Endotoxin inactivation by endotoxin binding proteins : Significance in severe liver disturbances

通过临床和实验研究，探讨了内毒素结合蛋白在严重肝功能障碍中的意义。临床研究：本研究证实血清白蛋白具有Et结合和Et失活作用。终末期肝硬化Et失活率（EIR）降低。肝硬化患者EIR与血清HDL-胆固醇水平、白蛋白Et结合力呈正相关，与转铁蛋白Et结合力呈负相关。在晚期肝硬化患者中，血浆白细胞介素（IL）-1 β、IL-6和肿瘤坏死因子（TNF）-α水平升高，这与白蛋白Et结合能力降低有关。这些数据表明，白蛋白降低Et失活可能导致内毒素增加和上述细胞因子升高。实验研究：当枯否细胞在含乙醇的培养基中预孵育并将所得培养上清液加入肝细胞培养系统中时，肝Et结合蛋白的产生增加。肝细胞产生的Et结合蛋白的量随着Kupffer细胞培养基中乙醇浓度的增加而增加。这种内毒素结合蛋白被证明能增强枯否细胞对内毒素的摄取，并抑制枯否细胞产生TNF。在急性乙醇负荷大鼠，白蛋白结合和高密度脂蛋白（HDL）结合Et显着增加。在慢性乙醇负荷大鼠，HDL结合Et增加。在慢性乙醇喂养的大鼠，额外的5g/kg体重的乙醇负荷，血液TNF和ALT水平增加，当HDL结合Et没有进一步增加。体外研究表明，白蛋白和HDL抑制枯否细胞摄取Et和产生TNF。这些数据表明，白蛋白和HDL可能作为Et结合蛋白和减弱酗酒者的内毒素。

Significance of endotoxin (Et) binding proteins in severe liver disturbance was investigated in clinical and experimental studies. Clinical studies : In the present study, we confirmed that serum albumin has Et binding and Et inactivating actions. There was a decrease in Et inactivating rate (EIR) in terminal liver cirrhosis. EIR was positively correlated to serum HDL-cholesterol level and Et binding capacity of albumin and negatively correlated to Et binding capacity of transferrin in liver cirrhosis. In patients with advanced cirrhosis, plasma interleukin (IL) -1beta, IL-6 and tumor necrosis factor (TNF) -alpha levels were increased, which was related to decreased Et binding capacity of albumin. These data suggested that decreased Et inactivation by albumin may lead to augmentatin of endotoxicity and elevations of the above cytokines. Experimental studies : The hepatic production of Et binding protein was increased when the Kupffer cells were preincubated in the medium containing ethanol and the resultant culture supernatant was added to the hepatocyte culture system. The amount of Et binding protein produced by the hepatocytes was increased as the ethanol concentration in the culture medium of Kupffer cells was increased. This endotoxin binding protein was proved to enhance the uptake of endotoxin and to suppress the production of TNF by the Kupffer cells. In acute ethanol-loaded rats, albumin-bound and highdensity lipoprotein (HDL) -bound Et was markedly increased. In chronic ethanolloaded rats, HDL-bound Et was increased. In the chronic ethanol-fed rats with an additional 5g/kg bw of ethanol load, blood TNF and ALT levels were increased, when the HDL-bound Et was not further increased. In vitro study revealed that albumin and HDL inhibited Et uptake and TNF production by Kupffer cells. These data suggest that albumin and HDL may act as Et binding proteins and attenuate endotoxicity in alcoholics.