The two most widely used experimental models of advanced liver disease are the administration of carbon tetrachloride, and common bile duct ligation (BDL), however, neither has been systematically evaluated as a model...The two most widely used experimental models of advanced liver disease are the administration of carbon tetrachloride, and common bile duct ligation (BDL), however, neither has been systematically evaluated as a model of hepatorenal syndrome (HRS). The BDL model in rats, studied at diverse time points, induced a progressive renal dysfunction without structural changes in the kidney. The authors concluded that BDL is a good model for further studies of HRS and its treatment. However, the renal impairment observed at the acute phase of the BDL model is based on a different pathophysiology than that of HRS. Specifi cally, in acute obstructive jaundice, cholemia predominates over parenchymal liver disease (reversible at this stage without portal hypertension or cirrhosis) and independently induces negative inotropic and chronotropic effects on the heart, impaired sympathetic vasoconstriction response and profound natriuresis and diuresis that might lead to volume depletion. In addition, systemic endotoxemia contributes to the prerenal etiology of renal impairment and promotes direct nephrotoxicity and acute tubular necrosis. On the other hand, the renal failure observed in the chronic BDL model (with development of biliary cirrhosis, portal hypertension and ascites) shares pathophysiological similarities with HRS, but the accordance of the chronic BDL model to the diagnostic criteria of HRS (e.g. absence of spontaneous bacterial peritonitis, no renal function improvement after plasma volume expansion) should have been confirmed. In conclusion, we think that the BDL model is not suitable for the study of the natural history of HRS, but the chronic BDL model might be valid for the study of established HRS and its potential therapies.展开更多
AIM: Retention and accumulation of toxic hydrophobic bile salts within hepatocyte may cause hepatocyte toxicity by inducing apoptosis. Apoptosis is a pathway of cell death orchestrated by a family of proteases called ...AIM: Retention and accumulation of toxic hydrophobic bile salts within hepatocyte may cause hepatocyte toxicity by inducing apoptosis. Apoptosis is a pathway of cell death orchestrated by a family of proteases called caspases. Z-ValAla-Asp (OMe)-fluoromethyl ketone (ZVAD-fmk) is a cellpermeable irreversible inhibitor of caspase. The purpose of this study was to evaluate the possible effect of ZVAD-fmk on hepatocyte apoptosis after bile duct ligation in the rat.METHODS: Male Sprague-Dawley rats, weighing 250-300 g,were randomized to five groups of five rats each. Group 1 underwent common bile duct ligation and simultaneous treatment with ZVAD-fmk (dissolved in dimethylsulfoxide (DMSO)). Group 2 underwent common bile duct ligation and simultaneous treatment with Z-Phe-Ala-fluoromethyl ketone ( ZFA-fmk, dissolved in DMSO). Group 3 underwent sham operation and simultaneous treatment with the same amount of DMSO. Group 4 underwent sham operation and simultaneous treatment with the same amount of normal saline. Group 5 underwent common bile duct ligation without other manipulation. After three days, liver tissue was harvested for histopathologic analysis and measurements of apoptosis.RESULTS: When compared with sham operation, common bile duct ligation significantly increased hepatocyte apoptosis (P= 0.008) and ductular proliferation (P= 0.007).ZVAD-fmk significantly diminished the increased hepatocyte apoptosis and ductular proliferation after common bile duct ligation (P = 0.008 and P = 0.007, respectively). ZFA did not show the same effects.CONCLUSION: Hepatocyte apoptosis and ductular proliferation significantly increased after common bile duct ligation. ZVAD-fmk effectively diminished the increased hepatocyte apoptosis and ductular proliferation after common bile duct ligation, whereas ZFA-fmk did not.展开更多
AIM: To evaluate the effects of dexamethasone on liver damage in rats with bile duct ligation. METHODS: A total of 40 male Sprague-Dawley rats, weighing 165-205 g, were used in this study. Group 1 (sham-control, n = 1...AIM: To evaluate the effects of dexamethasone on liver damage in rats with bile duct ligation. METHODS: A total of 40 male Sprague-Dawley rats, weighing 165-205 g, were used in this study. Group 1 (sham-control, n = 10) rats underwent laparotomy alone and the bile duct was just dissected from the surrounding tissue. Group 2 rats (untreated, n = 10) were subjected to bile duct ligation (BDL) and no drug was applied. Group 3 rats (low-dose dexa, n = 10) received a daily dose of dexamethasone by orogastric tube for 14 d after BDL. Group 4 rats (high-dose dexa, n = 10) received a daily dose of dexamethasone by orogastric tube for 14 d after BDL. At the end of the two-week period, biochemical and histological evaluations were processed. RESULTS: The mean serum bilirubin and liver enzyme levels signifi cantly decreased, and superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) values were significantly increased in low-dose dexa and high-dose dexa groups when compared to the untreated group. The histopathological score was significantly less in the low-dose and high-dose dexa groups compared to the untreated rats. In the low-dose dexa group, moderate liver damage was seen, while mild liver damage was observed in the high-dose dexa group. CONCLUSION: Corticosteroids reduced liver damage produced by bile duct obstruction. However, the histopathological score was not signifi cantly lower in the high-dose corticosteroid group as compared to the low-dose group. Thus, low-dose corticosteroid provides asignifi cant reduction of liver damage without increased side effects, while high dose is associated not with lower fi brosis but with increased side effects.展开更多
Objective To develop and evaluate the rat model of chronic glaucoma by episcleral veins ligation （EVL）. Methods Experimental glaucoma was induced unilaterally in 28 male Sprague-Dawley rats by ligating two episclera...Objective To develop and evaluate the rat model of chronic glaucoma by episcleral veins ligation （EVL）. Methods Experimental glaucoma was induced unilaterally in 28 male Sprague-Dawley rats by ligating two episcleral veins. Intraocular pressure （10P） in rats was measured by a Goldmann applanation tonometer under 3 % pentobarbital sodium anesthesia. The optic nerve head and retinal vasculature were assessed by repeated fundus examinations. The amount of optic nerve axons was assessed by Image-Pro Plus image analysis system in a masked fashion. Results lOP without EVL was （ 19.21 ± 1.23） mmHg, whereas the EVL eyes gained about 1.8-fold higher 10P[ （33.96 ±2. 73） mmHg]after EVL immediately （ P 〈 0. 001 ）. The elevated IOP gradually decreased over time. However, the differences were kept significant up to 8 weeks after EVL. The lOP was reduced to similar levels as contralateral eyes at 12 and 16 weeks after EVL. The glaucomatous optic nerve excavation appeared in EVL eyes at 8 weeks after EVL, and the optic nerve excavation enlarged gradually with the increasing post-operation time. The amount of optic nerve axons also significantly decreased in EVL eyes at 8 weeks after EVL, and the amount of axons decreased gradually with the increasing post-operation time. Conclusion Increase of lOP caused by EVL represents a useful and efficient model of experimental glaucoma in rats.展开更多
文摘The two most widely used experimental models of advanced liver disease are the administration of carbon tetrachloride, and common bile duct ligation (BDL), however, neither has been systematically evaluated as a model of hepatorenal syndrome (HRS). The BDL model in rats, studied at diverse time points, induced a progressive renal dysfunction without structural changes in the kidney. The authors concluded that BDL is a good model for further studies of HRS and its treatment. However, the renal impairment observed at the acute phase of the BDL model is based on a different pathophysiology than that of HRS. Specifi cally, in acute obstructive jaundice, cholemia predominates over parenchymal liver disease (reversible at this stage without portal hypertension or cirrhosis) and independently induces negative inotropic and chronotropic effects on the heart, impaired sympathetic vasoconstriction response and profound natriuresis and diuresis that might lead to volume depletion. In addition, systemic endotoxemia contributes to the prerenal etiology of renal impairment and promotes direct nephrotoxicity and acute tubular necrosis. On the other hand, the renal failure observed in the chronic BDL model (with development of biliary cirrhosis, portal hypertension and ascites) shares pathophysiological similarities with HRS, but the accordance of the chronic BDL model to the diagnostic criteria of HRS (e.g. absence of spontaneous bacterial peritonitis, no renal function improvement after plasma volume expansion) should have been confirmed. In conclusion, we think that the BDL model is not suitable for the study of the natural history of HRS, but the chronic BDL model might be valid for the study of established HRS and its potential therapies.
基金Supported by the grant NSC 89-2314-B-182A-165 from the National Science Council of Taiwan China
文摘AIM: Retention and accumulation of toxic hydrophobic bile salts within hepatocyte may cause hepatocyte toxicity by inducing apoptosis. Apoptosis is a pathway of cell death orchestrated by a family of proteases called caspases. Z-ValAla-Asp (OMe)-fluoromethyl ketone (ZVAD-fmk) is a cellpermeable irreversible inhibitor of caspase. The purpose of this study was to evaluate the possible effect of ZVAD-fmk on hepatocyte apoptosis after bile duct ligation in the rat.METHODS: Male Sprague-Dawley rats, weighing 250-300 g,were randomized to five groups of five rats each. Group 1 underwent common bile duct ligation and simultaneous treatment with ZVAD-fmk (dissolved in dimethylsulfoxide (DMSO)). Group 2 underwent common bile duct ligation and simultaneous treatment with Z-Phe-Ala-fluoromethyl ketone ( ZFA-fmk, dissolved in DMSO). Group 3 underwent sham operation and simultaneous treatment with the same amount of DMSO. Group 4 underwent sham operation and simultaneous treatment with the same amount of normal saline. Group 5 underwent common bile duct ligation without other manipulation. After three days, liver tissue was harvested for histopathologic analysis and measurements of apoptosis.RESULTS: When compared with sham operation, common bile duct ligation significantly increased hepatocyte apoptosis (P= 0.008) and ductular proliferation (P= 0.007).ZVAD-fmk significantly diminished the increased hepatocyte apoptosis and ductular proliferation after common bile duct ligation (P = 0.008 and P = 0.007, respectively). ZFA did not show the same effects.CONCLUSION: Hepatocyte apoptosis and ductular proliferation significantly increased after common bile duct ligation. ZVAD-fmk effectively diminished the increased hepatocyte apoptosis and ductular proliferation after common bile duct ligation, whereas ZFA-fmk did not.
文摘AIM: To evaluate the effects of dexamethasone on liver damage in rats with bile duct ligation. METHODS: A total of 40 male Sprague-Dawley rats, weighing 165-205 g, were used in this study. Group 1 (sham-control, n = 10) rats underwent laparotomy alone and the bile duct was just dissected from the surrounding tissue. Group 2 rats (untreated, n = 10) were subjected to bile duct ligation (BDL) and no drug was applied. Group 3 rats (low-dose dexa, n = 10) received a daily dose of dexamethasone by orogastric tube for 14 d after BDL. Group 4 rats (high-dose dexa, n = 10) received a daily dose of dexamethasone by orogastric tube for 14 d after BDL. At the end of the two-week period, biochemical and histological evaluations were processed. RESULTS: The mean serum bilirubin and liver enzyme levels signifi cantly decreased, and superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) values were significantly increased in low-dose dexa and high-dose dexa groups when compared to the untreated group. The histopathological score was significantly less in the low-dose and high-dose dexa groups compared to the untreated rats. In the low-dose dexa group, moderate liver damage was seen, while mild liver damage was observed in the high-dose dexa group. CONCLUSION: Corticosteroids reduced liver damage produced by bile duct obstruction. However, the histopathological score was not signifi cantly lower in the high-dose corticosteroid group as compared to the low-dose group. Thus, low-dose corticosteroid provides asignifi cant reduction of liver damage without increased side effects, while high dose is associated not with lower fi brosis but with increased side effects.
基金Supported by Shanghai Education Committee Project Foundation (06BZ040)
文摘Objective To develop and evaluate the rat model of chronic glaucoma by episcleral veins ligation （EVL）. Methods Experimental glaucoma was induced unilaterally in 28 male Sprague-Dawley rats by ligating two episcleral veins. Intraocular pressure （10P） in rats was measured by a Goldmann applanation tonometer under 3 % pentobarbital sodium anesthesia. The optic nerve head and retinal vasculature were assessed by repeated fundus examinations. The amount of optic nerve axons was assessed by Image-Pro Plus image analysis system in a masked fashion. Results lOP without EVL was （ 19.21 ± 1.23） mmHg, whereas the EVL eyes gained about 1.8-fold higher 10P[ （33.96 ±2. 73） mmHg]after EVL immediately （ P 〈 0. 001 ）. The elevated IOP gradually decreased over time. However, the differences were kept significant up to 8 weeks after EVL. The lOP was reduced to similar levels as contralateral eyes at 12 and 16 weeks after EVL. The glaucomatous optic nerve excavation appeared in EVL eyes at 8 weeks after EVL, and the optic nerve excavation enlarged gradually with the increasing post-operation time. The amount of optic nerve axons also significantly decreased in EVL eyes at 8 weeks after EVL, and the amount of axons decreased gradually with the increasing post-operation time. Conclusion Increase of lOP caused by EVL represents a useful and efficient model of experimental glaucoma in rats.
