Relation of endotoxin, endotoxin binding proteins and macrophages to severe alcoholic liver injury and multiple organ failure
Relation of endotoxin, endotoxin binding proteins and macrophages to severe alcoholic liver injury and multiple organ failure
复制标题
DOI：
10.1097/01.alc.0000189278.30237.e9
复制
发表时间：
2005-11-01
影响因子：
3.2
通讯作者：
Fukui, H
中科院分区：
文献类型：
--
作者：
Fukui, H
我们对105例酒精性肝损伤患者的回顾性分析证实，重度酒精性肝炎（SAH）患者表现为严重的高胆红素血症，肝脏生物合成能力降低，明显的急性炎症反应，并发展为多器官功能衰竭（MOF）。多因素分析采用考克斯比例风险模型显示血清C反应蛋白和DIC是SAH、LC+AH和AH组中显著的独立预后因素。改良的内毒素测定法显示血浆内毒素水平随酒精性肝损伤的加重而升高。在大多数幸存者中，血浆Et水平在恢复期下降。AH和LC+AH患者急性期血清IL-6和IL-8水平较高，尤其是死亡者和SAH患者。在恢复期，存活者的这些细胞因子水平趋于降低，但在非存活者中，IL-6保持高水平，IL-8进一步升高。血清中HDL和白蛋白水平随着酒精性肝损伤的进展而降低，它们通过抑制巨噬细胞的内毒素摄取和TNF产生来对抗内毒素。动物实验支持HDL和白蛋白的内毒素结合能力的增加可以作为慢性乙醇负荷大鼠中对抗内毒素的保护机制，并且向这些大鼠添加高剂量乙醇可能导致内毒素的结合和灭活受损。脂多糖结合蛋白（LBP）可增强巨噬细胞的内毒素摄取和TNF产生，在酒精性肝损伤患者中普遍增加。这种血液中内毒素结合蛋白之间的不平衡可能诱导严重酒精性肝损伤患者中巨噬细胞过度产生细胞因子。我们的动物实验进一步表明，额外给予高剂量乙醇，慢性酒精喂养大鼠的内毒素清除率下降，增加肝外蓄积的内毒素和血浆TNF升高。脾巨噬细胞和肺泡巨噬细胞被证明是重要的内毒素摄取，并在大鼠给予大量的酒精TNF的过度生产。在大鼠LBP存在下的体外培养实验表明这些巨噬细胞在TNF-α过量产生中的作用。当比较给予酒精的大鼠中各种巨噬细胞的功能时，注意到肺泡巨噬细胞分泌最大的TNF-α。总之，内毒素血症及其对肝外巨噬细胞的影响可能在严重酒精性肝损伤和MOF的进展中起关键作用。
Our retrospective analysis of 105 patients with alcoholic liver injury confirmed that patients with severe alcoholic hepatitis (SAH) showed severe hyperbilirubinemia, reduced hepatic biosynthetic capacity, and marked acute inflammatory reactions, and developed multiple organ failure (MOF). Multivariate analysis using the Cox proportional hazards model showed serum C-reactive protein and DIC as significant independent prognostic factors among SAH, LC+AH, and AH groups. Improved assay showed an increase of plasma endotoxin with the progression of alcoholic liver injury. In most survivors, plasma Et levels decreased in the recovery phase. Serum interleukin (IL)-6 and IL-8 levels in the acute phase were high in patients with AH and LC+AH, especially in non-survivors and in patients with SAH. In the recovery phase, these cytokine levels in survivors tended to decrease, but in non-survivors, IL-6 remained high, and IL-8 further increased. Serum levels of HDL and albumin, which are protective against endotoxicity by inhibiting endotoxin uptake and TNF production by macrophages, were decreased with the progression of alcoholic liver injury. Animal experiments supported that the increase in endotoxin-binding capacity of HDL and albumin may serve as a protective mechanism against endotoxin in chronic ethanol-loaded rats and that an addition of high-dose ethanol to these rats may lead to impaired binding and inactivation of endotoxin. Lipopolysaccharide-binding protein (LBP) which enhances endotoxin uptake and TNF production by macrophages, was generally increased in patients with alcoholic liver injury. This imbalance among endotoxin binding proteins in the blood may induce overproduction of cytokines by macrophages in patients with severe alcoholic liver injury. Our animal experiments further revealed that an additional administration of a high-dose ethanol to chronic alcohol-fed rats led to decrease of endotoxin clearance, increased extrahepatic accumulation of endotoxin and elevation of plasma TNF. The splenic macrophages and pulmonary alveolar macrophages are demonstrated to be important for endotoxin uptake, and excessive production of TNF in rats given large amounts of alcohol. An in vitro culture experiment in the presence of rat LBP suggested a role of these macrophages in excessive production of TNF-alpha. When the functions of various macrophages were compared in rats given alcohol, maximum TNF-alpha secretion was noted in alveolar macrophages, In conclusion, endotoxemia and its effects on extrahepatic macrophages may play key roles in the progression of severe alcoholic liver injury and MOF.