Klintman Daniel, Li Xiang, Sato Tohru, Wang Yusheng, Jeppsson Bengt, Thorlacius Henrik
Department of Surgery, Malmö University Hospital, Lund University, S-205 02 Malmö, Sweden.
Ann Surg. 2004 Dec;240(6):1065-72; discussion 1072-3. doi: 10.1097/01.sla.0000146159.88918.d2.
To determine the role of tumor necrosis factor alpha (TNF-alpha) and Fas ligand (FasL, CD95L) in superantigen-induced and endotoxin-induced liver injury.
Gram-positive bacteria are increasingly common causes of sepsis and multiorgan failure, but the pathophysiologic mechanisms of superantigen-provoked hepatotoxicity remain elusive.
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.
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.
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.
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。
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。
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。
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。
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。
