葡萄球菌肠毒素A诱导的肝毒性主要由Fas配体（CD95L）介导。
Staphylococcal enterotoxin A-induced hepatotoxicity is predominantly mediated by Fas ligand (CD95L).
作者信息
Klintman Daniel, Li Xiang, Sato Tohru, Wang Yusheng, Jeppsson Bengt, Thorlacius Henrik
机构信息
Department of Surgery, Malmö University Hospital, Lund University, S-205 02 Malmö, Sweden.
出版信息
Ann Surg. 2004 Dec;240(6):1065-72; discussion 1072-3. doi: 10.1097/01.sla.0000146159.88918.d2.
OBJECTIVE
To determine the role of tumor necrosis factor alpha (TNF-alpha) and Fas ligand (FasL, CD95L) in superantigen-induced and endotoxin-induced liver injury.
SUMMARY BACKGROUND DATA
Gram-positive bacteria are increasingly common causes of sepsis and multiorgan failure, but the pathophysiologic mechanisms of superantigen-provoked hepatotoxicity remain elusive.
METHODS
Intravital fluorescence microscopy was used to study the liver microcirculation in mice challenged with superantigen (staphylococcal enterotoxin A, SEA) or endotoxin (lipopolysaccharide, LPS) combined with D-galactosamine.
RESULTS
Administration of 10 microg LPS and 50 microg SEA caused similar hepatocellular damage as determined by liver enzymes and apoptosis. Notably, TNF-alpha-deficient mice were completely protected against hepatic injury provoked by LPS, whereas no protection was observed in response to SEA. On the other hand, FasL-deficient mice were protected against liver injury induced by SEA, but no protection was found when challenged with LPS. LPS increased clear-cut leukocyte recruitment, whereas SEA had no significant effect on leukocyte responses in the liver microcirculation. Leukocyte responses to LPS were decreased by >56% in TNF-alpha gene-targeted animals. Moreover, antiadhesive therapy, ie, immunoneutralization of P-selectin, which is an effective inhibitor of leukocyte recruitment, protected against LPS-induced but not against SEA-induced hepatic damage.
CONCLUSIONS
These novel findings demonstrate that the mechanisms of hepatic injury in endotoxin-induced and superantigen-induced sepsis are principally different. On one hand, SEA-provoked hepatotoxicity is mediated by FasL and is not associated with leukocyte recruitment. On the other hand, liver damage provoked by LPS is mediated by TNF-alpha and characterized by prominent leukocyte responses. These data may facilitate development of more specific therapies against sepsis of different origins.
目的
确定肿瘤坏死因子α（TNF-α）和Fas配体（FasL，CD95L）在超抗原诱导和内毒素诱导的肝损伤中的作用。
总结背景资料
革兰氏阳性菌日益成为脓毒症和多器官功能衰竭的常见病因，但超抗原诱发肝毒性的病理生理机制仍不清楚。
方法
采用活体荧光显微镜术研究用超抗原（葡萄球菌肠毒素A，SEA）或内毒素（脂多糖，LPS）联合D-半乳糖胺攻击的小鼠的肝微循环。
结果
给予10μg LPS和50μg SEA所引起的肝细胞损伤，经肝酶和细胞凋亡测定显示相似。值得注意的是，TNF-α缺陷小鼠完全免受LPS诱发的肝损伤，而对SEA诱发的肝损伤未观察到保护作用。另一方面，FasL缺陷小鼠免受SEA诱导的肝损伤，但用LPS攻击时未发现保护作用。LPS显著增加白细胞募集，而SEA对肝微循环中的白细胞反应无显著影响。在TNF-α基因靶向动物中，白细胞对LPS的反应降低>56%。此外，抗黏附治疗，即P-选择素的免疫中和，P-选择素是白细胞募集的有效抑制剂，可预防LPS诱导的肝损伤，但不能预防SEA诱导的肝损伤。
结论
这些新发现表明，内毒素诱导和超抗原诱导的脓毒症中肝损伤的机制主要不同。一方面，SEA诱发的肝毒性由FasL介导，且与白细胞募集无关。另一方面，LPS诱发的肝损伤由TNF-α介导，其特征为显著的白细胞反应。这些数据可能有助于开发针对不同来源脓毒症的更特异性治疗方法。
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