van Langevelde P, Ravensbergen E, Grashoff P, Beekhuizen H, Groeneveld P H, van Dissel J T
Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.
Antimicrob Agents Chemother. 1999 Dec;43(12):2984-9. doi: 10.1128/AAC.43.12.2984.
Antibiotics release inflammatory fragments, such as lipoteichoic acid (LTA) and peptidoglycan (PG), from the cell wall of Staphylococcus aureus. In this study, we exposed S. aureus cultures to a number of beta-lactam antibiotics (imipenem, flucloxacillin, and cefamandole) and protein synthesis-inhibiting antibiotics (erythromycin, clindamycin, and gentamicin) and investigated whether supernatants of these cultures differ in their capacity to stimulate endothelial cells (EC). After 24 h of incubation, endothelial adhesiveness for leukocytes, surface expression of various adhesion molecules, and secretion of the chemokines interleukin-8 (IL-8) and monocyte chemotactic protein-1 (MCP-1) were measured. Supernatants of beta-lactam-exposed cultures (designated beta-lactam supernatants) enhanced the adhesiveness of EC for granulocytes, whereas those of protein synthesis-inhibiting antibiotic-exposed cultures (designated protein synthesis-inhibitor supernatants) did not. This hyperadhesiveness coincided with a higher intercellular adhesion molecule-1 expression on the surface of the stimulated EC. In addition, EC stimulated with beta-lactam supernatants secreted significantly higher concentrations of the chemokines IL-8 and MCP-1 than those stimulated with protein synthesis-inhibitor supernatants. The finding that the concentrations of LTA and PG in beta-lactam supernatants were much higher than those in protein synthesis-inhibitor supernatants suggests that the observed differences in stimulatory effect between these supernatants are a result of differences in the release of cell wall fragments, although the presence of other stimulatory factors in the supernatants cannot be excluded. In conclusion, our results argue for a release of LTA and PG from S. aureus after exposure to beta-lactam antibiotics that enhances the development of a systemic inflammatory response by stimulating EC such that adhesiveness for granulocytes is increased and large amounts of IL-8 and MCP-1 are secreted.
抗生素会从金黄色葡萄球菌细胞壁释放炎性片段，如脂磷壁酸（LTA）和肽聚糖（PG）。在本研究中，我们将金黄色葡萄球菌培养物暴露于多种β-内酰胺类抗生素（亚胺培南、氟氯西林和头孢孟多）以及抑制蛋白质合成的抗生素（红霉素、克林霉素和庆大霉素）中，并研究这些培养物的上清液在刺激内皮细胞（EC）方面的能力是否存在差异。孵育24小时后，测量白细胞的内皮黏附性、各种黏附分子的表面表达以及趋化因子白细胞介素-8（IL-8）和单核细胞趋化蛋白-1（MCP-1）的分泌情况。暴露于β-内酰胺类抗生素的培养物的上清液（称为β-内酰胺类上清液）增强了内皮细胞对粒细胞的黏附性，而暴露于抑制蛋白质合成的抗生素的培养物的上清液（称为蛋白质合成抑制剂上清液）则没有。这种高黏附性与受刺激内皮细胞表面更高的细胞间黏附分子-1表达相一致。此外，用β-内酰胺类上清液刺激的内皮细胞分泌的趋化因子IL-8和MCP-1的浓度明显高于用蛋白质合成抑制剂上清液刺激的内皮细胞。β-内酰胺类上清液中LTA和PG的浓度远高于蛋白质合成抑制剂上清液中的浓度，这一发现表明，尽管不能排除上清液中存在其他刺激因子，但这些上清液在刺激作用上观察到的差异是细胞壁片段释放差异的结果。总之，我们的结果表明，金黄色葡萄球菌在暴露于β-内酰胺类抗生素后会释放LTA和PG，通过刺激内皮细胞来增强全身炎症反应的发展，从而增加对粒细胞的黏附性并分泌大量的IL-8和MCP-1。
