The effect of N-acetylcysteine on pulmonary lipid peroxidation and tissue damage

BACKGROUND: We aimed to investigate the effect of N-acetylcysteine (NAC) on pulmonary lipid peroxidation and tissue damage in experimental obstructive jaundice (OJ) stimulated by lipopolysaccharide (LPS) in this study. MATERIALS AND METHODS: We randomized 40 rats into five groups. Group A: Sham (n = 8); group B: OJ (n = 8); group C: OJ + lipopolysaccharide (LPS; n = 8); group D: OJ + NAC + LPS (n = 8); group E: OJ + LPS + NAC (n = 8). OJ was performed by common bile duct ligation and division in all groups except the sham group. At the fifth day, the rats were jaundiced. At the fifth day of OJ, LPS was injected 10 mg/kg intraperitoneally to the rats and at the tenth day, the rats were sacrificed in group C. In group D; at the fifth day of OJ, NAC was started 100 mg/kg subcutaneously and the same dose NAC injection repeated every day for 5 days. At the tenth day of OJ, LPS was injected 10 mg/kg intraperitoneally to the rats and then after 6 h they were sacrificed. In group E; 10 mg/kg LPS was administered intraperitoneally at fifth day of OJ and after then NAC was started 100 mg/kg subcutaneously and the same dose NAC injection repeated every day for 5 days and at the tenth day, the rats were sacrificed. Tissue samples were harvested through a midline incision, and lungs were resected and examined histopathologically and immunohistochemically for tissue damage scoring. The blood was taken by cardiac puncture and malondialdehyde (MDA), myeloperoxidase (MPO), and levels of total antioxidant status were detected with biochemical methods to evaluate lung tissue damage. RESULTS: Increase in lung and serum MDA and MPO levels, as well as decrease in total antioxidant status, were observed in groups B and C when compared with the sham group (P = 0.0001, for each comparison). Furthermore, the lung tissue damage was observed in the same groups by histopathological examination when compared with sham group. There was significant decrease at serum and lung MPO and MDA levels after the NAC application in groups D and E, when compared with group C (P = 0.0001, for each comparison). Antioxidant status in groups D and E were increased in the presence of NAC (P = 0.0001, for each comparison). Lung histology was prevented relatively in group D when compared with groups B and C. CONCLUSION: Results of the study indicate that NAC has protective effect on pulmonary lipid peroxidation and tissue damage before and after LPS administration.     

Effect of nimodipine and N-acetylcysteine on lipid peroxidation after experimental spinal cord injury

The effectiveness of nimodipine and N-acetylcysteine in experimental spinal cord injury was evaluated by measuring tissue lipid peroxidation levels of the damaged spinal cords 1 hour after the injury. We used the clip compression method to produce acute spinal cord injury in 40 female Sprague-Dawley rats were used. The rats were divided into four groups of 10 each. Lipid peroxidation was assessed by measuring the tissue content of malonil dialdehyde (MDA). In group 3, nimodipine, and in group 4,n-acetylcysteine, was administered i.p. as a single dose immediately after the injury. The rats were sacrificed 1 hour after clip application. The tissue mean MDA content was 3,992 mol MDA/gww in group 1 (sham operated), 10,192 mol MDA/gww in group 2 (trauma), 10,449 mol MDA/gww in group 3 (nimodipine treatment) and 9,009 mol MDA/gww in group 4 (n-acetylcysteine treatment). These results demonstrated that a single dose of nimodipine andn-acetylcysteine had no effect on peroxidation of lipid membranes in the early period of experimental spinal cord injury.     

N-乙酰半胱氨酸对大鼠胆道梗阻肝功能损伤的保护作用及机制研究

目的 探讨N-乙酰半胱氨酸(N-acetylcysteine,NAC)对大鼠胆道梗阻所致肝功能损伤的保护作用及其机制。方法Wistar大鼠72只随机均分成3组：(1)胆道结扎+NAC组(DBL+NAC,n=24)：开腹结扎并切断胆总管,建模成功后经腹腔注射NAC（150 mg·kg-1·d-1）连续注射7 d;(2)胆道结扎组（DBL组,n=24）;(3)假手术组(SO组,n=24)：仅行开腹游离胆总管不予结扎和切断。建模成功后1、3、5、7d每组分别活杀6只大鼠,取静脉血及肝组织,检测肝功能、血浆肿瘤坏死因子α(TNF-α)在各时相点的变化并采用Griess法检测一氧化氮(NO)产生情况。结果 在DBL组、DBL+ NAC组谷-草转氨酶(AST)、血清谷丙转氨酶(ALT)、总胆红素(TBIL)、直接胆红素(DBIL)均随胆道梗阻时间延长而升高,但DBL组AST、ALT在各时间点均较DBL+NAC组明显升高(P＜0.05),而TBIL、DBIL在这两组间无明显差异(P＞0.05)。DBL组和DBL+ NAC组TNF-α、NO浓度变化也随梗阻时间延长而升高,但DBL组较DBL+ NAC组TNF-α、NO浓度升高更明显(P＜0.05)。结论N-乙酰半胱氨酸能有效改善胆道梗阻所致肝损害,并有可能是通过下调肝组织中TNF-α、NO的表达这一途径实现的。     

Improvement of portal flow and hepatic microcirculatory tissue flow with N-acetylcysteine in dogs with obstructive jaundice produced by bile duct ligation.

OBJECTIVE: To find out if N-acetylcysteine (NAC) would improve hepatic circulation in dogs with obstructive jaundice. DESIGN: Open laboratory study. SETTING: University hospitals, Japan and France. MATERIALS: 14 male beagle dogs and 10 male Wistar rats. INTERVENTIONS: Obstructive jaundice was produced by ligation of the common bile duct (CBD) for 7 days in both dogs and rats. Either 5% dextrose (control group, n = 7) or NAC (NAC group, n = 7) was given to dogs. Sinusoidal endothelial cells were obtained from rats after ligation by elutriation, and varying amounts of NAC were given. MAIN OUTCOME MEASURES: The volumes of portal blood flow and hepatic microcirculatory tissue flow were reduced after ligation of the CBD, but those increased after NAC had been given to dogs with obstructive jaundice. NAC increased the concentrations of plasma cyclic 3',5'-guanosine monophosphate (cGMP). It also increased concentrations of serum and hepatic-reduced glutathione, and hepatic adenosine triphosphate (ATP) in cholestatic dogs, and secretion of cGMP from sinusoidal endothelial cells from rats with obstructive jaundice. CONCLUSION: These results suggest that NAC given intravenously effectively improves hepatic circulation and hepatic function in dogs with obstructive jaundice.     

胆道内、外引流术对梗阻性黄疸患者红细胞膜脂变化的影响

目的　探讨不同的胆道引流手术对梗阻性黄疸病人胆红素的病理生理变化的影响。方法　以梗阻性黄疸病人为研究对象 ,采用质谱法测定其胆道引流术前后的红细胞膜脂变化。结果　胆道内引流术后 2周 ,病人红细胞膜脂的长链脂肪酸、不饱和脂肪酸增多 ,双键含量增加 ,膜脂成分趋向正常 ;而外引流术后膜脂成分也有所好转 ,但变化缓慢 ,病人早期恢复不明显。结论　胆道内引流术能较快改善梗阻性黄疸病人的细胞膜结构与功能 ,有利于疾病的及早恢复。     

The effect of aminoguanidine on blood and tissue lipid peroxidation in jaundiced rats with endotoxemia induced with LPS.

Obstructive jaundice (OJ) is a severe condition that leads to several complications. One of the important problems in OJ is the increased incidence of endotoxemia, which is the result of bacterial translocation (BT) and defective host immune response. Lipid peroxidation (LP) is an important problem in OJ and sepsis in which nitric oxide (NO) production and inducible nitric oxide synthase (iNOS) activity are increased and antioxidative activity is decreased. Formation of peroxynitrite (ONOO(-)) anion leads to cellular damage and apoptosis. In this experimental study, we explore the effect of specific iNOS inhibitor aminoguanidine (AG) on blood and tissue (liver and renal) LP and iNOS levels in jaundiced rats with endotoxemia induced with lipopolysaccharide (LPS). Rats were randomized into six groups; group A, sham; group B, obstructive jaundice (OJ); group C, OJ + LPS; group D, OJ + AG; group E, OJ + LPS + AG; group F, OJ + AG + LPS. Serum malondialdehyde (MDA) and serum myeloperoxidase (MPO) activity and liver and renal tissue MDA, MPO, and Na(+)/K(+)-ATPase activity levels were detected in biochemical methods. Liver and renal tissue iNOS levels were examined immunohistopathologically. Serum and tissue MDA and MPO levels and tissue iNOS expression were increased significantly in groups B, C, and E, while tissue ATPase levels were decreased significantly in the same groups. In the group treated with AG (group D), serum and tissue MDA and MPO levels and tissue iNOS expression were decreased while tissue ATPase levels were increased significantly. In group F, if AG was administrated before LPS, we observed that serum and tissue MDA and MPO levels and tissue iNOS expression were decreased while tissue ATPase levels were increased significantly. Thus, our study showed that AG had a protective effect when it was administrated before LPS, but it failed to prevent tissue iNOS expression and LP if there was established endotoxemia in OJ.     

Effect of gamma-hydroxybutyric acid on lipid peroxidation and tissue lactate level in experimental head trauma

BACKGROUND: This study was designed to determine the effects of gamma-hydroxybutyric acid (GHB) on tissue lactate and malondialdehyde (MDA) levels in rabbit brain after experimental head trauma. METHODS: Thirty New Zealand rabbits were divided equally into three groups: group S was the sham-operated group, group C, and group GHB received head trauma, where group C was the untreated and group GHB was the treated group. Head trauma was delivered by performing a craniectomy over the right hemisphere and dropping a weight of 10 g from a height of 80 cm. GHB was administered 400 mg/kg intravenously for 10 minutes after the head trauma to group GHB. The nontraumatized side was named "1" and the traumatized side was named "2." One hour after trauma, brain cortices were resected from both sides and the concentrations of lactate and MDA were determined. RESULTS: There were significant differences between lactate and MDA levels of group S and all other groups (C1, C2, GHB1, and GHB2) except between lactate levels of group S and group GHB1, the nontraumatized and traumatized sides of groups C and group GHB, group C2 versus group GHB2, and group C1 versus group GHB1 (p < 0.05). Rectal temperature after the administration of GHB in group GHB was found lower than in groups S and C (p < 0.05). CONCLUSION: These results demonstrate that head trauma leads to an increase in brain tissue lactate and MDA levels, and GHB effectively suppresses the increase of lactate and MDA.     

Endotoxemia in human obstructive jaundice. Effect of polymyxin B

A clinical trial was undertaken to study endotoxemia in 14 patients with obstructive jaundice given the antiendotoxin polymyxin B, 13 patients with obstructive jaundice who were not given the antiendotoxin , and 13 nonjaundiced control patients undergoing comparable surgery. Endotoxins were detected by the limulus assay. Endotoxemia did not occur in the nonjaundiced patients but was common before (68 percent), during (70 percent), and after (81 percent) surgery in the jaundice patients. Thirty-six percent of the jaundiced patients had postoperative oliguria. Endotoxemia before surgery was associated with death after surgery, all deaths occurring in patients who were endotoxemic before operation (p less than 0.05). Polymyxin B infusion had no effect on endotoxemia or outcome. Measurement of indicators of fibrinolysis, soluble fibrin, and fibrin degradation products showed no prognostic significance. We conclude that preoperative endotoxemia is an important predictor of outcome in patients who undergo surgery for jaundice.     

内皮素对阻塞性黄疸肾功能影响的实验研究

目的：研究内皮素与阻塞性黄疸肾功能障碍的关系,方法：大鼠胆总管结扎后分为5天,10天、15天3组,同时建立相应的对照组,观察血和肾组织内皮素与肝肾功能的变化,并用原位杂交观察肾组织ET－1mRNA的表达。结果：随着胆管梗阻时间的延长,血和肾组织内皮素持续升高,与内生肌酐清除率,肾皮质血流量呈明显负相关,肾小球,肾小管,集合管,肾内小血管ET－1 mRNA的表达持续增加,排钠分数梗阻5天时升,15 时低于对照组,结论：内皮素是引起阻塞性黄疸肾功能障碍的原因之一,肾组织内ET水平升高是由于肾小管,集合管,肾内小血管ET－1mRNA表达升高的缘故,在阻黄早期ET可促进利尿排钠,后期则可抑制水钠排泄。     

Effect of obstructive jaundice on wound healing. An experimental study in rats

The effect of obstructive jaundice on wound healing was investigated in an experimental study of gastric and abdominal wounds in rats after ligation and division of the common bile duct. The healing of a parietal defect in these animals showed histologic evidence of delayed healing compared with controls. The bursting strength of the abdominal incision was also decreased, but not that of the stomach. These findings suggest that the biochemical changes in the wounds of jaundiced animals interfere with wound repair. The possible causes of this delay in healing and its clinical implications require further investigation.     

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。     

Effect of dobutamine infusion on endotoxin-induced lipid peroxidation in awake sheep.

beta-agonists are known to not only increase oxygen delivery, but also attenuate the inflammatory response. We studied the effect of infusing the beta-agonist, dobutamine, on the oxidant-induced lung and liver tissue lipid peroxidation seen after endotoxemia. Twelve unanesthetized adult sheep with lung and soft tissue (prefemoral) lymph fistulae were given 5 micrograms/kg of Escherichia coli endotoxin intravenously. In six sheep, dobutamine 10 to 15 micrograms/kg/min was infused beginning 3 hours after endotoxin to increase oxygen delivery by 75% above baseline. Animals were killed at 6 hours, and lung and liver lipid peroxidation, measured as malondialdehyde, was obtained. Data were compared to six control sheep. Endotoxin alone produced increased lung and soft tissue vascular permeability as evidenced by a twofold increase in protein-rich lymph flow. Lung and liver malondialdehyde increased to 116 +/- 40 nmol/gm and 202 +/- 64 nmol/gm, respectively, compared to control values of 42 +/- 7 nmol/gm and 110 +/- 20 nmol/gm, respectively. Dobutamine infusion after endotoxin increased oxygen delivery by 75%, although changes in total oxygen consumption were not different from those seen with endotoxin alone. Lung and soft tissue lymph flow did not change with dobutamine. However, lung malondialdehyde was 41 +/- 17 nmol/gm, not different from controls. Liver malondialdehyde remained elevated at 164 +/- 26 nmol/gm. We conclude that dobutamine infusion prevents further oxidant-induced lung tissue lipid peroxidation but does not reverse the increased permeability already present. Liver lipid peroxidation was not decreased, suggesting the liver oxidant process may not be caused by the same mechanism as the lung lipid peroxidation.     

Experimental study on lipid and bilirubin metabolism after biliary drainage for obstructive jaundice

BACKGROUND: The present experimental study was carried out to determine variations in bilirubin and lipid metabolism in obstructive jaundice after external biliary drainage alone and in combination with intraintestinal administration of the drained bile. MATERIALS AND METHODS: Variations in lipid and bilirubin metabolism were studied in adult mongrel dogs with obstructive jaundice treated by external biliary drainage (EBD) and EBD plus intraintestinal administration of autologous bile (IBD). RESULTS: There was no difference between these two groups in regard to the volume of excreted bile after drainage. The biliary concentration and total daily excretion of bilirubin were higher in the IBD group (P < 0.0001), but there was no intergroup difference in the rate of decrease of serum bilirubin. In regard to lipid metabolism, the levels of total cholesterol, triglyceride, and low-density lipoprotein were decreased after biliary drainage; improvement in lipid metabolism was more rapid in the EBD group. Although the triglyceride level was lower after drainage, the activity of HMG-CoA reductase, the level of high-density lipoprotein 3-C, and the carrier protein apolipoprotein A-I were increased after drainage, with more rapid improvement in the EBD group. CONCLUSIONS: To improve lipid metabolism in obstructive jaundice, external biliary drainage is superior in the early stages of treatment, while replacement by EBD plus intraintestinal administration of autologous bile may be advantageous in cases of prolonged use.     

Effect of activated protein C on impaired fibrinolysis in rats with obstructive jaundice.

We studied the effect of activated protein C (APC) on impaired fibrinolysis using a rat model in which disseminated intravascular coagulation (DIC) is induced by the intravenous injection of endotoxin in rats with obstructive jaundice. An intravenous injection of endotoxin in rats with obstructive jaundice resulted in pulmonary hemorrhages and a marked increase in the plasma levels of tissue-type plasminogen activator (t-PA) antigen and plasminogen activator inhibitor activity. Prophylaxis with APC before the injection of endotoxin resulted in a decrease of the number of lung hemorrhages and an accelerated release of t-PA antigen. Thus, DIC in obstructive jaundice may be due to impairment of fibrinolysis and an increased susceptibility of endothelial cells to endotoxin. APC may be effective as a treatment for patients with obstructive jaundice associated with DIC.     

Protein oxidation and lipid peroxidation after renal ischemia-reperfusion injury: protective effects of erdosteine and N-acetylcysteine

Oxygen radicals have roles in the renal ischemia-reperfusion (IR) injury usually encountered in several conditions such as renal transplantation. The aim of this study was to investigate the effects of erdosteine and N-acetylcysteine (NAC) on the oxidant/antioxidant status and microscopy of renal tissues after IR injury. Male Sprague–Dawley rats were randomly assigned to four groups: control untreated rats, IR (30 min ischemia and 120 min reperfusion), IR + NAC (i.p.; 180 mg/kg) and IR + erdosteine (oral; 50 mg/kg/day for 2 days before experiments) groups. After unilateral renal IR, the right kidney was rapidly excised and sectioned vertically into two pieces for microscopic examination and biochemical analysis. Erdosteine and NAC treatment did not cause any significant change in the activity of superoxide dismutase (SOD) in comparison with the IR group, even if the SOD activity increased in IR groups than in the control group. Catalase (CAT) activity was decreased in the IR group in comparison with control and IR + erdosteine groups (P<0.05), whereas it was higher in the IR + erdosteine group than in the IR + NAC group (P<0.05). Xanthine oxidase (XO) activity was higher in all the IR-performed groups than in the control group (P<0.05). Thiobarbituric acid-reactive substances (TBARS) level and protein carbonyl (PC) content were increased after IR injury (P<0.05). Erdosteine or NAC treatments ameliorated these increased TBARS and PC contents in comparison with the IR group (P<0.05). Light microscopy of the IR group showed tubular dilatation, tubular necrosis and vacuole formation in epithelial cells. Erdosteine but not NAC apparently reduced the renal tissue damage. The pathological damage score after IR was significantly reduced after erdosteine treatment (P<0.05), but not after NAC treatment. In conclusion, renal IR resulted in oxidative damage as seen in biochemical lipid peroxidation and protein oxidation results with aggravated tubular necrosis. Erdosteine and NAC treatments improved the biochemical results of IR injury. However, on microscopic evaulations, animals receiving erdosteine showed a great reduction in renal damage when compared with the NAC group. This study was presented in part at the “29th National Congress of Physiology” in Ankara, Turkey, 1–5 September 2003     

Principles of treating blood coagulation disorders in patients with obstructive jaundice

Activation of blood anticoagulative potential, fibrinolysis in particular, facilitates the development of hemorrhagic complications of obstructive jaundice. Increase of blood platelet adhesion and fibrinogen concentration and reduction of fibrinolysis are evidence of the risk of occurrence of thrombotic complications in the postoperative period. Changes in the findings of laboratory tests for blood coagulation precede the appearance of clinical signs of complications as a rule. The use of protease inhibitors in hemorrhages is an essential supplement to the scope of measures of hemostatic therapy and increases its efficacy significantly. This method was used for treating 28 patients with hemorrhagic complications of jaundice among 96 patients suffering from hemocoagulation disorders caused by prolonged obstruction of the bile tract.