Jaeschke H, Essani N A, Fisher M A, Vonderfecht S L, Farhood A, Smith C W
Cardiovascular Pharmacology, Pharmacia & Upjohn Inc., Kalamazoo, MI 49001, USA.
Hepatology. 1996 Mar;23(3):530-6. doi: 10.1002/hep.510230318.
Neutrophil-induced liver injury during endotoxemia is dependent on the adhesion molecules Mac-1 (CD11b/CD18) on neutrophils and its counterreceptor on endothelial cells and hepatocytes, intercellular adhesion molecule 1 (ICAM-1). To investigate a potential release of a soluble form of ICAM-1 (sICAM-1), animals received 100 micrograms/kg Salmonella abortus equi endotoxin alone or in combination with 700 mg/kg galactosamine. In endotoxin-sensitive mice (C3Heb/FeJ), injection of endotoxin did not cause liver injury but induced a time-dependent increase of sICAM-1 in serum (300%) and in bile (615%) without affecting bile flow. In galactosamine/endotoxin-treated animals, which developed liver injury, the increase in both compartments was only 97% and 104%, respectively. In either case, the increase in sICAM-1 concentrations paralleled the enhanced ICAM-1 expression in the liver. The endotoxin-resistant strain (C3H/HeJ) did not show elevated sICAM-1 levels in serum or bile after endotoxin administration. In contrast, the intravenous injection of murine tumor necrosis factor alpha (TNF-alpha), interleukin-1 alpha (IL-1 alpha) or IL-1 beta (13-23 micrograms/kg) into endotoxin-resistant mice induced a 225% to 364% increase in serum sICAM-1 and a 370% elevation of the biliary efflux of sICAM-1, again independent of changes in bile flow. These data indicate that cytokines are major inducers of sICAM-1 formation during endotoxemia in vivo. The described experimental model can be used to investigate the role of sICAM-1 in the pathophysiology of inflammatory liver disease.
内毒素血症期间中性粒细胞诱导的肝损伤依赖于中性粒细胞上的黏附分子Mac-1（CD11b/CD18）及其在内皮细胞和肝细胞上的反受体细胞间黏附分子1（ICAM-1）。为了研究可溶性ICAM-1（sICAM-1）的潜在释放情况，动物单独接受100微克/千克马流产沙门氏菌内毒素或与700毫克/千克半乳糖胺联合使用。在内毒素敏感小鼠（C3Heb/FeJ）中，注射内毒素未引起肝损伤，但诱导血清中sICAM-1（300%）和胆汁中sICAM-1（615%）呈时间依赖性增加，且不影响胆汁流量。在发生肝损伤的半乳糖胺/内毒素处理动物中，两个部位的增加分别仅为97%和104%。在任何一种情况下，sICAM-1浓度的增加都与肝脏中ICAM-1表达的增强平行。内毒素抗性品系（C3H/HeJ）在内毒素给药后血清或胆汁中的sICAM-1水平未升高。相反，向内毒素抗性小鼠静脉注射小鼠肿瘤坏死因子α（TNF-α）、白细胞介素-1α（IL-1α）或IL-1β（13 - 23微克/千克）可诱导血清sICAM-1增加225%至364%，胆汁中sICAM-1的流出增加370%，同样与胆汁流量的变化无关。这些数据表明，细胞因子是体内内毒素血症期间sICAM-1形成的主要诱导因素。所描述的实验模型可用于研究sICAM-1在炎症性肝病病理生理学中的作用。
