Role of heme oxygenase-carbon monoxide pathway in pathogenesis of cirrhotic cardiomyopathy in the rat

2001 ◽  
Vol 280 (1) ◽  
pp. G68-G74 ◽  
Author(s):  
Hongqun Liu ◽  
Daisheng Song ◽  
Samuel S. Lee
Keyword(s):  
Bile Duct ◽  
Protein Expression ◽  
Heme Oxygenase ◽  
Papillary Muscle ◽  
Cardiac Contraction ◽  
Zinc Protoporphyrin ◽  
Sham Operation ◽  
Muscle Contractility ◽  
Cirrhotic Cardiomyopathy ◽  
Duct Ligation

The enzyme heme oxygenase (HO), which exists in inducible (HO-1) and constitutive (HO-2) isoforms, degrades heme to biliverdin and CO. CO depresses cardiac contraction via cGMP. We aimed to clarify a possible role for the HO-CO pathway in the pathogenesis of cirrhotic cardiomyopathy in bile duct-ligated rats. Four weeks after bile duct ligation or sham operation, rat ventricles were examined for HO-1 and HO-2 mRNA by RT-PCR and for protein expression by Western blotting. Total HO enzyme activity and cGMP levels were also measured. The effects of a HO inhibitor, zinc protoporphyrin IX (ZnPP), on ventricular cGMP levels and isolated papillary muscle contractility were studied. We found that HO-1 mRNA transcription and protein expression were significantly augmented in cirrhotic hearts compared with sham-operated controls, whereas there was no difference in HO-2 mRNA or protein levels. Total HO activity and cGMP levels were significantly increased in cirrhotic ventricles vs. controls. In cirrhotic ventricles, treatment with ZnPP significantly decreased cGMP production and improved the blunted papillary muscle contractility, whereas it had no effect on control muscles. CO perfusion inhibited papillary muscle contractility, an effect completely blocked by methylene blue and partially blocked by ZnPP. These results indicate that activation of the HO-CO-cGMP pathway is involved in the pathogenesis of cirrhotic cardiomyopathy.

Ammonia reduction with ornithine phenylacetate restores brain eNOS activity via the DDAH-ADMA pathway in bile duct-ligated cirrhotic rats

2012 ◽  
Vol 302 (1) ◽  
pp. G145-G152 ◽  
Author(s):  
Vairappan Balasubramaniyan ◽  
Gavin Wright ◽  
Vikram Sharma ◽  
Nathan A. Davies ◽  
Yalda Sharifi ◽  
...  
Keyword(s):  
Bile Duct ◽  
Protein Expression ◽  
Ammonia Concentration ◽  
Sham Operation ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Duct Ligation ◽  
Tnf Α ◽  
No Signaling ◽  
Brain Water

Ammonia is central in the pathogenesis of hepatic encephalopathy, which is associated with dysfunction of the nitric oxide (NO) signaling pathway. Ornithine phenylacetate (OP) reduces hyperammonemia and brain water in cirrhotic animals. This study aimed to determine whether endothelial NO synthase activity is altered in the brain of cirrhotic animals, whether this is associated with changes in the endogenous inhibitor, asymmetric-dimethylarginine (ADMA) and its regulating enzyme, dimethylarginine-dimethylaminohydrolase (DDAH-1), and whether these abnormalities are restored by ammonia reduction using OP. Sprague-Dawley rats were studied 4-wk after bile duct ligation (BDL) ( n = 16) or sham operation ( n = 8) and treated with placebo or OP (0.6 g/kg). Arterial ammonia, brain water, TNF-α, plasma, and brain ADMA were measured using standard techniques. NOS activity was measured radiometrically, and protein expression for NOS enzymes, ADMA, DDAH-1, 4-hydroxynonenol (4HNE), and NADPH oxidase (NOX)-1 were measured by Western blotting. BDL significantly increased arterial ammonia ( P < 0.0001), brain water ( P < 0.05), and brain TNF-α ( P < 0.01). These were reduced significantly by OP treatment. The estimated eNOS component of constitutive NOS activity was significantly lower ( P < 0.05) in BDL rat, and this was significantly attenuated in OP-treated animals. Brain ADMA levels were significantly higher and brain DDAH-1 significantly lower in BDL compared with sham ( P < 0.01) and restored toward normal following treatment with OP. Brain 4HNE and NOX-1 protein expression were significantly increased in BDL rat brain, which were significantly decreased following OP administration. We show a marked abnormality of NO regulation in cirrhotic rat brains, which can be restored by reduction in ammonia concentration using OP.

A new method for the experimental induction of secundary biliary cirrhosis in wistar rats

2001 ◽  
Vol 16 (2) ◽  
pp. 75-81 ◽  
Author(s):  
Gracinda De Lourdes Jorge ◽  
Luiz Sergio Leonardi ◽  
Ilka de Fatima Santana Ferreira Boin ◽  
Orlando de Castro e Silva Jr ◽  
Cecilia Amelia Fazzio Escanhoela
Keyword(s):  
Bile Duct ◽  
Morphological Study ◽  
Wistar Rats ◽  
Hepatic Duct ◽  
Control Group ◽  
Sham Operation ◽  
Biliary Cirrhosis ◽  
Technical Failure ◽  
Duct Obstruction ◽  
Duct Ligation

The aim of this study was to describe a method for the induction of experimental secondary biliary fibrosis (SBF). Forty-seven Wistar rats were submitted to hepatic duct obstruction (OB group) for thirty days without ligature, section or cannulization causing interruption of biliary flow. This technique was carried out by simple traction of the bile duct passing it through the xiphoid appendix. Nine rats were submitted to a sham operation for bile duct stricture and seven rats comprised the control group. Blood samples were collected for the measurement of total bilirubin (TB), alkaline phosphatase (AP), alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Liver fragments were removed for morphological study. Thirty days after surgery TB, AP, ALT and AST levels were significantly increased in the hepatic duct ligation group compared to the sham operated group and the presence of SBF in the OB group was confirmed by morphological study of the liver. There was technical failure in 31.92% cases. The survival was 100% at fifteen days and 82.97% at the end of the experiment. We concluded that this simple surgical technique may be used to study the consequence of bile duct obstruction which could be a reversible process depending on the obstruction time. This technique can be carried out from cholestasis to fibrosis.

scholarly journals Liver histological, portal flow and plasmatic nitric oxide alterations caused by biliary obstruction and drainage in rats

2008 ◽  
Vol 23 (suppl 1) ◽  
pp. 2-7 ◽  
Author(s):  
Miguel Angel Dias ◽  
Reginaldo Ceneviva ◽  
Jorge Elias Jr. ◽  
Sergio Zucoloto ◽  
Caroline Floreoto Baldo ◽  
...  
Keyword(s):  
Bile Duct ◽  
Biliary Obstruction ◽  
Bile Duct Ligation ◽  
Sham Operation ◽  
Portal Flow ◽  
Histological Alterations ◽  
Duct Occlusion ◽  
Duct Ligation ◽  
Male Wistar Rats ◽  
Periodic Evaluation

PURPOSE: To evaluate liver alterations caused by biliary obstruction and drainage. METHODS: Thirty-nine male Wistar rats were randomly distributed in 4 groups: BO (n=18) bile duct ligation for 20 days, with a periodic evaluation of liver histological alterations, Doppler echography portal flow and measurements of NO and malondialdehyde (MDA); BO/DB (n=13) bile duct occlusion for 20 days followed by biliary drainage by choledochoduodenal anastomosis, 5 days follow-up, same BO group parameters evaluations; group CED (n=4) sham operation and portal flow evaluation trough 20 days; CHB (n=4) sham operation, with hepatic biopsy on 25th day and followed-up trough 25 days, by the same parameters of group BO, with exception of portal flow. Direct bilirubin (DB) and alkaline phosphatase (AP) were evaluated in the group BO, BO/DB and CHB. RESULTS: The bile duct ligation led to an increase of DB and AP, development of liver histological alterations, reduction of portal flow and increase of plasmatic NO and of MDA levels. The bile duct clearing resulted in a reduction of DB, AP, NO, MDA histological alterations and increase of portal flow. CONCLUSION: The biliary occlusion resulted in cholestasis and portal flow reduction, besides the increase of plasmatic NO and of hepatic MDA levels, and histological liver alterations, with a tendency of normalization after the bile duct clearing.

scholarly journals Protective Effect of Vitamin E on Gastric Mucosal Injury in Rats with Biliary Obstruction

2000 ◽  
Vol 14 (6) ◽  
pp. 499-503 ◽  
Author(s):  
Nuh Zafer Cantürk ◽  
Zeynep Cantürk ◽  
G Özbilim ◽  
C Yenisey
Keyword(s):  
Vitamin E ◽  
Bile Duct ◽  
Common Bile Duct ◽  
Mucosal Injury ◽  
Mucosal Damage ◽  
Gastric Mucosal Injury ◽  
Gastric Mucosal Damage ◽  
Sham Operation ◽  
Gastric Mucosal Lesions ◽  
Duct Ligation

Patients with liver disease display increased susceptibility to gastric mucosal damage. A role of free radicals has been suggested in the development of gastric mucosal damage in normal subjects. The effects of antioxidant vitamin E treatment on the liver and stomach in cirrhotic rats were examined. Fifty rats were divided into three groups. Cirrhosis was induced by bile duct ligation in 40 of 50 rats. Controls underwent a sham operation. Gastric mucosal lesions were produced by intragastric administration of 1 mL of 95% ethanol in all three groups. Twenty bile duct-ligated rats were injected intramuscularly with vitamin E (100 mg/kg/day). Liver and stomach histology, and stomach malondialdehyde and glutathione levels were determined. Portal hypertension was measured. Macroscopic and microscopic gastric mucosal injury were significantly greater in the control and common bile duct-ligated groups than in the vitamin E-pretreated group (P<0.05). The tissue malondialdehyde and glutathione levels were significantly decreased in the vitamin E-administrated group compared with the common bile duct-ligated group (P<0.001). Vitamin E administration may be cytoprotective for both the liver and gastric mucosa in bile duct-ligated rats.

Plasma Membrane Form of Phosphatidate Phosphohydrolase: A Possible Role in Signal Transduction during Liver Fibrogenesis

1993 ◽  
Vol 85 (3) ◽  
pp. 281-287 ◽  
Author(s):  
Christopher P. Day ◽  
Alastair D. Burt ◽  
Ashley Stj. M. Brown ◽  
Mark K. Bennett ◽  
Desmond J. Farrell ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Liver Disease ◽  
Bile Duct ◽  
Common Bile Duct ◽  
Alcoholic Liver Disease ◽  
Bile Duct Ligation ◽  
Sham Operation ◽  
Common Bile Duct Ligation ◽  
Duct Ligation ◽  
Phosphatidate Phosphohydrolase

1. Several growth factors important in liver regeneration and fibrosis stimulate phospholipase D in plasma membranes via a receptor/G-protein-coupled mechanism resulting in hydrolysis of phosphatidylcholine to phosphatidate. Phosphatidate can be further hydrolysed to diacylglycerol by phosphatidate phosphohydrolase. Phosphatidate and diacylglycerol can act as ‘second-messengers’ and regulation of phosphatidate phosphohydrolase activity could control the balance between them. 2. A form of phosphatidate phosphohydrolase, located in the plasma membrane and insensitive to inhibition by N-ethylmaleimide, has recently been identified that is distinct from the ‘metabolic’ form, which is present in the cytosol and microsomes and is sensitive to N-ethylmaleimide. 3. We have investigated the hypothesis that the balance between regeneration and fibrosis is, in part, determined by the activity of plasma membrane phosphatidate phosphohydrolase through its effect on the phosphatidate/diacylglycerol ratio. N-Ethylmaleimide-insensitive and -sensitive phosphatidate phosphohydrolase activities were measured in three hepatic conditions characterized by regeneration and/or fibrosis: alcoholic liver disease in humans (regeneration and fibrosis) and rat livers after either acute CCl-4-induced injury (regeneration) or common bile duct ligation (fibrosis). 4. In patients with alcoholic liver disease, N-ethylmaleimide-insensitive phosphatidate phosphohydrolase activity was higher in cirrhotic biopsies (5.82±0.3 nmol of Pi min−1 mg−1 of protein, n = 19) than in non-cirrhotic biopsies (2.17 ±0.2, n = 23) or in wedge biopsies from healthy subjects undergoing routine cholecystectomy (2.16 ±0.5, n = 6). N-Ethylmaleimide-insensitive phosphatidate phosphohydrolase activity was unchanged in the 10 days after CCl4 treatment but increased progressively in common bile duct-ligated rats (e.g. day 28: ‘sham’ operation, 1.97 ±0.3, chronic bile duct ligation, 6.91 ±1.24 nmol of Pi min−1 mg−1 of protein). N-Ethylmaleimide-insensitive phosphatidate phosphohydrolase activity correlated closely with the degree of fibrosis in humans and rats. N-Ethylmaleimide-sensitive phosphatidate phosphohydrolase activity was unchanged after CCI4 treatment or common bile duct ligation and was not increased in cirrhotic livers. 5. Plasma membrane N-ethylmaleimide-insensitive phosphatidate phosphohydrolase increases in liver fibrosis but not regeneration. Stimulation of phosphatidate phosphohydrolase activity with its effect on the diacylglycerol/phosphatidate ratio may play a role in transduction of the fibrosis signal.

scholarly journals Infection by Gram-Negative Organisms via the Biliary Route Results in Greater Mortality than Portal Venous Infection

2003 ◽  
Vol 10 (4) ◽  
pp. 664-669 ◽  
Author(s):  
D. Rohan Jeyarajah ◽  
Mariusz L. Kielar ◽  
Nicole Frantz ◽  
Guy Lindberg ◽  
Christopher Y. Lu
Keyword(s):  
Bile Duct ◽  
Portal Vein ◽  
Biliary Obstruction ◽  
Bile Duct Ligation ◽  
Lethal Dose ◽  
Bile Duct Obstruction ◽  
Sham Operation ◽  
Duct Obstruction ◽  
E Coli ◽  
Duct Ligation

ABSTRACT Cholangitis requires bile duct obstruction and infection. Patients with cholangitis are often more affected than those with infections that reach the liver through the portal vein. We will attempt to study the influences of (i) route of entry and (ii) presence of bile duct obstruction on hepatic infection. C57BL/6 mice received injections of Escherichia coli or lipopolysaccharide into the obstructed bile duct or portal vein and were monitored for survival. Livers were assayed for bacteria, and cytokine mRNA was measured. In order to examine the effect of biliary obstruction on hepatic infection, animals were subjected to bile duct ligation 1 day prior to portal vein injection and were monitored for survival. The 50% lethal dose (LD50) for E. coli injected into the bile duct was 50 CFU/animal; the LD50 for E. coli injected into the portal vein was 5 × 107 CFU/animal. Initial hepatic delivery of bacteria was equivalent 1 h after injection into the bile duct or portal vein. However, by 24 h, a significantly greater amount of bacteria was recovered from the livers of the bile duct-injected group. Interleukin 10 (IL-10) and IL-1RA mRNA was expressed at greater levels in the bile duct-injected group. Prior bile duct ligation followed by portal vein injection resulted in a higher incidence of death than when sham operation was performed prior to portal vein injection. Our data suggest that the increased mortality from cholangitis, compared with that from other hepatic infections, is related to the different route of delivery of pathogen and the maladaptive response (possibly involving IL-10 and IL-1RA) to biliary obstruction itself.

scholarly journals MicroRNA-29a mitigation of endoplasmic reticulum and autophagy aberrance counteracts in obstructive jaundice-induced fibrosis in mice

2017 ◽  
Vol 243 (1) ◽  
pp. 13-21 ◽  
Author(s):  
Ying-Hsien Huang ◽  
Ya-Ling Yang ◽  
Fu-Chen Huang ◽  
Mao-Meng Tiao ◽  
Yen-Cheng Lin ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Bile Duct ◽  
Protein Expression ◽  
Bile Duct Ligation ◽  
Binding Protein ◽  
Wild Type ◽  
Innovative Strategy ◽  
Over Expression ◽  
Duct Ligation

Hepatic fibrosis was caused by a number of signaling pathways that damage liver integrity. We have previously shown that microRNA-29a (miR-29a) protects against liver fibrosis. Aberrant endoplasmic reticulum (ER) and autophagy function reportedly exaggerate hepatic disorders. The aim of this study was to characterize the biological influence of miR-29a on ER function in injured livers with bile duct ligation (BDL). We performed BDL on miR-29a transgenic mice (miR-29aTg) and wild-type mice to induce cholestatic liver injury. Rat T6 cells were transfected with miR-29a mimic and tunicamycin. Compared to the wild-type mice, the BDL deterioration of liver function in terms of total bilirubin, alanine transaminase, and aspartate transaminase activity in the miR-29aTg mice was significantly reduced. Affected livers in the miR-29aTg mice demonstrated a slight fibrotic matrix formation. miR-29a over-expression reduced the BDL disturbance of the expressions of inositol-requiring kinase 1alpha, double-stranded RNA-activated protein kinase-like endoplasmic reticulum kinase, spliced-X-box binding protein 1 (sXBP1), CCAAT/enhancer-binding protein homologous protein (CHOP), ULK, LC3BII, p62, and cleaved caspase-8, 9 and 3. In vitro, T6 cells exposed to tunicamycin by increasing abundances of CHOP, sXBP1, cleaved caspase-3, and LC3BII were diminished in the cell cultures transfected with the miR-29a mimic. On the other hand, we observed that miR-29a signaling protected liver tissues from BDL-mediated metabolic dysfunction and excessive fibrosis histopathology. This study provides new molecular insight into the miR-29a stabilization of ER integrity that slows the progression of cholestatic liver deterioration. Impact statement Long-term hepatic damage caused by hepatitis and cholestasis can accelerate fibrosis matrix over-production, which is a harmful process attributed to the dysregulation of a number of cellular and molecular events. The purpose of this study is to characterize the biological influence of miR-29a on endoplasmic reticulum (ER) function in bile duct ligation (BDL)-injured livers. To the best of our knowledge, this report is the first demonstration that miR-29a over-expression diminishes BDL provocation of ER stress (unfolded protein response, UPR) effector protein expression. This work also demonstrates that miR-29a decreased caspases protein expression in cholestatic livers, while an increase in miR-29a function reduced sXBP1 and CHOP expressions in T6 cells in mice. Analyses of this study highlight that controlling miR-29a signaling can serve as an innovative strategy in the future for microRNA regulation of ER homeostasis to combat cholestasis induction hepatic disorders.

Hemodynamic characterization of conscious and ketamine-anesthetized bile duct-ligated rats

1991 ◽  
Vol 260 (1) ◽  
pp. G161-G166 ◽  
Author(s):  
E. Sikuler ◽  
A. E. Buchs ◽  
A. Yaari ◽  
A. Keynan
Keyword(s):  
Bile Duct ◽  
Portal Pressure ◽  
Peripheral Resistance ◽  
Sham Operation ◽  
Animal Suffering ◽  
Additional Information ◽  
Duct Ligation ◽  
Portosystemic Shunting ◽  
Arteriolar Resistance ◽  
Ketamine Anesthesia

The present study was conducted to characterize the hemodynamic alterations in common bile duct-ligated (CBDL) rats under ketamine anesthesia and in the awake restrained state. Hemodynamic studies using the radioactive microspheres technique were performed 17.6 +/- 0.6 (SE) days after bile duct ligation or sham operation. CBDL rats had lower mean arterial pressure, reduced systemic and renal resistance, and increased renal blood flow compared with sham-operated rats. This was found both in the conscious and anesthetized states. Anesthetized CBDL rats had higher portal pressure (13.2 +/- 0.5 vs. 9.2 +/- 0.4 mmHg; P less than 0.001) and lower splanchnic arteriolar resistance (15.4 +/- 1.3 vs 26.8 +/- 4.6 mmHg.ml-1.min.100 g body wt; P less than 0.05) than sham-operated rats. Portosystemic shunting was 52.3 +/- 11.7% in CBDL and negligible in sham-operated rats. The last three parameters could not be measured in conscious animals. Total peripheral resistance was lower in the conscious than in the anesthetized state, diverting a higher fraction of cardiac output at the expense of splanchnic organs and leading to a significant reduction of portal venous inflow in sham-operated but not in CBDL rats [3.36 +/- 0.47 vs. 5.38 +/- 0.65 (P less than 0.05) and 5.33 +/- 0.58 vs. 6.34 +/- 0.37 ml.min-1.100 g body wt-1 (P = NS), respectively]. These findings indicate that CBDL and normal rats respond differently to anesthesia and restraint. Because the restrained state is stressful and studies in anesthetized animals are technically simpler, provide additional information such as portal pressure and portosystemic shunting, and diminish animal suffering, we suggest that hemodynamic studies in rats, using the microsphere technique, should be preferably performed under ketamine anesthesia.

scholarly journals Cholestasis in a murine experimental model: lesions include hepatocyte ischemic necrosis

2003 ◽  
Vol 58 (1) ◽  
pp. 27-32 ◽  
Author(s):  
Ivete Bedin Prado ◽  
Marília Harumi Higuchi dos Santos ◽  
Fábio Pinatel Lopasso ◽  
Kiyoshi Iriya ◽  
Antonio Atílio Laudanna
Keyword(s):  
Bile Duct ◽  
Experimental Model ◽  
Bile Duct Ligation ◽  
Histological Study ◽  
Biliary Tree ◽  
Sham Operation ◽  
Ischemic Necrosis ◽  
Sham Operation Group ◽  
Visceral Peritoneum ◽  
Duct Ligation

OBJECTIVE: To establish a murine experimental model of bile duct obstruction that would enable controlled observations of the acute and subacute phases of cholestasis. METHODOLOGY: Adult male isogenic BALB/c mice underwent a bile duct ligation (22 animals) or a sham operation (10 animals). Fifteen days after surgery, or immediately after the animal's death, macroscopic findings were noted and histological study of the liver, biliary tree, and pancreas was performed (hematoxylin-eosin and Masson trichromic staining). RESULTS: Beginning 24 hours after surgery, all animals from the bile duct ligation group presented progressive generalized malaise. All animals presented jaundice in the parietal and visceral peritoneum, turgid and enlarged liver, and accentuated dilatation of gallbladder and common bile duct. Microscopic findings included marked dilatation and proliferation of bile ducts with accentuated collagen deposits, frequent areas of ischemic necrosis, hepatic microabscesses, and purulent cholangitis. Animals from the sham operation group presented no alterations. CONCLUSION: We established a murine experimental model of induced cholestasis, which made it possible to study acute and subacute tissue lesions. Our data suggests that in cholestasis, hepatic functional ischemia plays an important role in inducing hepatic lesions, and it also suggests that the infectious process is an important factor in morbidity and mortality.

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