肠源性内毒素血症与肝病

肠道内有大量细菌生长,如细菌过度繁殖,内毒素产生过量,或肠黏膜屏障受损内毒素吸收入门静脉增多,或肝内Kupffer细胞吞噬功能低下,内毒素的吸收量超过了肝脏的清除能力,内毒素即可“泛滥”（spillover）进人体循环而形成内毒素血症。     

Kupffer细胞在内毒素诱导肝损伤发病机制中的作用

内毒素脂多糖(lipopolysaccharide,LPS)诱导的肝损伤参与了多种肝脏疾病发生发展的进程,肝脏巨噬细胞(即Kupffer细胞)在LPS诱导肝损伤的过程中发挥着重要作用.一方面,Kupffer细胞通过LPS4信号转导系统被激活而释放促炎因子,并在肝脏内其他细胞的相互作用下介导肝脏损害:另一方面,Kupffer细胞的活性又被LPS耐受和其他生理调控机制所抑制,避免Kupffer细胞活化而诱导肝脏损害.因此,Kupffer细胞同时受到激活和抑制性因素的共同作用并维持在相对平衡状态,一旦这种平衡机制被病理因素打破,就可能招致肝脏损伤;而Kupffer细胞活性的抑制性干预就成为保护内毒素诱导肝损伤的重要策略.     

肝硬化时肠源性内毒素血症形成机制的研究进展

大量实验证实,多种肝病尤其是慢性肝病不同程度伴随肠源性内毒素血症（intestinal endotoxemia,IETM）,其中肝硬化患者IETM的发生率为79．0％～92．0％,肝功能损害越重,内毒素水平越高。肝硬化时肠道菌群失调,肠黏膜屏障功能减低,肝脏清除内毒素能力下降,内毒素水平升高,IETM发生率增加,IETM形成后进一步加重肝脏损伤,导致肝硬化患者感染、腹水、上消化道出血、肝肾综合征、肝性脑病等并发症的发生,两者之间形成恶性循环。现将目前关于肝硬化时IETM形成机制的研究进展综述如下。     

内毒素对正常和肝硬化大鼠肝功能的影响及其与肿瘤坏死因子-α的关系

肝硬化门脉高压患者由于机体抵抗力的降低,极易发生革兰阴性菌感染,并形成内毒素血症;由于门体分流的形成、肝脏对内毒素清除能力的减退以及肠道内毒素生成和摄取的增多,也容易导致内毒素血症的发生。内毒素血症不仅具有加剧门脉高压高动力循环、加重肝硬化时的肾功能损害、诱发或加重肝性脑病等多种作用,而且可以造成肝功能不全综合征［１］。肿瘤坏死因子α（ｔｕｍｏｒｎｅｃｒｏｓｉｓｆａｃｔｏｒα,ＴＮＦα）是介导内毒素毒性作用的主要细胞因子［２］。本文主要研究了内毒素对实验性肝硬化和正常大鼠肝功能的损伤作用及…     

诺氟沙星、米雅对肝硬化患者自发性腹膜炎的预防作用观察

肠源性内毒素血症与肝硬化的关系日益受到重视 ,肝硬化患者发生自发性腹膜炎 (SBP)及内毒素血症后 ,既可加重原有的肝脏损害 ,又可诱发全身代谢和血流动力学紊乱 ,参与多种并发症的发生和发展 ,严重影响肝硬化患者的预后。目前认为 ,SPB及内毒素血症与肝功能损害互为因果 ,而内毒素对肝脏的损伤除直接毒性作用外 ,主要由于某些细胞因子介导所致[1] 。 2 0 0 0年 6月至 2 0 0 1年 1 0月 ,我们对晚期肝硬化患者于肠道去污及调整微生态治疗前后测定其血清内毒素及白细胞介素 - 6 (IL- 6 )水平 ,观察 SBP的发生情况 ,旨在了解其治疗前后血…     

重型肝炎与肠源性内毒素血症

近年来,肠源性内毒素血症(intestinal endo-toxemia,IETM)与肝脏疾病之间的关系逐渐引起人们的关注。动物研究已经证实在各种实验性肝脏疾病均伴有IETM的发生,而且临床观察也显示在重型肝炎患者出现严重IETM的发生率高达80%～100%[1]。随着研究的深入,IETM在肝病患者的发生、发展、损伤机制及治疗方面都出现了一些新的理论和方法,同时也面临许多问题,本文将就此作一综述。内毒素的来源一般认为重型肝炎时内毒素主要来源于肠道菌群。正常情况下肠道菌群对许多外来物质的吸收起重要作用,但当某些疾病导致肠道菌群失调或移位时,产生的有…     

肠道菌群与酒精性肝病

酒精性肝病(alcoholic liver disease,ALD)是许多西方国家肝硬化最常见的病因。乙醇代谢所产生的中间产物之间复杂的相互作用是ALD重要的发病机制。长期饮酒的患者,肠道微生物的组成发生了变化,尤其是革兰氏阴性菌数量增多,这将导致内毒素血症,使得免疫系统超活化。肝脏的Kupffer细胞表面有两种可以识别内毒素的受体表明了肠-肝轴的重要性,近年来正在探索新的治疗方法以延缓ALD改变肠道菌群的进程。主要着力于抗生素、益生元、益生菌、合生元的合理利用。     

肝硬化肠源性内毒素血症临床研究现状

内毒素是革兰氏阴性菌（G-）菌胞壁的脂多糖（LPS）,其主要来源于肠道菌群,通常在细菌死亡后由胞壁崩解自溶时释放,也可在细菌代谢过程中以发疱方式产生。临床上约有79%~92%的肝硬化患者发生肠源性内毒素血症（IETM）。     

内毒素与肝脏微循环

肝脏微循环障碍是许多急、慢性肝损伤反应的重要步骤.尽管其确切病理机制尚不清楚,但普遍认为内毒素在肝脏微循环障碍过程中具有重要作用.内毒素通过直接损害肝脏或间接激活肝内的Kupffer细胞、内皮细胞和星状细胞等,诱导一系列介质的释放,引起肝脏微血管反应.本文就近年来有关内毒素诱导肝脏微循环障碍的细胞分子机制作一阐述.     

肝硬化肠源性内毒素血症的检测及其临床评价

内毒索血症在各种肝病，尤其是重症肝炎和肝硬化时发生率高，影响着病情发展及预后。肠源性内毒索是引起患者体循环内毒素水平升高的主要原因，故称这种内毒索血症为肠源性内毒索血症。其发生的主要原因有：肠内菌群紊乱及细菌过度生长、肠粘膜屏障功能受损、肝脏对内毒索的降解功能减弱、门体分流以及体液解毒功能降低等原因。肝硬化患者内毒索血症的发生率高，可反复波动出现，直接或间接的加剧肝细胞的损害，加     

Endotoxemia and its compensatory mechanisms in experimental liver cirrhosis

This study was performed in order to elucidate the mechanisms of systemic endotoxemia in liver cirrhosis. For this purpose, the method of measuring biliary endotoxin was established. Endotoxin levels between in the bile and in the plasma in cirrhosis were compared using a modified method of chromogenic quantitative endotoxin assay in an attempt to clarify liver function of clearing portal endotoxin originated from the gut. And functional activities of the reticuloendothelial system were also examined by radioassay with 59Fe-labelled iron-chondroitin sulfate colloid and by enzymohistochemistry of acid phosphatase. Both the plasma and biliary endotoxin levels in liver cirrhosis were significantly higher, compared to those in control. The functional activities of the reticuloendothelial system, particularly of the Kupffer cells, were decreased in liver cirrhosis. These data provide evidence that in liver cirrhosis systemic endotoxemia is mainly due to a decrease of functional activities of Kupffer cells. On the other hand, the excretion of endotoxin into the bile is increased, compensating the decreased functional activities of Kupffer cells. This implies that the uptake of endotoxin and its excretion into the bile by hepatocytes might be one of the mechanisms of clearing excess endotoxin in the plasma in liver cirrhosis. This study also draws the importance of measurements of endotoxin levels in the bile in liver diseases.     

Kupffer cells and alcoholic liver disease.

Liver disease is a major cause of illness and death worldwide. A central component in the complex network leading to the development of alcoholic liver disease is the activation of Kupffer cells by endotoxin and other soluble mediators. Alcohol consumption induces a state of "leaky gut increasing plasma and liver endotoxin levels. When Kupffer cells become activated, they interact with a complex of proteins located on the extracellular membrane signaling to produce a wide array of soluble factors, including cytokines, chemokines, growth factors, cyclooxygenase and lipoxygenase metabolites, and reactive oxygen species such as superoxide anion, hydrogen peroxide, and nitric oxide, all of which provide physiologically diverse and pivotal paracrine effects on all other liver cell types and, ultimately, liver injury. Kupffer cells are also central to the liver homeostatic response to injury as upon cellular degenerative changes, they immediately respond to the insult and release mediators to orchestrate inflammatory and reparative responses. Thus, the homeostatic responses are initiated by Kupffer cell-derived mediators at the cellular level and underlie the liver s defense and reparative mechanisms against injury. In order to understand better the role of Kupffer cells in the onset of liver injury, animal models in which Kupffer cells are inactivated, and cell culture settings (e.g. co-cultures) are being used with promising results that advance our understanding of alcoholic liver disease.     

Mannose-conjugated alendronate selectively depletes Kupffer cells and inhibits endotoxemic shock in the mice.

To elucidate the roles of Kupffer cells in the host-defense mechanisms and liver injury, we synthesized a mannose-conjugated alendronate (MANA) and examined its effects on Kupffer cells and lipopolysaccharide (LPS)-induced liver injury in the mice. Intravenous administration of a small amount of MANA (50mumol/kg) rapidly and selectively depleted Kupffer cells in the mice. The depletion of Kupffer cells by MANA resulted in a marked decrease of the production of both TNF-alpha and IL-1beta in the plasma during the liver injury induced by low (1mg/kg) and lethal (75mg/kg) doses of LPS. The effect was so remarkable that all animals treated with a lethal dose of LPS survived without any sign of endotoxemia. These findings indicate that Kupffer cells play critical roles in the development of endotoxemia, and that MANA will be useful in studies to elucidate pathophysiological roles of Kupffer cells in various liver diseases.     

Superoxide anion generating capacity and lysosomal enzyme activities of Kupffer cells in galactosamine induced hepatitis

To elucidate the function of the reticuloendothelial system of liver in hepatic injury, we investigated the effect of endotoxins on superoxide anion (O-2) generating capacity and lysosomal enzyme activities of Kupffer cells isolated from rats treated with galactosamine (Gal N), with Gal N supplemented with polymyxin B (Polymyxin B-Gal N), with lipopolysaccharide (LPS) and from control rats. After collagenase digestion of the liver and centrifugation over metrizamide gradient, Kupffer cells were prepared by the dish adherence procedure. O-2 production by the cells was examined as chemiluminescence during phagocytosis of latex particles and beta-glucuronidase activities were analyzed. High titers of endotoxemia were detected in LPS and Gal N rats by limulus test, while a low endotoxemia titer was found in Polymyxin B-Gal N rats. Hepatocyte damage was found in Gal N rats, but little was recognized in LPS and Polymyxin B-Gal N rats. In the latter groups, Kupffer cells, activated by endotoxins, showed the enhancement of chemiluminescence and a release of lysosomal enzyme. Though lysosomal enzyme was released from Kupffer cells in Gal N rats, chemiluminescence was slightly suppressed in spite of the high titer of endotoxemia. These results appear to be related to the consumption of O-2 during liver injury. The functional state of Kupffer cells was thus changed by the grade of endotoxemia and hepatic injury.     

The role of intestinal endotoxin in liver injury: a long and evolving history

From the mid-1950s, it was observed that liver injury by a variety of toxins greatly sensitized the host to the effects of administered lipopolysaccharide. In the nutritional cirrhosis of choline deficiency, and in acute toxic injury as well, the need for the presence of enteric endotoxin was demonstrated. The universality of this association was striking for almost all agents associated with liver injury. In addition, the presence of endotoxemia in human liver disease was documented in the 1970s, when the hypothesis was first proposed, and correlated with the severity of the disease. Despite imposing evidence of the critical role of enteric endotoxin in liver injury, it did not excite much interest in investigators until the 1980s. With the ability to study effects of alcohol in newer delivery systems, and an increased understanding of the role of Kupffer cells in the process, the original hypothesis has been accepted. This historical review details the progress of this novel concept of disease initiation and suggests future directions to bring potential therapies to the bedside.     

Toll-like receptor-4 signaling and Kupffer cells play pivotal roles in the pathogenesis of non-alcoholic steatohepatitis

BACKGROUND/AIMS: Studies in animal models and humans suggest a link between endotoxemia and non-alcoholic steatohepatitis. Since Kupffer cells are responsible for clearing endotoxin and are activated via endotoxin interaction with Toll-like receptor 4 (TLR-4), we examined the relationship between hepatic TLR-4 expression and Kupffer cell content during the genesis of steatohepatitis. METHODS: Male C57BL/6, C3H/HouJ and TLR-4 mutant C3H/HeJ mice were fed control or methionine/choline-deficient diet (MCDD). In one group of C57BL/6 mice, Kupffer cells were depleted by weekly intraperitoneal injections of clodronate liposomes. After 3 weeks, serum ALT activity and portal endotoxin levels were measured. Real-time PCR was used to examine mRNA expression of TLR-4, TLR-2, CD14, MD-2, TGFbeta, TNFalpha, CD36, PPAR-alpha, liver fatty acid binding protein (L-FABP) and collagen alpha1. RESULTS: We observed histological evidence typical of steatohepatitis, portal endotoxemia and enhanced TLR-4 expression in wild type mice fed MCDD. In contrast, injury and lipid accumulation markers were significantly lower in TLR-4 mutant mice. Destruction of Kupffer cells with clodronate liposomes blunted histological evidence of steatohepatitis and prevented increases in TLR-4 expression. CONCLUSIONS: These findings demonstrate the importance of TLR-4 signaling and underscore a direct link between TLR-4 and Kupffer cells in the pathogenesis of steatohepatitis.     

Modulation of F-met-leu-phe Induced Chemotactic Activity and Superoxide Production by Neutrophils during Chronic Ethanol Intoxication

Chronic alcohol consumption has been associated with increased migration of neutrophils into liver that could contribute to the development of alcoholic liver disease. Mild endotoxemia may be at least partially responsible for this condition since endotoxemia was shown to be present in virtually all chronic alcoholics. This study examines the release of superoxide anion and chemotactic activity by Kupffer cells and sequestered hepatic as well as blood neutrophils during chronic alcohol intoxication (16 weeks) alone, and following an intravenous injection of Escherichia coli lipopolysaccharide (LPS) (1 mg/kg) 3 hr before cell isolation. Chronic ethanol consumption increased the total neutrophil yield per liver, but did not change the f-met-leu-phe induced chemotactic activity by both hepatic and blood neutrophils. However, the combined insults of ethanol and LPS increased the chemotactic activity and superoxide anion generation by these cells. Plasma from ethanol-fed rats was highly chemotactic to syngeneic normal rat neutrophils. This activity was increased 1.75-fold in the plasma obtained from chronic ethanol plus endotoxin-injected rats. The chemotactic activity of Kupffer cells was not significantly modulated during ethanol intoxication plus endotoxin treatment. The f-met-leu-phe-induced superoxide anion release by Kupffer cells was enhanced after LPS treatment. Chronic ethanol consumption did not induce any effect on this parameter. These observations suggest that functional alterations in neutrophils during chronic ethanol intoxication may contribute to hepatic injury.