Obstructive jaundice impairs hepatic sinusoidal endothelial cell function and renders liver susceptible to hepatic ischemia/reperfusion

BACKGROUND/AIMS: Obstructive jaundice is associated with increased surgical morbidity and mortality. While parenchymal injury has been defined in obstructive jaundice, the pathogenesis of hepatic sinusoidal endothelial cell injury in obstructive jaundice is unclear. The aims of this study were to investigate hepatic sinusoidal endothelial cell injury in obstructive jaundice by determining serum hyaluronic acid levels, purine nucleoside phosphorylase/alanine aminotransferase ratios, and hyaluronic acid elimination rate, and also to determine whether hepatic parenchymal cell injury in obstructive jaundice is induced more than in normal liver after hepatic ischemia/reperfusion. METHODS: Male Wistar rats underwent ligation and division of the common bile duct (obstructive jaundice group) or sham operation (Sham group). Serum hyaluronic acid levels and purine nucleoside phosphorylase/alanine aminotransferase ratios in both groups were examined at intervals up to 21 days after surgery. Hepatic blood flow, permeability, neutrophil accumulation, and hyaluronic acid elimination rates in both groups were measured 14 days after surgery. Changes in serum hyaluronic acid and alanine aminotransferase concentrations were determined after 15 min of hepatic ischemia followed by reperfusion. RESULTS: Serum hyaluronic acid levels remained elevated after bile duct ligation. Hepatic sinusoidal endothelial cell swelling was observed by electron microscopy, and hepatic permeability was increased 14 days after bile duct ligation in association with neutrophil accumulation. Hepatic blood flow in obstructive jaundice remained unchanged, but hyaluronic acid elimination capacity was less than that in the Sham group. After hepatic reperfusion, the disappearance rate of serum hyaluronic acid in obstructive jaundice was lower, and serum alanine aminotransferase levels were higher than those in the Sham group. CONCLUSIONS: Our findings suggest that obstructive jaundice impairs sinusoidal endothelial cells and that sinusoidal endothelial cell damage in association with sinusoidal deterioration during obstructive jaundice renders liver susceptible to ischemia/reperfusion relative to normal liver.     

Hepatic resection under the Pringle maneuver induces endotoxemia and lipoperoxidative attack in the jaundiced rat liver

Sixty percent hepatectomy under two times of the Pringle maneuver (temporal occlusion of the hepatic inflow of the hepatic artery and portal vein) for 25 min was carried out on rats with obstructive jaundice. Hepatic energy charge which was markedly decreased during the Pringle maneuver did not recover 3 hrs after release of the maneuver. In addition, systemic endotoxemia associated with increased level of malondialdehyde and decreased levels of total glutathione and alpha-tocopherol in the liver was demonstrated. These changes were more dominant in rats with obstructive jaundice for 3 weeks than those for 1 week. It can be said that deteriorated hepatic energy charge after release of the Pringle maneuver may partly be caused by the production of oxygen free radicals which may be enhanced by endotoxemia in resection of the jaundiced liver. In contrast, after release of the Pringle maneuver, deterioration of hepatic energy charge due to oxidative attack was not found in jaundiced rats without hepatic resection.     

Hepatic protein synthesis and cytokines in obstructive jaundice]

To clarify the mechanism of the increase of hepatic protein synthesis observed in the obstructive jaundiced rats, hepatocellular protein synthesis (HPS) and secretory protein synthesis (SPS) were estimated in the rats with obstructive jaundice and the contents of the following in the peripheral blood were determined in 21 patients with obstructive jaundice before and two weeks after percutaneous transhepatic biliary drainage (PTBD): interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF alpha), endotoxin (Et), acute-phase protein (APP) and negative acute-phase protein (NAPP). The results: (1) HPS and SPS were markedly increased by obstructive jaundice; (2) IL-1 beta and IL-6 were significantly high and were reduced after PTBD; (3) neither TNF alpha nor Et was detected; (4) APP were significantly high and failed to decline after PTBD; (5) NAPP were significantly low and the contents were restored to the normal levels after PTBD. These results suggest that increased hepatic protein synthesis observed in the rats with obstructive jaundice correspond to the increased hepatic production of APP in patients with obstructive jaundice.     

Hepatic macrophage malfunction in rats with obstructive jaundice and its biological significance.

The present study was designed to investigate the pathophysiology of obstructive jaundice by analyzing the function of hepatic macrophages and their role in immune responses and homeostasis in rats. The phagocytic index, determined by the rate of disappearance of 51Cr-endotoxin from the peripheral blood after intravenous injection, was increased in obstructive jaundice 2 weeks after bile duct ligation. The superoxide production of isolated hepatic macrophages and peripheral blood monocytes, measured by the superoxide dismutase inhibitable ferricytochrome c reduction method, was increased. Prostaglandin E2 release, measured by RIA, was markedly increased in rats with obstructive jaundice, but there was no significant difference in interleukin-1 release between jaundiced and control rats. The flow-cytometric analysis of surface molecules of hepatic macrophages showed decreased expression of interleukin-2 receptor in rats with obstructive jaundice. Thus, the functions of hepatic macrophages in rats with obstructive jaundice were impaired. This malfunction may disturb the immunoregulatory network and metabolism, although the exact implications of the altered function of hepatic macrophages have not yet been clarified.     

Effects of sera from patients with obstructive jaundice on the generation of oxygen intermediates by normal polymorphonuclear leukocytes

Recently it has been suggested that oxygen intermediates play an important role in the pathogenesis of tissue damage. The effect of sera from patients with obstructive jaundice on the generation of oxygen intermediates by normal polymorphonuclear leukocytes (PMNs) was investigated. Sera from patients with obstructive jaundice increased superoxide anion (O2-), hydrogen peroxide (H2O2) and hydroxol radical (OH.) generation compared with sera from healthy individuals or patients with biliary tract stones and/or tumors of the biliary tract or pancreas (without obstructive jaundice). In particular, the hydroxyl radical, which is one of the most potent oxidants capable of causing tissue damage, was produced in large quantities. Sera from patients with obstructive jaundice have a strong capacity to induce production of oxygen intermediates from PMNs, and oxygen intermediates may play a role in the pathogenesis of hepatic and other organ injury in obstructive jaundice.     

Obstructive jaundice results in increased liver expression of uncoupling protein 2 and intact skeletal muscle glucose metabolism in the rat

BACKGROUND: A majority of patients with pancreatic cancer have obstructive jaundice and diabetes with skeletal muscle insulin resistance. Surgery for these patients is associated with significant morbidity. Uncoupling protein 2 (UCP2) has been proposed to regulate energy expenditure and promote liver vulnerability. The effects of obstructive jaundice on muscle glucose metabolism and expression of UCP2 in liver and muscle are unknown. METHODS: Rats were operated with bile duct ligation (BDL). After 7 days, UCP2 mRNA levels were determined in liver and muscle. Simultaneously, insulin-stimulated glucose transport and glycogen synthesis in skeletal muscle were analyzed in vitro. RESULTS: The jaundiced rats lost more weight than pair-fed controls. UCP2 mRNA levels were increased 5-fold in liver but not in muscle in jaundiced rats compared to pair-fed controls. The jaundiced rats were hypoglycemic and hypoinsulinemic but demonstrated intact or enhanced insulin action on skeletal muscle glucose transport and glycogen synthesis in vitro. Muscle glycogen content was increased in the jaundiced rats. CONCLUSIONS: Experimental obstructive jaundice in the rat is associated with increased liver expression of UCP2, rapid weight loss, and intact insulin action on skeletal muscle glucose metabolism. Obstructive jaundice, by upregulated liver UCP2, may contribute to the cachexia and high surgical morbidity observed in these patients, but not to skeletal muscle insulin resistance in pancreatic cancer patients.     

Obstructive Jaundice Results in Increased Liver Expression of Uncoupling Protein 2 and Intact Skeletal Muscle Glucose Metabolism in the Rat

Background: A majority of patients with pancreatic cancer have obstructive jaundice and diabetes with skeletal muscle insulin resistance. Surgery for these patients is associated with significant morbidity. Uncoupling protein 2 (UCP2) has been proposed to regulate energy expenditure and promote liver vulnerability. The effects of obstructive jaundice on muscle glucose metabolism and expression of UCP2 in liver and muscle are unknown. Methods: Rats were operated with bile duct ligation (BDL). After 7 days, UCP2 mRNA levels were determined in liver and muscle. Simultaneously, insulin-stimulated glucose transport and glycogen synthesis in skeletal muscle were analyzed in vitro. Results: The jaundiced rats lost more weight than pair-fed controls. UCP2 mRNA levels were increased 5-fold in liver but not in muscle in jaundiced rats compared to pair-fed controls. The jaundiced rats were hypoglycemic and hypoinsulinemic but demonstrated intact or enhanced insulin action on skeletal muscle glucose transport and glycogen synthesis in vitro. Muscle glycogen content was increased in the jaundiced rats. Conclusions: Experimental obstructive jaundice in the rat is associated with increased liver expression of UCP2, rapid weight loss, and intact insulin action on skeletal muscle glucose metabolism. Obstructive jaundice, by upregulated liver UCP2, may contribute to the cachexia and high surgical morbidity observed in these patients, but not to skeletal muscle insulin resistance in pancreatic cancer patients.     

Experimental bile-duct ligation resulted in accumulation of oxidized low-density lipoproteins in BALB/c mice liver

BACKGROUND AND AIM: Oxidized low-density lipoproteins (LDL), which are produced during oxidative stress by the process of lipid peroxidation, have also been proposed to have complex roles in many other immuno-inflammatory mechanisms. It has been shown that bile-duct ligation results in oxidative stress in the liver of animals. The aim of this study was to investigate if oxidized LDL are produced in the liver tissues of bile-duct-ligated mice. METHODS: Obstructive jaundice was induced in BALB/c mice by the ligation and division of the common bile duct. Liver concentrations of glutathione and malondialdehyde were measured in the sham-operated (n = 10) and bile-duct-ligated (n = 10) mice on the 10th day of obstructive jaundice. The presence of oxidized LDL in the liver tissue sections was evaluated using a special, novel immunofluorescent staining method. The final step was to explore the existence of oxidized LDL under fluorescent microscopy. RESULTS: Compared with sham-operated mice, jaundiced mice showed significantly higher levels of malondialdehyde and lower concentrations of reduced glutathione in the liver. While there was no staining in the sham-operated group, bile-duct ligation resulted in positive oxidized LDL staining in the liver tissues of mice. The present study testifies that bile-duct ligation results in oxidative stress and enhanced lipid peroxidation in the hepatic tissues of BALB/c mice and moreover, that oxidized LDL accumulate in the liver of mice with experimental obstructive jaundice. CONCLUSION: Oxidized LDL may be an important and direct indicator of ongoing oxidative stress and enhanced lipid peroxidation in obstructive jaundice. The potential roles of this finding were also discussed, briefly.     

Suppression of cellular immunity in obstructive jaundice is caused by endotoxins: a study with germ-free rats

The increased susceptibility to infections after surgery in jaundiced patients is considered to be caused by an impairment of cellular immunity and/or nutritional status. Endotoxins are suggested to play a role in the pathogenesis. However, the mechanism of action is unknown. Germ-free rats were used to study the effect of biliary obstruction in a model with negligible amounts of endotoxin. Cellular immunity, production of tumor necrosis factor (as a mediator of endotoxin toxicity) by peritoneal macrophages, and the nutritional status were assessed. Significant suppression of cellular immunity was found in conventional rats with obstructive jaundice. In contrast, cellular immunity was not suppressed in jaundiced germ-free rats. Large amounts of tumor necrosis factor were spontaneously secreted by peritoneal macrophages of jaundiced conventional rats, whereas macrophages from jaundiced germ-free rats did not. Moreover macrophage activation (expressed in tumor necrosis factor production) was significantly related to suppression of cellular immunity. Weight changes and depression of albumin levels were not different in germ-free and conventional rats after bile duct ligation. The data presented indicate that suppression of cellular immunity in obstructive jaundice is caused by endotoxins, whereas the impaired nutritional status seems to not be affected by the presence of endotoxins.     

Intestinal ischemia-reperfusion injury augments intestinal mucosal injury and bacterial translocation in jaundiced rats

BACKGROUND/AIMS: The aim of this study was to evaluate local effects and degree of bacterial translocation related with intestinal ischemia-reperfusion injury in a rat obstructive jaundice model. METHODOLOGY: Thirty adult Sprague-Dawley rats (200-250 g) were divided into three groups; including Group 1 (jaundice group), Group 2 (jaundice-ischemia group) and Group 3 (ischemia group). All rats had 2 laparotomies. After experimental interventions, tissue samples for translocation; liver and ileum samples for histopathological examination, 25 cm of small intestine for mucosal myeloperoxidase and malondialdehyde levels and blood samples for biochemical analysis were obtained. RESULTS: Jaundiced rats had increased liver enzyme levels and total and direct bilirubin levels (p<0.05). Intestinal mucosal myeloperoxidase and malondialdehyde levels were found to be high in intestinal ischemia-reperfusion groups (p<0.05). Intestinal mucosal damage was more severe in rats with intestinal ischemia-reperfusion after bile duct ligation (p<0.05). Degree of bacterial translocation was also found to be significantly high in these rats (p<0.05). CONCLUSIONS: Intestinal mucosa is disturbed more severely in obstructive jaundice with the development of ischemia and reperfusion. Development of intestinal ischemia-reperfusion in obstructive jaundice increases bacterial translocation.     

Effects of S-adenosyl-L-methionine on liver damage in experimental obstructive jaundice

S-adenosyl-l-methionine (SAMe) is a naturally occurring molecule distributed throughout the body tissues, including the liver. It acts as a methyl group donor and as an enzyme activator in a number of biochemical reactions. Methionine is metabolized in the liver, where it is converted to SAMe by SAMe-synthetase. In patients with liver diseases, these pathways are impaired because of the decreased contents of glutathione, the major abnormality being a reduction in SAMe-synthetase activity. Exogenous SAMe may overcome the results of impaired SAMe-synthetase activities. We conducted this study to evaluate the effect of SAMe administration on liver damage induced by biliary obstruction. Rats with common bile duct ligation exhibited abnormal liver functions, increased lipid peroxide levels, and decreased reduced glutathione contents when compared with the shammed-controls, which indicated that there was oxidative stress in rats with obstructive jaundice; however, SAMe application improved these injuries. There were significant alterations of the levels of amino acid profiles in animals with obstructive jaundice. The ratio between branch chain and aromatic amino acid was depressed, which indicated that the condition of liver was worsening, but SAMe administration improved these alterations significantly. In conclusion, SAMe administration alleviated the liver damage, indicating an important hepatoprotective effect of this methyl donor.     

急性胆道梗阻大鼠肝脏iNOS的表达及意义

目的 探讨大鼠阻塞性黄疸时诱导型一氧化氮合酶（iNOS）在肝脏中的变化及其意义.方法 选择成年SD大鼠60只,随机分为假手术对照组（S组）30只和阻塞性黄疸组（OJ组）30只.各组分别于术后1、3、7、10、14 d时点处死大鼠6只,检测血清丙氨酸氨基转移酶（ALT）、谷草转氨酶（AST）、血清总胆红素（TB）;观察肝组织普通病理改变以及iNOS蛋白、iNOS mRNA的表达情况.结果 S组肝细胞无肿胀、坏死,肝细胞索排列整齐.OJ组大鼠肝组织可见炎性细胞浸润,细小胆管和无管腔的小胆管增生,纤维组织细胞增生,肝细胞出现变性坏死.OJ组术后ALT、AST、TB迅速增高,与S组比较差异有统计学意义（P均＜0.05）.OJ组术后iNOS基因和蛋白水平表达升高,于第14天达到峰值,与S组比较差异有统计学意义（P均＜0.05）.结论 NO在阻塞性黄疸肝损害中具有双重作用.OJ早期NO可扩张血管,改善肝脏功能;随着iNOS增加,过量的NO产生细胞毒性可损伤肝脏.     

Is mannitol effective against platelet-activating factor (PAF)-induced liver damage in obstructive jaundice?

BACKGROUND/AIMS: Platelet-activating factor, is a unique phospholipid with a broad range of biological activities that may be relevant in the development of inflammatory reactions. Platelet-activating factor has been suspected to play an important role in liver pathophysiology. The cultured Kupffer and endothelial cells produce and release platelet-activating factor in order to facilitate communication between hepatic sinusoidal and parenchymal cells. In this study, in the experimental jaundice model, platelet-activating factor levels were measured in liver tissue and plasma and the possible effects of mannitol on this mediator were assessed. METHODOLOGY: The experimental model consisted of 7 rats in the control group (CG), 7 rats in the sham operation group (ShG), and 7 rats in the obstructive jaundice group (JG) created by ligating the common bile duct. The last group was the mannitol-treated jaundiced group (MJG) and all animals in this group received 20% mannitol in doses of 2 mL/day, intraperitoneally, following common bile duct ligation. A week later all animals were sacrificed and plasma and liver tissue samples were collected. Platelet-activating factor levels were measured by radioimmunoassay technique. RESULTS: Liver tissue platelet activating factor levels (pg/mg tissue protein) were 72 +/- 18 in the CG, 183 +/- 51 in the JG, 84 +/- 17 in ShG, and 124 +/- 36 in MJG. Plasma levels were 460 +/- 13, 1600 +/- 40, 560 +/- 19, and 1200 +/- 23, respectively. In both sample types, MJG and JG values were significantly different from CG and ShG as well. MJG levels were also different from JG. CONCLUSIONS: These results showed that plasma and liver tissue platelet-activating factor levels are increased in experimental obstructive jaundice; and activation of this mediator contributes to the ongoing liver injury. Mannitol may improve or lessen this damage.     

The effect of ischemia on the regeneration of the cholestatic liver. An experimental study

BACKGROUND/AIMS: Cholestatic liver is known to be more susceptible to ischemia than normal liver. In this study we assessed the histopathologic features of hepatic ischemic damage and liver regeneration in rats with experimental obstructive jaundice. METHODOLOGY: The study comprised 90 male Wistar rats. These were assigned randomly to 4 groups according to the surgical procedure they underwent: I (n = 10) controls (non-operated), II (n = 10) sham-operated, III (n = 30) occlusion of hepatic artery and portal vein (total liver ischemia), and IV (n = 40) ligation and division of the common bile duct ligation. Rats of group III were sacrificed 15 (IIIa), 30 (IIIb) and 60 min (IIIc) after total liver ischemia was done. Ten days after bile duct ligation, 10 rats of group IV underwent euthanasia, whereas the remaining 30, underwent total liver ischemia and were sacrificed after 15 min (IVb), 30 min (IVc), and 60 min (IVd). Liver wedge biopsies (left anterior lobe) were obtained and histologic examination included hematoxylin and eosin, and immunohistochemical stains for cytokeratin AE1, HEPPAR (hepatocyte paraffin antigen), and antigen Ki67. Immunohistochemical results for Ki67 were expressed following morphometric analysis. RESULTS: Liver sections from category IVa showed large duct obstruction features, and those from group III, ischemic chages including centrilobular hepatocellular swelling and necrosis, hepatocanalicular cholestasis, and mild portal mononuclear/mixed inflammation. Sections from groups IVB, IVc, IVd displayed together changes of large duct obstruction and ischemia, and in categories IVc (bile duct ligation +30 min total liver ischemia), and IVd (bile duct ligation +60 min total liver ischemia) necrosis of the large bile ducts was present. The total liver parenchymal area affected (% necrosis) was higher in categories IVd, and IVc compared to categories IVb (P < 0.05), and IIIc, IIIb, IIIa (P < 0.01). All 60 total liver ischemia-liver biopsies, developed features of liver regeneration that originated from zone 2, extended to zone 1 and occasionally to zone 3. Immunohistochemical stains revealed cells positive to AE1 and cells positive to HEPPAR. Proliferation rate (% Ki67+ cells) was higher in category IIIa compared to categories IIIb, IIIc, IVb, IVc, and IVd (P < 0.05). CONCLUSIONS: Our study shows that liver ischemia induces more severe hepatocyte damage in livers with obstructive cholangiopathy compared to normal ones. Liver regenerative process is mediated mainly by proliferation of non-necrotic cells that express hepatocellular or ductular epithelial features. Proliferation rate of hepatocytes is lower when liver ischemia and obstructive jaundice coexist.     

Pathophysiological effect of hepatic ischemia and reperfusion after hepatectomy in dogs with obstructive jaundice,focusing on the effect of coenzyme Q10 and styrene-co-maleic acid superoxide dismutase

The purpose of the present study was to elucidate the effect of hepatic reflow following ischemia on the remnant liver after hepatectomy with occluded hepatic blood inflow in dogs with obstructive jaundice. When 40% hepatectomy was performed with 10-min occlusion of hepatic blood inflow in dogs with obstructive jaundice, the lipid peroxide content in the remnant liver increased significantly, together with a reduction in superoxide dismutase (SOD)-like activity. The levels of endotoxin and β-N-acetyl hexosaminase (NAH) in peripheral blood also increased. The phagocytic index increased transiently after 30 min, followed by a marked decrease after 3h. Histologically, degeneration and necrosis of the hepatic parenchymal cells were demonstrated, and survival rate at 7 days was only 23.1%. With the administration of coenzyme Q10 (CoQ10) or styrene-co-maleic acid SOD (SM-SOD), these phenomena were significantly inhibited, and the survival rate improved. After hepatectomy, Kupffer cells in the remnant liver were activated by increased endotoxin levels in the portal vein, inducing the production of free radicals, which, in turn, damaged the Kupffer cells by reducing endotoxin clearance. Finally, the impaired functional reserve in the remnant liver provoked liver failure. The administration of CoQ10 or SM-SOD prevented the occurrence of these phenomena triggered by the free radicals generated by Kupffer cells, stimulated by endotoxin in the portal vein. Abstracts of this study were presented at the 28th Annual Meeting of the Japan Society of Hepatology (Tokyo, 1992), at the 20th Annual Meeting of the Japanese Society for Vascular Surgery (Sapporo, 1992), and at the 41st Annual Meeting of the Japanese Society of Gastroenterological Surgery (Kobe, 1993).     

Oxygen metabolism of the liver during an HA clamp: HV saturation and free radicals

BACKGROUND/AIMS: To clarify changes in the hepatic oxygen metabolism and tissue damage resulting from oxygen-derived free radical generation from polymorphonuclear cells during a hepatic arterial clamp. METHODOLOGY: Subjects were 32 male Wistar rats. Hepatic tissue blood flow, and hepatic venous chemiluminescence, indicating oxygen-derived free radicals from polymorphonuclear cells, and liver lipid peroxide were measured, and hepatic and portal venous blood gas analysis were performed before and after 130 minutes of hepatic arterial clamping. RESULTS: Hepatic tissue blood flow decreased by hepatic arterial clamp. The values of hepatic arterial oxygen pressure (HTBF), hepatic venous oxygen saturation (ShvO2), and O2 contents after hepatic arterial clamp were lower than those before hepatic arterial clamp (P = 0.035, 0.024, and 0.028, respectively). Hepatic venous chemiluminescence decreased and the lipid peroxide level of the liver increased by hepatic arterial clamp (P = 0.001). CONCLUSIONS: ShvO2 is useful for the evaluation of hepatic oxygen metabolism and hepatic tissue blood flow during acute hepatic arterial clamp. This condition should prepare the following tissue damage due to oxygen-derived free radicals from polymorphonuclear cells.     

Influence of obstructive jaundice on pancreatic growth and on basal plasma levels of cholecystokinin and gastrin in rats

Obstructive jaundice was produced in rats by ligation and transection of bile duct outside the liver; the control group underwent laparotomy alone. Pancreatic wet weight, amylase, lipase, protein, DNA, RNA, RNA/DNA ratio, and weight/100 g DNA were significantly increased in jaundiced rats when compared to control rats. Histologic evaluation of pancreatic tissue obtained from jaundiced rats revealed the appearance of large or multiple nuclei in pancreatic acinar cells. Basal plasma levels of immunoreactive CCK were significantly increased in haundiced rats at two weeks and four weeks but, when compared to the levels obtained in laparotomized controls at those time intervals, CCK levels were not significantly different. In jaundiced rats, plasma immunoreactive gastrin was found to be significantly decreased at two and four weeks. Plasma gastrin levels were also found significantly decreased when the jaundiced group was compared with laparotomized control group. The results suggest that obstructive jaundice induced enlargement of the pancreas, probably due to hyperplasia and hypertrophy of pancreatic cells. Whether or not this phenomenon is related to changes in gastrin and CCK is not known.This work was presented in part at the 36th Kinki Section Meeting of Japanese Gastroenterological Association (January 1982) in Osaka, Japan; at the Annual Meeting of the Japanese Pancreatic Association (March 1982) in Hiroshima, Japan; and at the American Gastroenterological Association (May 1983) in Washington, D.C.; and appeared in abstract form inGastroenterology 84: 1095, 1983.     

Protective effects of thromboxane A2 synthetase inhibitor (OKY-046) on hepatic ischemia-reperfusion injury in rats with obstructive jaundice

The effects of OKY-046, a thromboxane A₂ synthetase inhibitor, on complete hepatic ischemia with obstructive jaundice were studied in male Wistar rats in vivo. The objective of this study was to investigate the influence of OKY-046 (i) on the hepatic microcirculation, as measured by tissue partial oxygen pressure (tPO₂), and (ii) on the release of interleukin-8 (IL-8) in hepatic tissue after reperfusion. Fourteen days after bile duct clamping, the rats were subjected to 30-min warm complete liver ischemia and then reperfusion. The rats were divided into three groups; one group received no treatment (controls, group C), one group received OKY-046 from 15 min before hepatic ischemia to the end of the experiment (group OKY), and the third group received gadolinium chloride (group Gd), injected intravenously to evaluate the contribution of the Kupffer cell to IL-8 production. Group OKY maintained significantly higher tPO₂ levels 5, 10, and 15 min after declamping compared to group C (P<0.05). The IL-8 level in liver tissue in group OKY was lower than that in group C, but the difference was not significant. Group Gd exhibited the lowest IL-8 level of the three groups (P < 0.05). These findings demonstrated that OKY-046 improved the hepatic microcirculation during the reperfusion period, influenced the Kupffer cells in terms of the avoidance of hypoxia, and depressed the concentration of IL-8 in liver tissue.