Obstructive Jaundice In Rats Research Articles

Bovine lactoferrin decreases histopathological changes in the liver and regulates cytokine production by splenocytes of obstructive jaundiced rats.

The aim of this study was to evaluate effects of bovine lactoferrin (BLF) on histopathological changes in the liver of 14 day obstructive jaundiced (OJ) rats and production of tumor necrosis factor (TNF-alpha) and interleukin 6 (IL-6) by splenocytes from 7- and 14-day OJ rats. In the study 50 male rats of the Buffalo strain (170-270 g, mean 230 g) were used. Rats were given 10 mg BLF in 0.5 ml saline daily, using a stomach tube. BLF was applied 2 days before operation and for 13 days following operation. The specimens of liver were prepared using standard techniques. Sections, 5 mm thick were stained with hematoxylin and eosin and reviewed histologically. Microscopic estimation using semiquantitive 4-grade scale was used for evaluation of liver changes. For cytokine measurement splenocyte cultures were stimulated with 5 microg/ml lipopolysaccharide (LPS). After overnight incubation the activities of TNFalpha and IL-6 were determined using bioassays. For statistical evaluation of data the nonparametric Mann-Whitney test was applied. In rats with 14-day OJ, treated with BLF, the pathological changes in the liver were markedly reduced, in particular foci of necrosis with disseminated lymphocytes, cellular necrobiosis, bile duct proliferation and dilation. Neither proliferation of fibrous and reticular connective tissue nor activation of Kupffer cells was revealed. In the 7-day OJ rats treatment with BLF caused significant inhibition of both spontaneous (mean 253, median 275, vs mean 160, median 148 pg/ml, p=0.002) and LPS-induced TNF-alpha production (mean 4967, median 4102, vs mean 2291, median 2234 pg/ ml, p = 0.004) in the splenocyte cultures. The spontaneous (mean 120, median 81, vs mean 43, median 26 pg/ml, p=0.005) as well as LPS-induced IL-6 production (mean 422, median 378, vs mean 293, median 230 pg/ml, p = 0.025) were also lowered. On the other hand, in 14-day OJ, BLF upregulated cytokine production, in particular spontaneous (mean 148, median 158, vs mean 338, median 196, p = 0.001) and LPS-induced TNF-alpha (m ean 1331, median 1507, vs mean 2239, median 1707 pg/ml, p = 0.027). We conclude that oral administration of BLF is beneficial in alleviating deleterious effects of OJ.

The Effects of Dimethylsulfoxide in Experimental Obstructive Jaundice

Material and methods: Thirty rats were divided into three groups, as sham, control and DMSO groups. Laparatomy was performed on each animal in the control and DMSO groups and common bile ducts were ligated. Common bile duct was observed but was not ligated for the rats in the sham group. Saline solution injection (1.5 mg/kg/intraperitoneally (ip)) was begun on the first day of surgical procedure and repeated once a day for the next 5 days. The same procedure was performed with DMSO (1.5 mg/kg/ip) instead of saline in the DMSO group. The rats were sacrificed on the postoperative seventh day, at which time venous blood and liver tissue specimens were taken. Main outcome measurements: On the 7th postoperative day, the bilirubin, AST, ALT, ALP and GGT levels of the control and DMSO groups were significantly higher in comparison with the sham group (p < 0.01). On the 7th postoperative day, the erythrocyte superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) levels of the control and DMSO groups were significantly lower than those of the sham group (p < 0.01), but there was no statistical difference between the two groups (p > 0.05). Erythrocyte and liver malondialdehyde (MDA) levels in the control and DMSO groups were significantly higher compared with the sham group (p < 0.01). However, the MDA levels were significantly lower in the DMSO group compared to the control group (p < 0.01).Conclusion: It is stated that free oxygen radicals seem to play a role in the liver tissue injury, secondary to obstructive jaundice. In our experimental study, exogenic DMSO seems to have decreased lipid peroxidation and to have improved some of the parameters of liver tissue injury due to the obstructive jaundice in rats.

Hepatocellular apoptosis after hepatectomy in obstructive jaundice in rats

To investigate the hepatocellular apoptosis after hepatectomy in obstructive jaundice and biliary decompression rats. After bile duct ligation for 7 days, rats were randomly divided into OB group in which the rats underwent 70% hepatectomy, OB-CD group in which the rats underwent hepatectomy accompanied by choledochoduodenostomy, CD-Hx group in which the rats underwent choledochoduodenostomy and then received 70% hepatectomy on the fifth day after biliary decompression. The control group (Hx group) only underwent hepatectomy. The level of total serum bilirubin and serum enzymes was significantly lower in CD-Hx group than in OB-CD and OB groups on day 1, 3 and 5 after hepatectomy. The apoptotic index was significantly lower in CD-Hx group than in OB-CD and OB groups on day 3 and 5. The oligonucleosomal DNA fragments and Caspase-3 activity were also lower in CD-Hx group than in OB-CD and OB groups 3 days after hepatectomy, without differences between CD-Hx and Hx groups. Hepatocellular apoptosis plays vital roles in jaundice rats, and biliary decompression is more effective in treatment of patients with severe jaundice before operation.

Promotion of bacterial translocation by major liver resection in obstructive jaundice in rats colonised predominantly with indigenous Escherichia coli.

The influence of major liver resection in obstructive jaundice on bacterial translocation was evaluated in rats that were colonised predominantly with a genetically labelled strain of Escherichia coli. The strain, JNW14, originally isolated from rat faeces, was labelled with bacitracin, neomycin and streptomycin resistance markers. Fifty-two specific-pathogen-free male Wistar rats were divided into three experimental groups and were treated as follows: group 1 (n = 8), sham ligation of common bile duct; group 2 (n = 7), common bile duct ligation (CBDL); and group 3 (n = 37), 70% hepatectomy 7 days after CBDL. The rats were treated with the above antibiotics and then given E. coli strain JNW14 in their drinking water. Translocation of E. coli JNW14 from the gastrointestinal tract to the mesenteric lymph nodes (MLNs), lungs, liver, spleen and portal vein was evaluated in each group. In group 3 (CBDL plus hepatectomy), the incidence of translocation of E. coli JNW14 to the liver and spleen after hepatectomy was significantly higher than in groups 1 and 2. This result indicates that major liver resection in obstructive jaundice promotes bacterial translocation to systemic organs. Furthermore, the numbers of viable E. coli JNW14 in the MLNs in the lung culture-positive rats were significantly higher than those in the lung culture-negative rats, suggesting that lymphatic-thoracic duct systemic circulation is a major route of bacterial translocation.

Differences in Biliary Lipid Excretion after Major Hepatectomy in Obstructive Jaundiced Rats with Preoperative Internal, External, or No Biliary Drainage

Necessity of preoperative biliary drainage for patients with obstructive jaundice is still controversial. We recently reported that liver regeneration after major hepatectomy was better restored in a rat model of obstructive jaundice with preoperative internal biliary drainage than that without biliary drainage or with external biliary drainage. The aim of this study was to investigate the differences in biliary lipid excretion after hepatectomy in obstructive jaundiced rats with or without preoperative internal or external biliary drainage. After bile duct ligation for 7 days, rats were randomly divided into the three groups; obstructive jaundice-hepatectomy (OJ-Hx), internal biliary drainage-hepatectomy (ID-Hx), and external biliary drainage-hepatectomy (ED-Hx) groups. 70% hepatectomy and internal biliary drainage were carried out 7 days after biliary decompression in the latter two groups and without biliary decompression in the OJ-Hx group. On the day of and on days 1, 2, 3 and 7 after hepatectomy, the liver weight, DNA synthesis rate, biliary lipids excretion rates, and bile acid composition were determined. In the ID-Hx group, the DNA synthesis rate and relative liver weight were significantly higher than those of the OJ-Hx and ED-Hx groups. The excretion rates of biliary lipids were disturbed in the ED-Hx group compared with those in the ID-Hx group and the values in the OJ-Hx group were in-between the ID-Hx and ED-Hx group. The liver regeneration rate was significantly correlated with bile flow and excretion rates of biliary lipids. The maintenance of enterohepatic circulation of biliary lipids before hepatectomy may be important for the liver regeneration.

Increased Nitric Oxide Production in Hepatocytes Is Involved in Liver Dysfunction Following Obstructive Jaundice

Background. Obstructive jaundice damages critical functions in the liver. However, the mechanisms involved in hepatic dysfunction are obscure. Nitric oxide is implicated in liver injury under various pathological conditions. We previously reported that proinflammatory cytokine interleukin-1β (IL-1β) stimulated the production of nitric oxide in hepatocytes, which was associated with mitochondrial dysfunction. Studies were performed to examine whether obstructive jaundice influences the production of nitric oxide in hepatocytes and alters hepatic energy metabolism.Material and methods. Hepatocytes were isolated and cultured from a rat model of obstructive jaundice or sham control. Nitric oxide production, ATP content, and ketone body ratio (acetoacetate/β-hydroxybutyrate; KBR) were compared between the two groups in the presence of IL-1β.Results. Hepatocytes obtained from obstructive jaundice rats markedly increased the levels of nitric oxide production stimulated by IL-1β compared with those from sham control. Western blot analysis revealed that the enhancement of nitric oxide production was a posttranslational event, since protein levels of inducible nitric oxide synthase (NOS) were unchanged between the two groups. IL-1β decreased cellular ATP content in obstructive jaundice but not in sham control. Further, the KBR, which is a marker of mitochondrial redox state, was lower in obstructive jaundice than in sham control. Addition of NG-monomethyl-l-arginine, an inhibitor of NOS, abolished the decreases in ATP content and KBR as well as the nitric oxide production.Conclusions. These results indicate that a priming of nitric oxide production following obstructive jaundice is associated with the alteration of hepatic energy metabolism in part through mitochondrial dysfunction. Regulation of nitric oxide production may be a useful therapy for preventing liver dysfunction in obstructive jaundice.

Lack of intestinal bile results in delayed liver regeneration of normal rat liver after hepatectomy accompanied by impaired cyclin E–associated kinase activity

Background. The importance of bile in liver regeneration after hepatectomy is unknown, although we have recently shown that preoperative internal biliary drainage is superior to external biliary drainage for liver regeneration in obstructive jaundiced rats. This study examined the hypothesis that the presence or absence of bile in the intestinal tract modulates cyclins and cyclin-dependent kinases after hepatectomy in rats. Methods. In male Wistar rats, bile was drained externally (ED group) or into the duodenum (ID group) for 7 days before 70% hepatectomy. Relative liver weight, DNA synthesis rate, and proliferating cell nuclear antigen labeling index were determined at the time of hepatectomy (day 0) and on days 1, 3, and 7 after hepatectomy. Posthepatectomy expressions of cyclin D1 and E and of cyclin D1- and E-associated kinases were serially analyzed. Hepatic function tests were performed. Results. No significant difference in liver function was found between the 2 groups at hepatectomy except for the lower albumin level in the ED group. The relative liver weight was lower in the ED group than in the ID group on day 3 after hepatectomy (ED, 2.58% ± 0.06%; ID, 2.84% ± 0.08%; P <.05). Both the DNA synthesis rate and proliferating cell nuclear antigen labeling index in the ED group (77 ± 36 disintegrations per minute/μg DNA and 8.3% ± 1.9%, respectively) were lower than those in the ID group (262 ± 50 disintegrations per minute/μg DNA and 21.6% ± 5.6%, respectively) on day 1 after hepatectomy (P <.05, respectively). Cyclin D1-associated kinase activity and cyclin D1 expression were not significantly different between the 2 groups. Cyclin E-associated kinase activity was lower in the ED group than in the ID group at 18 hours after hepatectomy (ED, 84% ± 17%; ID, 146% ± 28% of the value at 0 hour in the ID group; P <.05), although expressions of cyclin E and p27 binding to cyclin E were not significantly different between the 2 groups. Conclusions. These results suggest that the absence of bile in the intestine delays liver regeneration associated with cyclin E-associated kinase inactivation after hepatectomy. (Surgery 2002;131:564-73.)

The bcl-2 mRNA expression in GCDC-induced obstructive jaundice in rats and its implication in hepatocellular apoptosis.

The modulatory role of bcl-2 gene in hepatocellular apoptosis of rats with glycochenodeoxycholate (GCDC)-induced obstructive jaundice was investigated. The hepatocytes in normal rats and those with bile duct-ligation for 7 days, 14 days and 21 days were isolated and obtained by in situ collagenase perfusion and primary culture. The expression of bcl-2 mRNA in the hepatocytes was detected by RT-PCR. Primary culture was performed on the hepatocytes from normal rats and those with bile duct-ligation for 14 days. 100 mumol/L GCDC was added to the hepatocytes for incubation for 24 h. The hepatocellular apoptotic ratio was measured by using FCM and hepatocellular apoptosis detected in situ by using TUNEL technique. Results showed that the expression of bcl-2 mRNA was not detectable in the hepatocytes of normal rats by RT-PCR technique, while detectable in the hepatocytes of those with bile duct ligation (BDL) for 7, 14 and 21 days. Hepatocellular apoptosis in the BDL group was obviously decreased as compared with normal control group after addition of 100 mumol/L GCDC to the cells for 24 h. It was concluded that the hepatocytes in the BDL rats expressed bcl-2. During obstructive jaundice, expression of bcl-2 from the hepatocytes can inhibit the bile salt-induced hepatocellular apoptosis.

Melatonin protects against renal oxidative stress after obstructive jaundice in rats

The goals of this study were to analyze the renal oxidative status in experimental biliary obstruction and to evaluate the impact of melatonin on renal oxidative stress. Cholestasis was done by double ligature and section of the extra-hepatic biliary duct. Melatonin was injected i.p. (500 μg/kg/day). Malondialdehyde, reduced glutathione, catalase, superoxide dismutase, glutathione reductase, glutathione peroxidase and glutathione transferase were determined in the renal tissue. After biliary obstruction, an increase in malondialdehyde ( P<0.0001) and a fall in reduced glutathione ( P<0.0001) were seen. Moreover, the scavenger enzyme activity had significantly diminished. After melatonin administration, the malondialdehyde fell significantly ( P<0.0001), whereas reduced glutathione showed an important increase ( P<0.0001) compared with the ligated bile duct group. Experimental bile duct obstruction was associated to an increase of renal oxidative stress. Treatment with melatonin decreased the renal lipid peroxidation, and both the reduced glutathione as well as the scavenger enzyme activity recovered.

Effect of 5-Lipoxygenase Inhibition on Kupffer Cell Clearance Capacity in Obstructive Jaundiced Rats

Background. Obstructive jaundice is a common surgical problem. It may cause hepatic and Kupffer cell dysfunction. Previous studies demonstrated that 5-lipoxygenase inhibition prevents hepatic injury. However, its effect on Kupffer cell clearance capacity has not been determined yet.Materials and methods. Rats were divided into four groups. In group 1 (sham control group), only bile duct dissection was performed. In other groups bile ducts were ligated and divided. In groups 1 and 2 saline, in group 3 ethanol, and in group 4 a 5-lipoxygenase inhibitor AA-861 was given intraperitoneally to the animals. Rats were sacrificed 14 days after the operations. Serum alkaline phosphatase, total bilirubin, and alanine aminotransferase levels were determined. Kupffer cell clearance capacity was measured using an in situ isolated hepatic perfusion technique. Hematoxylin–eosin-stained liver samples were evaluated under light microscope for histopathologic scoring.Results. Rats in the sham control group had significantly lower serum ALP and bilirubin values than those in the experimental groups with biliary obstruction. AA-861 administration significantly decreased serum ALT levels and histopathologic scores. There was no significant difference in ALT levels and histopathologic scores between the sham control and AA-861 groups. Kupffer cell clearance capacity was found to be significantly increased in the AA-861 group compared to other experimental groups with obstructive jaundice.Conclusions. This study shows that leukotriene synthesis inhibition using AA-861 prevents hepatic damage and improves Kupffer cell clearance capacity in obstructive jaundiced rats. This may have significant implications for the management of patients with obstructive jaundice.

Translocation of Enterococcus in jaundiced and anergic rats

Abstract Background Translocation of bacteria from the gut to other organs is one cause of systemic complications in obstructive jaundice. Furthermore, hyperbilirubinaemia appears to cause anergy. This study investigated whether these responses (translocation of gut bacteria and anergy) increase the postoperative mortality rate in rats in which obstructive jaundice is induced surgically by ligature of the bile duct. Methods Some 88 male Wistar rats were divided into six groups. All rats except those in group 1 received gentamicin by the oral route (0·7 mg in 1 ml water, daily for 6 days) to ensure intestinal decontamination. On day 7, all rats except those in groups 1 and 2, which had vehicle only, received Enterococcus. Statistical analysis was by Student's test and Fishers's exact test. All animals underwent standard blood testing, delayed hypersensitivity tests, haematimetry and serum endotoxin determinations. Flow cytometry was used to count CD3-, CD4- and CD8-positive lymphocytes. On the day 5 after surgery, these assays were repeated and, in addition, the rats were killed for microbiological analysis of gut and viscera contents (liver, spleen, mesentery and lung). Results Five days after surgery, mean bilirubin levels in groups 5 and 6 were greater than 14 mg dl−1. In addition, all rats in groups 5 and 6 showed absence of the delayed hypersensitivity response, indicating anergy. Lymphocyte counts in each group are shown in the Table. The mean proportion of CD8-positive lymphocytes in rats that had received Enterococcus (groups 3–6) was 16 per cent compared with 25 per cent in groups 1 and 2 (P &amp;lt; 0·05). The mean percentage of CD3-positive lymphocytes in groups 5 and 6 was 51 per cent, but 71 per cent in all other groups (P &amp;lt; 0·05). Likewise, the mean percentage of CD4-positive lymphocytes in groups 5 and 6 was 32 per cent, but 47 per cent in all other groups (P &amp;lt; 0·05). The postoperative mortality rate in group 4 (17 per cent) was significantly lower than that in the obstructive jaundice groups 5 and 6 (62 per cent) (P &amp;lt; 0·01). Post-mortem microbiological analyses revealed translocation of Enterococcus only in groups 5 (80 per cent) and 6 (70 per cent). Enterococci were most frequently present in the mesentery (80 and 70 per cent respectively), followed by the liver (40 and 40 per cent), spleen (20 and 20 per cent) and lungs (10 and 10 per cent). Conclusion (1) Obstructive jaundice in rats leads to immunological alterations including anergy. (2) Obstructive jaundice in rats favours translocation of enterococci from the gut to other organs. (3) The postoperative mortality rate in jaundiced rats was much higher than that in sham-operated rats.

Bacterial translocation in obstructive jaundice in rats: role of mucosal lacteals.

To study the ultrastructure of the ileal wall in rats with obstructive jaundice alone and after passive external biliary drainage to see if we could discover the reason for the increased risk of infective complications and multisystem failure in the presence of obstructive jaundice and after external biliary drainage. Histological examination of the wall of the terminal ileum using light microscopy, as well as scanning and transmission electron microscopy (EM). Experimental laboratory, Republic of Georgia. 56 adult male Wistar rats. Rats were divided into 7 groups: controls (not operated on, n = 6); sham-operated and studied after 6 and 12 days (n = 6 in each); bile duct ligation alone studied after 6 and 12 days (n = 10 in each); and bile duct ligation followed 6 and 12 days later by one-day of external biliary drainage (n = 9 in each). Percentage of destroyed villi. The extent of oedema of villi, necrosis of neurons, and disturbances in the secretory capacity of enterocytes correlated well with the duration of cholestasis. After 6 and 12 days ligation alone 7.2% and 17.3%, respectively, of villi were found to be destroyed; their connective tissue framework including lymphatics was in direct contact with the intestinal contents. The changes were not reversed by one day of external biliary drainage. The gaps in the ileal mucosa caused by obstructive jaundice (and not relieved by one day of external biliary drainage) may enable gut bacteria and their endotoxin to reach the systemic circulation through the lymphatic-system. This could increase the risk of infective complications.

Nitric oxide production by kupffer cells in obstructive jaundiced rats: The effect of internal andexternal drainage

Nitric oxide production by kupffer cells in obstructive jaundiced rats: The effect of internal andexternal drainage

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.

Somatostatin: possible cause of bacterial translocation in obstructive jaundiced rats.

The purpose of this study was to examine the effect of endogenous somatostatin hormone on bacterial translocation in obstructive jaundiced rats. Five groups of rats were studied: group I (n = 10), non-operated group (control); group II (n = 10), sham-operated group which underwent laparotomy and dissection of portal elements, while the common bile duct was not ligated and somatostatin was not injected; group III (n = 10), same as group II, plus injection of somatostatin; group IV (n = 10), common bile duct was ligated with laparotomy but somatostatin was not injected; group V (n = 10), same as group IV, plus somatostatin injection. The blood was analyzed for somatostatin, alkaline phosphatase, and bilirubin levels on the third and tenth days in all animals. At study termination (tenth day), peritoneal swab and blood cultures were taken, and liver, spleen, lung, and mesenteric lymph nodes were harvested for microbiological studies. Bacterial translocation levels were higher in groups III, IV, and V when compared with levels in groups I and II. Similar translocation levels were obtained when blood somatostatin levels were comparable. However, the highest translocation rate was found in groups IV and V in which the blood somatostatin level was also higher when compared with that in other groups. This finding shows that blood somatostatin level is increased in obstructive jaundice. This may explain the bacterial translocation and related sepsis found in obstructive jaundice.

Some pharmacological and toxicological studies on Balanites aegyptiaca bark.

The aqueous extract of Balanites aegyptiaca bark, which is used in Sudanese folk medicine in the treatment of jaundice, was without effect when studied on rabbit intestine, rabbit aortic strip, rat stomach strip, rat uterus and rat phrenic nerve-diaphragm in a dose up to 10 mg/mL gut bath. In a larger dose (25 mg) the extract decreased significantly the contractility and the rate of the isolated perfused rabbit heart. Administration of the aqueous extract to biliary duct-ligated rats, showed a dose-dependent significant decrease in serum bilirubin level. The chronic and subchronic toxicity investigations indicate the safety of the aqueous extract at a dose level which showed a significant decrease in serum bilirubin level in experimental obstructive jaundice in rats.

Some pharmacological and toxicological studies on Balanites aegyptiaca bark

The aqueous extract of Balanites aegyptiaca bark, which is used in Sudanese folk medicine in the treatment of jaundice, was without effect when studied on rabbit intestine, rabbit aortic strip, rat stomach strip, rat uterus and rat phrenic nerve–diaphragm in a dose up to 10 mg/mL gut bath. In a larger dose (25 mg) the extract decreased significantly the contractility and the rate of the isolated perfused rabbit heart. Administration of the aqueous extract to biliary duct-ligated rats, showed a dose-dependent significant decrease in serum bilirubin level. The chronic and subchronic toxicity investigations indicate the safety of the aqueous extract at a dose level which showed a significant decrease in serum bilirubin level in experimental obstructive jaundice in rats. Copyright © 1999 John Wiley & Sons, Ltd.

Hepatocyte Growth Factor Supply Accelerates Compensatory Hypertrophy Caused by Portal Branch Ligation in Normal and Jaundiced Rats

Background. Hepatocyte growth factor (HGF), first identified as the most potent mitogen for hepatocytes, significantly stimulates liver regeneration after hepatectomy. In this report, we examined whether HGF is also useful in accelerating compensatory hypertrophy caused by portal branch ligation in normal and jaundiced rats.Materials and Methods. Normal and reversible obstructive jaundiced rats underwent portal ligation of the left lateral and median branches, which supply approximately 70% of the total volume of the liver. Simultaneously, the animals were continuously treated with either recombinant human HGF (rhHGF) or vehicle alone via an intraperitoneally implanted osmotic pump. Two and four days after portal ligation, the degree of compensatory hypertrophy in unoccluded lobes was examined by measuring the wet weight ratios of the unoccluded lobes to the whole liver and the 5-bromo-2′-deoxyuridine labeling index of hepatocytes in each group.Results. The HGF treatment significantly increased the wet weight ratios and the DNA synthesis in nonoccluded lobes 2 and 4 days after portal ligation in both normal and jaundiced rats. Moreover, rhHGF supply promptly decreased serum total bilirubin level in jaundiced rats.Conclusions. Continuous rhHGF administration not only accelerates compensatory hypertrophy in normal and jaundiced rats but also ameliorates hyperbilirubinemia in jaundiced rats.

The Impairment of Wound Healing Processis Correlated With Abnormalities of TNF‐αProduction by Peritoneal Exudate Cellsin Obstructive Jaundiced Rats

The wound healing process and production of tumour necrosis factor alpha (TNF-α) by peritoneal cells of 7-day and 14-day obstructive jaundice (OJ) and sham-operated rats were investigated. In the study the skin wound breaking strength was measured, In addition such histological and biochemical parameters as fibroblast and endothelial cell proliferation, inflammatory cell infiltration and hydroxyproline content were evaluated in polyurethane sponge discs implanted subcutaneously into rats. TNF-α production by peritoneal exudate cells (PEC), both spontaneous and lipopolysaccharide (LPS)- induced was determined by a bioassay. In OJ rats the process of both early as well as late phase of healing was impaired. The breaking strength of skin wound was decreased, the fibroblast and endothelial cell proliferation and collagen deposition, as well as hydroxyproline content were diminished. In 7 day OJ the numbers of inflammatory cells in the implants were lowered with a subsequent slight increase on day 14 of OJ. The spontaneous and LPS induced TNF- α production by PEC were significantly higher in 7 day OJ as compared with sham-operated controls. On day 14 of OJ the LPS-induced TNF-α level was, in contrast, much lower and did not differ much from the spontaneous TNF-α production. We conclude that the impairment of wound healing in OJ results from disturbances in functioning of the immune system caused by systemic endotoxaemia.

Role of endothelin in obstructive jaundice.

Mediators responsible for renal changes in obstructive jaundice are not specified. This study is designed to study the role of endothelin-1 (ET-1) in obstructive jaundice in rats. Animals were randomly placed into five experimental groups. Group 1 (N = 3) was the sham-operated group. Group 2 (N = 8) after common bile duct (CBD) ligation, received bosentan, which is a nonselective endothelin receptor blocker, 50 mg/kg/day for seven days. Group 3 (N = 7) received 1 microg/kg/day captopril. Group 4 (N = 7) was given both drugs orally for seven days. Group 5 (N = 6) after CBD ligation, received Arabic gum as the vehicle. Blood was drawn from the infrahepatic vena cava for the determination of ET-1, bilirubin, creatinine, protein oxidation products, hyaluronic acid, and beta-N-acetyl-hexosaminase. Liver tissue samples were obtained to determine glutathione levels. ET-1, protein oxidation products, hyaluronic acid, bilirubin, and creatinine levels increased significantly in the control group when compared with sham. Bosentan effectively prevented ET-1 elevation but could not reverse creatinine or bilirubin elevation. Captopril with or without bosentan was cytoprotective but did not reverse increased creatinine levels. It is concluded that increased ET-1 in obstructive jaundice may be one of the contributing factors of renal damage.