Thromboxane as a possible hepatotoxic factor increased by endotoxemia in obstructive jaundice

In a study using rats, we investigated whether liver damage induced by endotoxemia in obstructive jaundice is associated with thromboxane (TX) in order to acertain whether its vasoconstrictive and platelet aggregating properties play a role in reducing liver blood flow. The rats were divided into the following 5 groups; a control group, an endotoxin (Et) group, a bile duct ligation (BDL) group, a bile duct ligation and endotoxin (BDL + Et) group and an OKY046 (Thromboxane synthetase inhibitor) treated bile duct ligation + endotoxin (OKY-BDL + Et) group. The blood TXB2 levels in the Et, BDL and BDL + Et groups were higher than those in the control group. The liver TXB2 levels in the Et and BDL + Et groups were also higher than those in the control group. Liver phospholipids and liver blood flow decreased in the BDL + Et group, whereas in the OKY-BDL + Et group they returned close to the control group levels by decreasing the TXB2 levels in both the liver and blood to normal. These results suggest that the high level of TX in the blood and liver tissue may further aggrevate the liver during endotoxemia in obstructive jaundice by inhibiting liver blood flow.     

Inhibition of thromboxane production might ameliorate liver blood flow in shock

We investigated whether thromboxane (TX), a vasoconstrictor, contributes to liver disturbance in shock by reducing liver blood flow. Subjects and methods: experimental groups: Sham, Et: endotoxin 4mg/kg, BDL + Et: bile duct ligation with Et, OKY. BDL + BDL + Et with infusion of OKYO46 (TX synthetase inhibitor) 5mg, HT: three days after 70% hepatectomy, OKY. HT: HT receiving OKYO46. We evaluated prostanoid and morbidity in hepatectomized cases. Measurement: TX, liver phospholipid, liver blood flow, endotoxin. Results: Higher TX levels in blood and liver, and reduced liver phospholipid and liver blood flow in BDL + Et returned close to sham by OKYO46. High blood endotoxin in HT decreased by OKYO46. Intraoperative blood losses in cases with postoperative intraabdominal infection or hepatic failure were greater than those without complication. Hepatectomized cases with intraabdominal infection showed higher blood TX than those without complication. TX might be associated with decreased liver blood flow and with postoperative complication during shock. To reduce TX production would be beneficial in shock by ameliorating liver blood flow.     

Gut endotoxin restriction prevents catabolic changes in glutamine metabolism after surgery in the bile duct-ligated rat.

OBJECTIVE: The objective of this study was to investigate the role of gut-derived endotoxemia in postoperative glutamine (GLN) metabolism of bile duct-ligated rats. SUMMARY BACKGROUND DATA: Postoperative complications in patients with obstructive jaundice are associated with gut-derived endotoxemia. In experimental endotoxemia, catabolic changes in GLN metabolism have been reported. Glutamine balance is considered important in preventing postsurgical complications. METHODS: Male Wistar rats were treated orally with the endotoxin binder cholestyramine (n = 24, 150 mg/day) or saline (n = 24). On day 7, groups received a SHAM operation or a bile duct ligation (BDL). On day 21, all rats were subjected to a laparotomy followed 24 hours later by blood flow measurements and blood sampling. Glutamine organ handling was determined for the gut, liver, and one hindlimb. Intracellular GLN muscle concentrations were determined. RESULTS: Compared to the SHAM groups, BDL rats showed lower gut uptake of GLN (28%, p < 0.05); a reversal of liver GLN release to an uptake (p < 0.05); higher GLN release from the hindlimb (p < 0.05); and lower intracellular muscle GLN concentration (32%, p < 0.05). Cholestyramine treatment in BDL rats maintained GLN organ handling and muscle GLN concentrations at SHAM levels. CONCLUSIONS: Disturbances in postoperative GLN metabolism in BDL rats can be prevented by gut endotoxin restriction. Gut-derived endotoxemia after surgery in obstructive jaundice dictates GLN metabolism.     

Effect of Oral Glutamine Administration on Bacterial Tanslocation, Endotoxemia, Liver and Ileal Morphology, and Apoptosis in Rats with Obstructive Jaundice

Postoperative complications in patients with obstructive jaundice remain increased when associated with endotoxemia and the inflammatory response due to gut barrier failure. Administration of glutamine has been proposed to maintain the integrity of the gut mucosa and thus reduce bacterial translocation (BT), but the effects of this pretreatment on apoptosis and histologic morphology of various organs affected by BT in obstructive jaundice have not been studied. We therefore studied the effects of oral glutamine supplementation on endotoxemia, BT, liver and terminal ileal morphology, and apoptosis in an experimental model of obstructive jaundice. A total of 60 male Wistar rats were randomly divided into four groups of 15 each: I, controls; II, sham-operated; III, bile duct ligation (BDL); IV, BDL + glutamine (4.5 g/kg/day in drinking water). Ileal samples for histology, DNA and protein content, liver biopsies, mesenteric lymph nodes (MLNs) for culture, and portal and systemic blood samples for endotoxin measurements were obtained 10 days later. Compared to the controls, a significant increase in contaminated MLN and liver samples and increased endotoxemia were noted in group III (p < 0.01) but were significantly reduced in group IV (p < 0.05). Group IV also had a significantly higher number of mitoses per crypt (M/c) (p < 0.05), less apoptotic body counts (ABCs) (p < 0.05), and a higher DNA content than did group III (p < 0.05). Liver biopsies from group III displayed typical changes of large duct obstruction that significantly improved after glutamine treatment, with decreased ductular proliferation. We concluded that supplementation of oral glutamine in the presence of obstructive jaundice ameliorates BT, endotoxemia, and apoptosis and improves the ileal and liver histology.     

阻塞性黄疸犬胆总管直径和压力及肝功能变化

目的：探讨阻塞性黄疸犬胆总管直径、压力和肝脏功能的变化规律。方法：建立犬结扎胆总管致阻塞性黄疸模型,30只犬随机分为对照组、阻塞5d组、阻塞10d组、阻塞15d组及阻塞20d组。分别测量各组实验犬胆总管直径、压力,并检测肝功能指标,包括血清总胆红素（TBIL）、直接胆红素（DBIL）、谷丙转氨酶（ALT）、谷草转氨酶（AST）和碱性磷酸酶（ALP）。结果：随着胆总管结扎时间的延长,胆总管压力逐渐升高,5d后达到最高峰;而阻塞期间胆总管直径则持续扩张,20d后为正常值的近10倍。血清中的ALP、TBIL、DBIL、ALT和AST水平快速升高,达到峰值后开始下降并趋于平稳,但仍高于对照组,且差异有统计学意义（P〈0.01）。结论：犬胆总管阻塞后持续扩张且压力迅速增加,肝脏功能发生明显的损害,但肝功能指标值的高低并不能反映肝脏组织的实际损害程度。     

Beneficial effects of growth hormone and insulin-like growth factor I on intestinal bacterial translocation, endotoxemia, and apoptosis in experimentally jaundiced rats

BACKGROUND: This study was undertaken to investigate the effect of growth hormone (GH) and insulin-like growth factor I (IGF-I), two well-known growth factors, on bacterial translocation, endotoxemia, enterocyte apoptosis, and intestinal and liver histology in a model of experimental obstructive jaundice in rats. STUDY DESIGN: One hundred six male Wistar rats were divided into five groups: I (n = 21), controls; II (n = 22), sham operated; III (n = 22), bile duct ligation (BDL); IV (n = 21), BDL and GH treatment; and V (n = 20), BDL and IGF-I administration. By the end of the experiment, on day 10, blood bilirubin was determined, and mesenteric lymph nodes, liver specimens, and bile from the bile duct stump were cultured. Endotoxin was measured in portal and aortic blood. Tissue samples from the terminal ileum and liver were examined histologically and apoptotic body count (ABC) in intestinal mucosa was evaluated. Mucosal DNA and protein content were also determined. RESULTS: Bilirubin increased significantly after BDL (p < 0.001). Bile from the bile duct was sterile. In group III, MLN and liver specimens were contaminated by gut origin bacteria (significant versus group I and II, p < 0.001, respectively). GH reduced significantly positive cultures (p < 0.01), and IGF-I had no effect. BDL resulted in significant increase in portal and aortic endotoxemia (p < 0.001); treatment with GH and IGF-I reduced it (p < 0.001). Mucosal DNA and protein content were reduced in animals with BDL and after treatment with GH or IGF-I; an increase to almost normal levels was noted in DNA, but not in protein. Overall the ileal architecture remained intact in all animal groups. The ABC increased after BDL. After GH and IGF-I administration, the ABC decreased significantly, and there was no difference between GH and IGF-I treated animals. After BDL, liver biopsies displayed typical changes of biliary obstruction, which were significantly improved after administration of GH and IGF-I. CONCLUSIONS: Treatment with GH and IGF-I in rats with experimental obstructive jaundice reduces endotoxemia, and it improves liver histology. Apoptosis, in the intestinal epithelium, may serve as a morphologic marker of the ileal mucosal integrity, demonstrating the proliferative potential of GH and IGF-I in cases of obstructive jaundice, and this might be of potential value in patients with such conditions.     

Experimental obstructive jaundice disrupts intestinal mucosal barrier by altering occludin expression: beneficial effect of bombesin and neurotensin

BACKGROUND: Little is known of the molecular events leading to increased intestinal permeability in obstructive jaundice. This study was undertaken to investigate the influence of experimental obstructive jaundice on the expression of the tight junction-associated protein occludin in the intestinal epithelium. STUDY DESIGN: Seventy male Wistar rats were randomly divided into five groups: I, controls; II, sham-operated; III, bile duct ligation (BDL); IV, BDL+Bombesin (BBS) (30 microg/kg/d); and V, BDL+Neurotensin (NT) (300 microg/kg/d). At the end of the experiment, on day 10, endotoxin was measured in portal and aortic blood. Tissue sections of the terminal ileum were examined histologically and immunohistochemically for evaluation of occludin expression in the intestinal epithelium. Lipid peroxidation and protein oxidation were determined on tissue homogenates from terminal ileum and microbiologic analysis was performed in cecal contents. RESULTS: Obstructive jaundice resulted in portal and aortic endotoxemia, which was significantly reduced after BBS or NT administration. In the BDL group, there was total loss of occludin expression in numerous enterocytes mainly at the upper third of the villi, while a gradient of positivity existed from crypt to tip. Occludin expression was restored to control state after treatment with BBS or NT. In addition, both peptides reduced intestinal lipid peroxidation, while BBS reduced protein oxidation as well. CONCLUSIONS: Experimental obstructive jaundice induces regional loss of occludin expression in the intestinal epithelium, which may be a key factor contributing to the disruption of the mucosal barrier. Gut regulatory peptides BBS and NT prevent this alteration, leading to lower portal and systemic endotoxemia.     

Effect of Bile Acid Replacement on Endotoxin-induced Tumor Necrosis Factor-a Production in Obstructive Jaundice

There is a high incidence of perioperative morbidity and mortality in patients with obstructive jaundice due to sepsis. Tumor necrosis factor-a (TNF-a) is considered a crucial mediator in inducing and processing the inflammatory cascade. We hypothesize that obstructive jaundice leads to an increased endotoxin-induced TNF-a production and that intestinal bile acid replacement can prevent this phenomenon. Sprague-Dawley rats were randomized to three groups of 12 animals each. Group 1 underwent common bile duct ligation (CBDL) with oral intestinal bile acid (deoxycholic acid 5 mg/100 g body weight/3 times daily) replacement (CBDL + bile acid); group 2 underwent common bile duct ligation with the same amount of normal saline replacement orally (CBDL + saline); and group 3 underwent a sham operation (sham control). After 2 days, endotoxin was given to the animals, and after 90 minutes, tissues (liver and lung) and blood were collected for checking the TNF-a levels and biochemical analyses. Comparisons among these three groups were performed and recorded. While serum and tissue (liver and lung) TNF-a levels of group 2 (CBDL + saline) were significantly increased after endotoxin challenge, these elevations were reduced to control levels (sham control) following oral replacement of intestinal bile acid (CBDL + bile acid). Obstructive jaundice leads to an increased endotoxin-induced TNF-a production and intestinal bile acid replacement can inhibit this phenomenon.     

The effect of oral sodium taurocholate on endotoxemia and intestinal anastomotic wound healing in rats with obstructive jaundice

The effect of sodium taurocholate (ST) on endotoxemia and intestinal anastomotic wound healing in obstructive jaundice was evaluated in a rat model. A total of 108 Wistar rats were divided into three main groups. Thus, 36 animals were given ileal anastomosis (IA) alone (IA group), 36 were given IA with bile duct ligation (BDL) (IA+BDL group), and 36 were given IA with BDL and oral sodium taurocholate (ST) (IA+BDL+ST group). These three main groups were then divided into three equal subgroups, A, B, and C, which were killed on postoperative days (POD), 3, 5, and 9, respectively. In the IA+BDL+ST group, ST was administrated perioperatively and ceased from POD 5 onwards. The anastomotic hydroxyproline level and bursting pressure were significantly lower in the IA+BDL animals compared with the others on POD 3, 5, and 9 (P<0.008). Endotoxemia was prominent in the IA+BDL group from POD 3 (P=0.011). After ST was stopped, 42% of the AI+BDL+ST animals developed endotoxemia by POD 9 (P=0.008). Anastomotic wound healing was better in the IA+BDL+ST group (P<0.01). These findings suggest that endotoxemia and its adverse effects on wound healing in obstructive jaundice can be prevented by the oral administration of ST.     

蛙皮素对梗阻性黄疸大鼠的肝脏保护性实验研究

目的探讨蛙皮素对梗阻性黄疸大鼠肝脏的保护作用。方法40只Wistar雄性大鼠随机分成4组：正常组、假手术组、阻黄组、阻黄＋蛙皮素治疗组。术后第10天，检测下腔静脉血ALT、BIL-T、LPS值，测定肝脏氧化应激SOD、MDA、GSH、GST水平，光镜观察肝脏组织结构，免疫组化表达肝脏MCP-1。结果蛙皮素降低ALT、LPS水平，减轻肝脏氧化应激，减少汇管区炎症细胞浸润，弱化MCP-1免疫组化阳性表达，对BIL-T无影响。讨论蛙皮素对梗阻性黄疸大鼠肝脏损伤有保护作用，这一结果为l临床治疗胆道梗阻肝脏损害提供一种新的方法。     

去氢胆酸钠治疗阻塞性黄疸内毒素血症的实验研究

目的:观察去氢胆酸钠降低阻塞性黄疸时血清内毒素的效果。方法:将CD大鼠随机分成对照组、胆总管结扎组和胆总管结扎-胆盐治疗组,测定各组血清胆红素、免疫球蛋白IgG、IgM和内毒素。结果:胆总管结扎-胆盐治疗组血清内毒素明显下降（P<0．01）,血清免疫球蛋白IgG、IgM有较明显升高。结论:口服去氢胆酸钠可能有助于降低阻塞性黄疸的血清内毒素。     

Bombesin and neurotensin reduce endotoxemia, intestinal oxidative stress, and apoptosis in experimental obstructive jaundice

OBJECTIVE: To evaluate the effect of bombesin (BBS) and neurotensin (NT) on intestinal histopathology, intestinal oxidative stress, and endotoxemia in experimental obstructive jaundice. SUMMARY BACKGROUND DATA: Obstructive jaundice compromises gut barrier function, resulting in endotoxemia. BBS and NT, exerting various biologic actions on gastrointestinal tissues, preserve gut mucosal integrity in cases of injury or atrophy. METHODS: Seventy male Wistar rats were randomly divided into 5 groups: I = controls, II = sham operated, III = bile duct ligation (BDL), IV = BDL + BBS (30 microg/kg/d), V = BDL + NT (300 microg/kg/d). By the end of the experiment, on day 10, endotoxin was measured in portal and aortic blood. Tissue sections of the terminal ileum were examined histologically, and villus density, mucosal thickness, mitotic activity and apoptosis in crypts were assessed. In addition, ileal mucosa was analyzed for DNA and protein content. To estimate intestinal oxidant/antioxidant equilibrium, lipid peroxidation, protein oxidation, and thiol redox state (reduced glutathione [GSH], oxidized glutathione [GSSG], total nonprotein mixed disulfides [NPSSR], protein thiols [PSH], and protein disulfides [PSSP]) were determined on tissue homogenates from the terminal ileum. RESULTS: BBS or NT administration significantly reduced portal and systemic endotoxemia observed in obstructive jaundice. Both factors reversed obstructive jaundice-induced morphologic features of intestinal atrophy, increasing villus density and mucosal thickness. This effect was accompanied by induction of mitoses and reduction of apoptosis in intestinal crypts. Mucosal DNA and protein content were reduced, although not to significant levels, in BDL animals and restored to control levels after BBS or NT treatment. Moreover, BBS or NT administration protected the intestine in jaundiced rats against oxidative stress, as demonstrated by reduction of intestinal lipid peroxidation, increase of the antioxidant GSH, and decrease of the oxidized forms GSSG and NPSSR, while BBS additionally reduced protein oxidation as well. CONCLUSIONS: Administration of BBS or NT in bile duct-ligated rats exerts beneficial effects on intestinal oxidative stress, cell proliferation, apoptosis, and endotoxemia. This observation might be of potential value in patients with extrahepatic cholestasis.     

Treatment with recombinant bactericidal/permeability-increasing protein to prevent endotoxin-induced mortality in bile duct-ligated rats.

BACKGROUND: Operation in patients with obstructive jaundice is associated with substantial morbidity because of increased susceptibility to endotoxin (lipopolysaccharide) and the inflammatory cascade. Different interventions to reduce endotoxemia and cytokine induction, and resulting complications, have been studied. Bactericidal/permeability-increasing protein (BPI) is a naturally occurring endotoxin-binding protein produced in neutrophils. It binds endotoxin, neutralizing the activity and inhibiting cytokine production by mononuclear cells. In experimental endotoxemia in animals and in healthy human volunteers, BPI has shown a protective effect. The aim of this study was to determine whether BPI could protect against increased endotoxin sensitivity in rats with obstructive jaundice and reduce endotoxin-induced mortality. STUDY DESIGN: Male Wistar rats were used. Intraperitoneal Escherichia coli 2mg/kg was given 1 week after sham operation or bile duct ligation (BDL). Three groups were studied: sham, BDL with placebo, and BDL with 5 mg/kg recombinant BPI21. RESULTS: BDL rats were jaundiced (mean bilirubin 186 micromol/L; no difference between BDL rats without or with BPI). Bilirubin remained less than 1 micromol/L in sham-operated rats (p = 0.002). Endotoxin levels were 3.4pg/mL in sham controls and 3.1 pg/mL in BDL rats before administration of lipopolysaccharide (p = NS). Two hours after administration, levels were 615.4ng/mL in placebo BDL rats and 10 times less in BPI-treated BDL rats, at 60.2ng/mL (p=0.03). The same trend was found at 6 hours. At 24 hours, mortality was 1 of 6 in sham-operated rats (15%) versus 8 of 11 in untreated BDL rats (75%). BPI intervention reduced the death rate to 1 of 12 BDL rats (8%) (p = 0.003). CONCLUSIONS: Intraperitoneal recombinant BPI21 in rats having BDL reduced endotoxin-induced mortality from 75% to 8%, a death rate comparable to that in nonjaundiced rats. BPI could be an interesting perioperative treatment in clinical obstructive jaundice.     

梗阻性黄疸鼠肝脏血红素氧化酶-1及一氧化碳含量的研究

目的 探讨梗阻性黄疸时肝脏血红素氧化酶-1(HO-1)及血浆中一氧化碳(CO)含量的变化。方法 48只 Wistar 大鼠随机分为 4组:假手术对照组(CG)、梗阻性黄疸 7 d组(7 d)、梗阻性黄疸 14 d组(14 d)和梗阻性黄疸 21 d组(21 d),采用免疫组织化学法对肝细胞中 HO-1表达进行分析,应用双波长分光光度计法测定大鼠肝静脉、门静脉及下腔静脉血浆中CO含量。结果 梗阻性黄疸时 HO-1不仅在 Kupffer细胞中表达,而且在肝实质细胞中呈弥漫性表达上调,14 d组和 21 d组肝实质细胞中HO-1表达均较7 d组增加(P<0.01)。梗阻性黄疸各组肝静脉血浆中CO含量较CG组增高(P<0.05,P<0.01);14 d组门静脉血浆中CO含量升高明显,与CG组比较差异有显著性(P<0.05);梗阻性黄疸各组肝静脉血浆中 CO含量与同时间组门静脉血浆中 CO含量相比均显著升高(P<0.01)。梗阻性黄疸各时间组肝静脉CO含量的增高与肝实质细胞中HO-1表达的变化呈显著正相关(P<0.01)。结论 梗阻性黄疸时肝细胞HO-1表达上调致CO产生增多,从而有助于增加肝血流量并减少肝脏功能损害。     

Development and reversal of endotoxemia and endotoxin-related death in obstructive jaundice

Gut-derived endotoxemia has been implicated in postoperative complications in patients with jaundice. It is thought that absence of bile in the gut predisposes to portal absorption of endotoxin and endotoxemia is reversed by oral bile salt replacement or internal biliary drainage and return of bile to the gut, but not by external drainage. We believe that the importance of gastrointestinal bile flow has been overestimated and biliary obstruction and the integrity of hepatocyte and Kupffer cell function are more important in the development and reversal of endotoxemia. In experiment 1, serum endotoxin concentrations were measured in control rats (n = 10) after choledochovesical fistula (n = 15) and bile duct ligation (n = 15) and after relief of biliary obstruction by internal drainage (choledochoduodenostomy; n = 8) and sterile external drainage (choledochovesical fistula; n = 8), with a quantitative limulus assay. In experiment 2, mortality rates were measured in similar groups 48 hours after administration of oral endotoxin (5 mg/100 gm) and intravenous lead acetate (5 mg/100 gm). Bilirubin levels were elevated in bile duct ligation (192 +/- 13 mumols/L) compared with control animals and those with choledochovesical fistula, internal drainage, and external drainage (10.6 +/- 1.5 mumols/L). In experiment 1, significant portal endotoxemia and systemic endotoxemia occurred in bile duct ligation (portal, 130.4 +/- 12.9 pg/ml; systemic, 91.8 +/- 11.0 pg/ml) but not in choledochovesical fistula (portal, 49.3 +/- 17.1 pg/ml; systemic, 27.2 +/- 11.5 pg/ml). Relief of obstruction by both internal and external drainage reversed endotoxemia. In experiment 2, significant death occurred in bile duct ligation (13 of 15) but not in choledochovesical fistula (3 of 15), and relief of obstruction by both internal and external drainage prevented death. These results confirm that biliary obstruction is a more important factor than is gastrointestinal bile flow in the development and reversal of endotoxemia.     

阻塞性黄疸大鼠法尼酯衍生物X受体表达及加味大柴胡汤作用的研究

目的:研究法尼酯衍生物X受体(FXR)对胆汁酸代谢的作用,以及加味大柴胡汤对FXR的表达的影响.方法:制作急性阻塞性黄疸大鼠模型,分为7、14、21 d 3个时段,每个时段又分为胆总管结扎 加味大柴胡汤组、胆总管结扎 TUDCA、胆总管结扎组 生理盐水组、假手术 生理盐水组等4组,每组6只.生化检测ALT、TB、TBA、ALP;免疫组化法检测FXR蛋白表达.结果:胆道梗阻后,随梗阻时间的延长,FXR表达减弱.血清TBA、ALT、ALP、TB含量明显增加.加味大柴胡汤使FXR表达上调,血清TBA、ALT、ALP、TB明显下降,肝脏病变减轻.结论:阻塞性黄疸时FXR表达可调节胆汁酸代谢.加味大柴胡汤可以上调FXR蛋白表达,促进胆汁酸代谢,从而减轻肝脏损害.     

加味大柴胡汤加用L-精氨酸对阻黄大鼠血浆内毒素的影响

目的　探讨L 精氨酸、加味大柴胡汤及两者合用对保护阻塞性黄疸大鼠的肝功能、抑制脂质过氧化损伤、缓解内毒素血症的作用。方法　制作急性阻塞性黄疸大鼠模型 ,分为 7、14及 2 1d 3个时段 ,每个时段分为 5组 ,每组 6只大鼠。在各时相点 ,检测内毒素和NO2 -/NO3 -的含量。结果　门静脉血浆内毒素的含量 :胆管结扎 7d后 ,门静脉血浆内毒素含量BDL NS组明显高于其他组 (P <0 .0 1)。而BDL L Arg 中药组与BDL L Arg及BDL 中药组间比较差异有显著性 (P <0 .0 5 )。胆管结扎 14d ,门静脉血浆内毒素含量BDL L Arg 中药组与BDL L Arg及BDL 中药组比较差异也有显著性 (P <0 .0 5 )。但在 2 1d时段门静脉内毒素含量BDL L Arg组与BDL NS组比差异无显著性 ,而BDL 中药组及BDL L Arg 中药组门静脉内毒素含量较上述两组差异有显著性 (P <0 .0 1)。结论　在阻塞性黄疸发病早、中期 ,采用加味大柴胡汤加L Arg治疗对保护肝功能与缓解内毒素血症作用较佳     

A research on the cholestasis caused by continuous endotoxemia

Intrahepatic cholestasis is often observed in patients without obstruction of the bile duct, who are suffering from severe prolonged infection in the field of peptic surgery. Clinical data were analyzed in recently experienced 18 cases which showed this kind of jaundice. In those case, high rates of endotoxemia and high rates of gram negative bacilli were seen. This fact made us infer that endotoxins might cause jaundice. In order to clarify the mechanism of the jaundice, we made an experimental model of persistent endotoxemia in rats. Low-dose endotoxin was infused continuously to Donryu-rats and bile-output was observed with external bile-guiding tube for 24 hours. In the endotoxin group, bile-output was significantly decreased whereas it was not changed in the control group. In addition, serum bilirubin was elevated in the endotoxin group, whereas it did not change in the control group. Blood-flow of liver tissue and systemic arterial blood pressure did not show any severe decrease under the continuous endotoxemia. Data of bile-output and bile acid showed bile acid independent flow might be depressed by endotoxin infusion. This model was thought to be under non-shock condition and useful to investigate jaundice seen in patients under continuous endotoxemia.     

Phenylalanine breath test as a method to evaluate hepatic dysfunction in obstructive jaundice

BACKGROUND: The purpose of this study was to investigate whether the hepatic dysfunction associated with obstructive jaundice can be measured from changes in expiratory 13CO2 levels after intravenous administration of l-[1-(13)C]phenylalanine, using a rat model of obstructive jaundice. MATERIALS AND METHODS: Under pentobarbital anesthesia, bile duct ligation (BDL) was performed (n=12). In the control group, simple laparotomy was performed (n=12). On postoperative day 7, 20 mg/kg l-[1-(13)C]phenylalanine was administered via the femoral vein. Phenylalanine breath test (PBT) was performed for 30 min. We compared single point of 13CO2 level (SPT: T: min) and sum of 13CO2 output (ST) values between BDL and control rats. We examined the correlation of SPT or ST with phenylalanine hydroxylase activity (PHA) and blood chemical parameters. RESULTS: Both SPT and ST values decreased in BDL compared to control 3 min after the start of PBT (SP10; 103+/-12 (per thousand) versus 84+/-16 (per thousand) P=0.025). PHA/g liver in BDL was significantly decreased compared to control (40.81+/-4.80 (U) versus 28.93+/-9.60 (U) P=0.008). PHA/g liver was correlated with SPT with correlation coefficient of more than 0.715, 10 min after the start of PBT, and the maximum correlation was at SP20 (r=0.801). Blood chemical parameters were correlated with S15 (total bilirubin, r=-0.717; alkaline phosphatase, r=-0.841; gamma-glutamyl transpeptidase, r=-0.759; alanine aminotransferase, r=-0.776; albumin, r=0.819). CONCLUSIONS: In the breath test with intravenously l-[1-(13)C]phenylalanine, hepatic dysfunction associated with obstructive jaundice could be measured in a short period.     

Altered peripheral amino acid uptake in obstructive jaundice

To characterize amino acid metabolism in obstructive jaundice, the amino acid uptake in tissues of bile duct-ligated (BDL) rats was determined. Fischer 344 rats underwent either bile duct ligation or sham laparotomy and were pair fed for 72 hr. Amino acid uptake was determined in peripheral skeletal muscle (quadriceps femoris, soleus, and rectus abdominis), liver, blood, and other tissues by accumulation of alpha-[14C]-aminoisobutyric acid following intracardiac injection. Although total hepatic amino acid uptake was unaltered in the BDL animals compared with the sham-operated controls, amino acid uptake in peripheral skeletal muscle was significantly decreased in all muscle groups studied in the BDL rats. The relative concentration (percentage dose per gram normalized to the animal mass) for quadriceps femoris was 0.16 +/- 0.02 for BDL and 0.32 +/- 0.04 for sham-operated rats, P less than 0.005. Muscle protein was lower in BDL animals when compared with sham-operated rats (P less than 0.05). Total trunk blood amino acid levels were not significantly different in the two groups; however, there was a decreased serum level of branched-chain amino acids in the BDL group, P less than 0.05. No differences in plasma glucose or serum insulin were found in the two groups; lactate levels were lower in the BDL group, and plasma triglyceride levels were three times higher in the BDL animals. These data suggest that obstructive jaundice in the rat is associated with organ-specific metabolic abnormalities consistent with impaired peripheral amino acid uptake.