Essani N A, Bajt M L, Farhood A, Vonderfecht S L, Jaeschke H
Cardiovascular Pharmacology, Pharmacia & Upjohn, Inc., Kalamazoo, MI 49007, USA.
J Immunol. 1997 Jun 15;158(12):5941-8.
Polymorphonuclear leukocytes (neutrophils) can cause hepatic parenchymal cell injury during endotoxin (ET) shock. Because adhesion molecules are critical for inflammatory cell damage, the role of vascular cell adhesion molecule-1 (VCAM-1) was studied in the pathophysiology of ET shock. ET-sensitive mice (C3Heb/FeJ) were treated with 700 mg/kg galactosamine in combination with 100 microg/kg Salmonella abortus equi ET, 15 microg/kg TNF-alpha, or 13 to 23 microg/kg IL-1. VCAM-1 mRNA formation was strongly activated in animals treated with ET, TNF-alpha, or IL-1. In contrast, only TNF-alpha and IL-1, not ET, induced VCAM-1 gene transcription in livers of ET-resistant mice (C3H/HeJ). Immunohistochemistry and isolation of liver cells during endotoxemia indicated that VCAM-1 mRNA and protein were only formed in endothelial cells and Kupffer cells, not in hepatocytes. Galactosamine/ET induced neutrophil accumulation in sinusoids (515 +/- 30 neutrophils/50 high power fields) followed by transmigration at 7 h. At that time, severe liver injury was observed (necrosis, 53 +/- 5%). An anti-VCAM-1 Ab (3 mg/kg) attenuated the area of necrosis by 60%. The Ab reduced neutrophil transmigration by 84%, but had no effect on the total number of cells in the liver vasculature. Flow cytometric analysis identified the presence of very late Ag-4 on mouse peripheral neutrophils. Our data demonstrated cytokine-dependent VCAM-1 gene transcription and protein expression in the liver during endotoxemia. Neutrophils were able to use very late Ag-4/VCAM-1 interactions to transmigrate into liver parenchyma in vivo. Preventing transmigration by blocking VCAM-1 protected hepatocytes against neutrophil-induced injury.
多形核白细胞（中性粒细胞）可在内毒素（ET）休克期间导致肝实质细胞损伤。由于黏附分子对炎症细胞损伤至关重要，因此研究了血管细胞黏附分子-1（VCAM-1）在ET休克病理生理学中的作用。对ET敏感的小鼠（C3Heb/FeJ）用700mg/kg半乳糖胺联合100μg/kg马流产沙门氏菌ET、15μg/kg肿瘤坏死因子-α（TNF-α）或13至23μg/kg白细胞介素-1（IL-1）进行处理。在用ET、TNF-α或IL-1处理的动物中，VCAM-1 mRNA的形成被强烈激活。相比之下，在ET抗性小鼠（C3H/HeJ）的肝脏中，只有TNF-α和IL-1而非ET诱导了VCAM-1基因转录。内毒素血症期间的免疫组织化学和肝细胞分离表明，VCAM-1 mRNA和蛋白仅在内皮细胞和库普弗细胞中形成，而不在肝细胞中形成。半乳糖胺/ET诱导中性粒细胞在肝血窦中积聚（515±30个中性粒细胞/50个高倍视野），随后在7小时时发生迁移。此时，观察到严重的肝损伤（坏死，53±5%）。一种抗VCAM-1抗体（3mg/kg）使坏死面积减少了60%。该抗体使中性粒细胞迁移减少了84%，但对肝血管系统中的细胞总数没有影响。流式细胞术分析确定小鼠外周中性粒细胞上存在极迟抗原-4。我们的数据表明，内毒素血症期间肝脏中存在细胞因子依赖性的VCAM-1基因转录和蛋白表达。中性粒细胞能够利用极迟抗原-4/VCAM-1相互作用在体内迁移到肝实质中。通过阻断VCAM-1来防止迁移可保护肝细胞免受中性粒细胞诱导的损伤。
