. However, complementary strategies using receptor desensitization, translation of messenger RNA by Xenopus laevis oocytes, and purification and analysis of factors from conditioned supernatants demonstrated that degranulating factors distinct from IL-8 are generated in response to LPS. The characteristics of a partially purified degranulating factor isolated from conditioned supernatants distinguished it from known chemokines and other factors that induce PMN degranulation and are generated by endothelial cells in response to LPS. Thus, cultured human endothelial cells and endothelial cell lines synthesize several unique signaling molecules that can trigger neutrophil granular secretion. If produced in vivo in response to LPS or other pathologic agonists, these degranulating signals may activate PMNs in combination or in sequence, initiating or propagating vascular damage.—Gill, E. A., Imaizumi, T.-a., Carveth, H., Topham, M. K., Tarbet, E. B., McIntyre, T. M., Prescott, S. M., Zimmerman, G. A. Bacterial lipo~polysaccharide induces endothelial cells to synthesize a degranulating factor for neutrophils. FASEB J. 12, 673–684 (1998)

Key Words: PMN • polymorphonuclear leukocytes • PMN degranulation • lactoferrin

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