Myhre Anders E, Stuestøl Jon Fredrik, Dahle Maria K, Øverland Gunhild, Thiemermann Christoph, Foster Simon J, Lilleaasen Per, Aasen Ansgar O, Wang Jacob E
Institute for Surgical Research, Rikshospitalet University Hospital, Oslo, Norway.
Infect Immun. 2004 Mar;72(3):1311-7. doi: 10.1128/IAI.72.3.1311-1317.2004.
Several studies have implicated a role of peptidoglycan (PepG) as a pathogenicity factor in sepsis and organ injury, in part by initiating the release of inflammatory mediators. We wanted to elucidate the structural requirements of PepG to trigger inflammatory responses and organ injury. Injection of native PepG into anesthetized rats caused moderate but significant increases in the levels of alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, and bilirubin (markers of hepatic injury and/or dysfunction) and creatinine and urea (markers of renal dysfunction) in serum, whereas PepG pretreated with muramidase to digest the glycan backbone failed to do this. In an ex vivo model of human blood, PepG containing different amino acids induced similar levels of the cytokines tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), IL-8, and IL-10, as determined by plasma analyses (enzyme-linked immunosorbent assay). Hydrolysis of the Staphylococcus aureus cross-bridge with lysostaphin resulted in moderately reduced release of TNF-alpha, IL-6, IL-8, and IL-10, whereas muramidase digestion nearly abolished the ability to induce cytokine release and IL-6 mRNA accumulation in CD14(+) monocytes compared to intact PepG. However, additional experiments showed that muramidase-treated PepG synergized with lipopolysaccharide to induce TNF-alpha and IL-10 release in whole blood, despite its lack of inflammatory activity when administered alone. Based on these studies, we hypothesize that the structural integrity of the glycan chain of the PepG molecule is very important for the pathogenic effects of PepG. The amino acid composition of PepG, however, does not seem to be essential for the inflammatory properties of the molecule.
多项研究表明，肽聚糖（PepG）作为脓毒症和器官损伤中的一种致病因素，部分是通过引发炎症介质的释放来发挥作用。我们想要阐明PepG引发炎症反应和器官损伤的结构要求。将天然PepG注射到麻醉大鼠体内，会导致血清中丙氨酸转氨酶、天冬氨酸转氨酶、γ-谷氨酰转移酶和胆红素（肝损伤和/或功能障碍的标志物）以及肌酐和尿素（肾功能障碍的标志物）水平适度但显著升高，而用溶菌酶预处理以消化聚糖主链的PepG则不会导致这种情况。在人血的体外模型中，通过血浆分析（酶联免疫吸附测定）确定，含有不同氨基酸的PepG诱导细胞因子肿瘤坏死因子α（TNF-α）、白细胞介素-6（IL-6）、IL-8和IL-10的水平相似。用溶葡萄球菌素水解金黄色葡萄球菌的交联桥，会使TNF-α、IL-6、IL-8和IL-10的释放适度减少，而与完整的PepG相比，溶菌酶消化几乎消除了诱导细胞因子释放和CD14(+)单核细胞中IL-6 mRNA积累的能力。然而，额外的实验表明，尽管单独给药时缺乏炎症活性，但经溶菌酶处理的PepG与脂多糖协同作用，可诱导全血中TNF-α和IL-10的释放。基于这些研究，我们推测PepG分子聚糖链的结构完整性对PepG的致病作用非常重要。然而，PepG的氨基酸组成似乎对该分子的炎症特性并非必不可少。
