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

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.

Download Full-text

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

Acta Cirurgica Brasileira ◽

10.1590/s0102-86502008000700002 ◽

2008 ◽

Vol 23 (suppl 1) ◽

pp. 2-7 ◽

Cited By ~ 1

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.

Download Full-text

Chondroitin sulfate protects liver in the experimental model of extra-hepatic cholestasis induced by common bile duct ligation

Journal of Hepatology ◽

10.1016/s0168-8278(17)31129-7 ◽

2017 ◽

Vol 66 (1) ◽

pp. S389

Author(s):

P.L.R. Guedes ◽

M.L. Gazarini ◽

M.Y. Icimoto ◽

J.A. Aguiar ◽

M. Kouyoumdjian ◽

...

Keyword(s):

Bile Duct ◽

Common Bile Duct ◽

Chondroitin Sulfate ◽

Experimental Model ◽

Bile Duct Ligation ◽

Common Bile Duct Ligation ◽

Duct Ligation

Download Full-text

The blockage of endogenous cholangiocyte serotonin secretion enhances the growth of the biliary tree after bile duct ligation (BDL): Evidence for autocrine regulation of cholangiocyte proliferation

Gastroenterology ◽

10.1016/s0016-5085(03)83505-9 ◽

2003 ◽

Vol 124 (4) ◽

pp. A693

Author(s):

Marco Marzioni ◽

Shannon Glaser ◽

Heather Francis ◽

Luca Marucci ◽

Antonio Benedetti ◽

...

Keyword(s):

Bile Duct ◽

Bile Duct Ligation ◽

Biliary Tree ◽

Autocrine Regulation ◽

Serotonin Secretion ◽

Duct Ligation

Download Full-text

Bile duct ligation in neonatal rats: Is it a valid experimental model for biliary atresia studies?

Pediatric Transplantation ◽

10.1111/j.1399-3046.2008.00947.x ◽

2009 ◽

Vol 13 (1) ◽

pp. 81-87 ◽

Cited By ~ 12

Author(s):

Nelson Elias Mendes Gibelli ◽

Uenis Tannuri ◽

Evandro Sobroza de Mello ◽

Consuelo Junqueira Rodrigues

Keyword(s):

Bile Duct ◽

Biliary Atresia ◽

Experimental Model ◽

Bile Duct Ligation ◽

Neonatal Rats ◽

Duct Ligation

Download Full-text

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

Clinical Science ◽

10.1042/cs0850281 ◽

1993 ◽

Vol 85 (3) ◽

pp. 281-287 ◽

Cited By ~ 5

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.

Download Full-text

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

Clinical and Diagnostic Laboratory Immunology ◽

10.1128/cdli.10.4.664-669.2003 ◽

2003 ◽

Vol 10 (4) ◽

pp. 664-669 ◽

Cited By ~ 1

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.

Download Full-text

Antioxidant and anti-inflammatory action of melatonin in an experimental model of secondary biliary cirrhosis induced by bile duct ligation

World Journal of Gastroenterology ◽

10.3748/wjg.v22.i40.8918 ◽

2016 ◽

Vol 22 (40) ◽

pp. 8918 ◽

Cited By ~ 17

Author(s):

Josieli Raskopf Colares ◽

Elizângela Gonçalves Schemitt ◽

Renata Minuzzo Hartmann ◽

Francielli Licks ◽

Mariana do Couto Soares ◽

...

Keyword(s):

Bile Duct ◽

Experimental Model ◽

Bile Duct Ligation ◽

Biliary Cirrhosis ◽

Duct Ligation ◽

Anti Inflammatory ◽

Secondary Biliary Cirrhosis ◽

Inflammatory Action

Download Full-text

Partial Ligation of the Common Bile Duct Results in Reversible Cholestasis in Rats

International Surgery ◽

10.9738/intsurg-d-15-00164.1 ◽

2016 ◽

Vol 101 (5-6) ◽

pp. 249-256 ◽

Cited By ~ 1

Author(s):

Jun Jiang ◽

Dongzheng Li ◽

Jishu Wei ◽

Kuirong Jiang ◽

Yi Miao

Keyword(s):

Bile Duct ◽

Common Bile Duct ◽

Bile Salt ◽

Bile Duct Ligation ◽

Serum Biochemistry ◽

Sham Operation ◽

Sprague Dawley ◽

Common Bile Duct Ligation ◽

Ductular Reaction ◽

Duct Ligation

The animal model of common bile duct ligation is very toxic; therefore, the aim of this study was to establish a new model of obstructive jaundice in rats with partial common bile duct obstruction. Male Sprague-Dawley rats were subjected to a sham operation or partial ligation of bile duct procedure. Serum biochemistry, liver histology, and expression of bile salt transporters were examined after surgery. Serum levels of aspartate aminotransferase, alkaline phosphatase, total bilirubin, and bile acids were significantly increased in the partial bile duct ligation group 3 days after surgery. However, these changes spontaneously normalized within 14 days after surgery in the partial bile duct ligation group compared with the sham group. Bile infarcts, ductular reaction, and abundant hepatocyte turnover were detected exclusively in the partial bile duct ligation group on postoperative day 3. However, these changes dramatically reversed 14 days after surgery. Bile salt transporter expression was significantly decreased at day 3 and gradually recovered in the following 2 weeks. In conclusion, the current rat model of obstructive cholestasis is reversible, representing the clinical characteristics of partial biliary obstruction, and may be used to investigate the effects of various therapeutic strategies on reversible acute cholestasis.

Download Full-text