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Bradosty SW, Hamad SW, Agha NFS, Shaikh FK, Qadir Nanakali NM, Aziz PY, Salehen N, Suzergoz F, Abdulla MA. In vivo hepatoprotective effect of Morinda elliptica stem extract against liver fibrosis induced by thioacetamide. ENVIRONMENTAL TOXICOLOGY 2021; 36:2404-2413. [PMID: 34436826 DOI: 10.1002/tox.23353] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 08/05/2021] [Accepted: 08/12/2021] [Indexed: 06/13/2023]
Abstract
Morinda elliptica L. (Rubiaceae) is a phytomedicinal herb, used to treat gastrointestinal complications in Peninsular Malaysia. The study evaluates the in vivo hepatoprotective activity of ethanolic extract of M. elliptica stem in thioacetamide (TAA) induced liver fibrosis in male Sprague Drawly rats. Thirty adult rats were divided into five groups of six rats each. Rats of the normal control group received intraperitoneal injections (i. p.) of vehicle 10% Tween-20, 5 ml/kg, and hepatotoxic group 200 mg/kg TAA three times per week respectively. Three supplementary groups were treated with TAA plus daily oral silymarin (50 mg/kg) or M. elliptica (250 or 500 mg/kg). After 8 weeks of treatment, all rats were sacrificed. Liver fibrosis was assessed by gross macroscopic and microscopic tissue analysis, histopathological, and biochemical analysis. The livers of the TAA treated group showed uniform coarse granules, hepatocytic necrosis with lymphocytes infiltration. Contrary, the livers of M. elliptica treated groups (250 and 500 mg/kg) were much smoother and the cell damage was much lesser. The livers of M. elliptica treated groups rats showed elevated activity of SOD and CAT with a significant decrease in MDA level at p < .0001. The level of liver damage parameters, that is, ALP, ALT, and AST, bilirubin, total protein, and albumin were restored to the normal comparable to silymarin. M. elliptica stem extract significantly promoted normal rat liver architecture with significant perfections in biochemical parameters. The molecular contents of M. elliptica with hepatoprotective influence could be discovered, is the future prospective of this study.
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Affiliation(s)
- Sarwan W Bradosty
- Department of Community Health, College of Health Technology, Cihan University-Erbil, Kurdistan Region, Iraq
- Department of Biology, Faculty of Arts and Sciences, Harran University, Sanliurfa, Turkey
| | - Saber W Hamad
- Department of Field Crops Production, College of Agricultural Engineering Sciences, Salahaddin University-Erbil, Kurdistan Region, Iraq
| | - Nabaz Fisal Shakir Agha
- Department of Anesthesia, Erbil Medical Technical Institute, Erbil Polytechnic University, Iraq
| | - Faiyaz Khudaboddin Shaikh
- Department of Biochemistry, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad, Maharashtra, India
| | - Nadir Mustafa Qadir Nanakali
- Department of General Biology, College of Science, Cihan University-Erbil, Kurdistan Region, Iraq
- Department of Biology, College of Education, Salahaddin University-Erbil, Kurdistan Region, Iraq
| | - Peshawa Yunis Aziz
- Department of Medical Laboratory Science, Technical college of Applied Science, Sulaimani Polytechnic University, Sulaymaniyah, Iraq
| | - Nur'Ain Salehen
- Department of Biomedical Sciences, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Faruk Suzergoz
- Department of Biology, Faculty of Arts and Sciences, Harran University, Sanliurfa, Turkey
| | - Mahmood Ameen Abdulla
- Department of General Biology, College of Science, Cihan University-Erbil, Kurdistan Region, Iraq
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Nascimento M, Piran R, Da Costa RM, Giordani MA, Carneiro FS, Aguiar DH, Dias MC, Sugizaki MM, Luvizotto RA, Nascimento AF, Bomfim GF. Hepatic injury induced by thioacetamide causes aortic endothelial dysfunction by a cyclooxygenase-dependent mechanism. Life Sci 2018; 212:168-175. [PMID: 30292829 DOI: 10.1016/j.lfs.2018.09.051] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2018] [Revised: 09/22/2018] [Accepted: 09/30/2018] [Indexed: 02/07/2023]
Abstract
Liver cirrhosis is associated with a wide range of cardiovascular abnormalities including hyperdynamic circulation and cirrhotic cardiomyopathy. The pathogenic mechanisms of these cardiovascular changes are multifactorial and include vascular dysregulations. AIM The present study tested the hypothesis that the systemic vascular hyporesponsiveness in thioacetamide (TAA)-induced liver injury model is dependent on nitric oxide (NO) and cyclooxygenase (COX) derivatives. MAIN METHODS Wistar rats were treated with TAA for eight weeks to induce liver injury. KEY FINDINGS The maximal contractile response in concentration-effect curves to phenylephrine was decreased in aorta from TAA-treated rats, but no differences were found in aorta without endothelium, suggesting an endothelium-dependent mechanism in decreased contractile response. There was no difference in the contractile response with and without L-NAME (N(ω)-nitro-l-arginine methyl ester) in rats with liver injury, showing that the TAA treatment impairs NO synthesis. Pre-incubation of the aorta with indomethacin, a COX-inhibitor, normalized the reduced contractile response to phenylephrine in arteries from TAA group. Also, COX-2 and iNOS (inducible nitric oxide syntase) protein expression was increased in aorta from TAA group compared to control group. Animals submitted to TAA treatment had a reduction in systolic blood pressure. Our findings demonstrated that liver injury induced by TAA caused a decrease in aortic contractile response by a COX-dependent mechanism but not by NO release. Also, it was demonstrated an inflammatory process in the aorta of TAA-treated rats by increased expression of COX-2 and iNOS. SIGNIFICANCE Therefore, there is an essential contribution of COX-2 activation in extra-hepatic vascular dysfunction and inflammation present in cirrhosis induced by TAA.
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Affiliation(s)
- M Nascimento
- Institute of Health Science, Federal University of Mato Grosso, Sinop, MT, Brazil
| | - R Piran
- Institute of Health Science, Federal University of Mato Grosso, Sinop, MT, Brazil
| | - R M Da Costa
- Department of Physiology, Institute of Health Sciences, Federal University of Goias, Jatai, Brazil
| | - M A Giordani
- Institute of Health Science, Federal University of Mato Grosso, Sinop, MT, Brazil
| | - F S Carneiro
- Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil
| | - D H Aguiar
- Institute of Health Science, Federal University of Mato Grosso, Sinop, MT, Brazil
| | - M C Dias
- Institute of Health Science, Federal University of Mato Grosso, Sinop, MT, Brazil
| | - M M Sugizaki
- Institute of Health Science, Federal University of Mato Grosso, Sinop, MT, Brazil
| | - R A Luvizotto
- Institute of Health Science, Federal University of Mato Grosso, Sinop, MT, Brazil
| | - A F Nascimento
- Institute of Health Science, Federal University of Mato Grosso, Sinop, MT, Brazil
| | - G F Bomfim
- Institute of Health Science, Federal University of Mato Grosso, Sinop, MT, Brazil.
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Koppula S, Yum MJ, Kim JS, Shin GM, Chae YJ, Yoon T, Chun CS, Lee JD, Song M. Anti-fibrotic effects of Orostachys japonicus A. Berger (Crassulaceae) on hepatic stellate cells and thioacetamide-induced fibrosis in rats. Nutr Res Pract 2017; 11:470-478. [PMID: 29209457 PMCID: PMC5712497 DOI: 10.4162/nrp.2017.11.6.470] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2017] [Revised: 07/10/2017] [Accepted: 07/31/2017] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND/OBJECTIVE Orostachys japonicus A. Berger (Crassulaceae) has been used in traditional herbal medicines in Korea and other Asian countries to treat various diseases, including liver disorders. In the present study, the anti-fibrotic effects of O. japonicus extract (OJE) in cellular and experimental hepatofibrotic rat models were investigated. MATERIALS/METHODS An in vitro hepatic stellate cells (HSCs) system was used to estimate cell viability, cell cycle and apoptosis by MTT assay, flow cytometry, and Annexin V-FITC/PI staining techniques, respectively. In addition, thioacetamide (TAA)-induced liver fibrosis was established in Sprague Dawley rats. Briefly, animals were divided into five groups (n = 8): Control, TAA, OJE 10 (TAA with OJE 10 mg/kg), OJE 100 (TAA with OJE 100 mg/kg) and silymarin (TAA with Silymarin 50 mg/kg). Fibrosis was induced by treatment with TAA (200 mg/kg, i.p.) twice per week for 13 weeks, while OJE and silymarin were administered orally two times per week from week 7 to 13. The fibrotic related gene expression serum biomarkers glutathione and hydroxyproline were estimated by RT-PCR and spectrophotometry, respectively, using commercial kits. RESULTS OJE (0.5 and 0.1 mg/mL) and silymarin (0.05 mg/mL) treatment significantly (P < 0.01 and P < 0.001) induced apoptosis (16.95% and 27.48% for OJE and 25.87% for silymarin, respectively) in HSC-T6 cells when compared with the control group (9.09%). Further, rat primary HSCs showed changes in morphology in response to OJE 0.1 mg/mL treatment. In in vivo studies, OJE (10 and 100 mg/kg) treatment significantly ameliorated TAA-induced alterations in levels of serum biomarkers, fibrotic related gene expression, glutathione, and hydroxyproline (P < 0.05-P < 0.001) and rescued the histopathological changes. CONCLUSIONS OJE can be developed as a potential agent for the treatment of hepatofibrosis.
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Affiliation(s)
- Sushruta Koppula
- Department of Biotechnology, College of Biomedical and Health Sciences, Konkuk University, 268 Chungwon-daero, Chungju-si, Chungbuk 27478, Korea
| | - Mun-Jeong Yum
- Department of Applied Life Science, Graduate School of Konkuk University, 268 Chungwon-daero, Chungju-si, Chungbuk 27478, Korea
- R&D center, Korean Drug Co., Ltd., Seoul 06300, Korea
| | - Jin-Seoub Kim
- Department of Applied Life Science, Graduate School of Konkuk University, 268 Chungwon-daero, Chungju-si, Chungbuk 27478, Korea
| | - Gwang-Mo Shin
- Department of Applied Life Science, Graduate School of Konkuk University, 268 Chungwon-daero, Chungju-si, Chungbuk 27478, Korea
| | - Yun-Jin Chae
- Department of Biotechnology, College of Biomedical and Health Sciences, Konkuk University, 268 Chungwon-daero, Chungju-si, Chungbuk 27478, Korea
| | - Tony Yoon
- Food One Corp., 260 Sincheoksandan 5-ro, Deoksan-myeon, Jincheon-gun, Chungbuk 27850, Korea
| | - Chi-Su Chun
- Food One Corp., 260 Sincheoksandan 5-ro, Deoksan-myeon, Jincheon-gun, Chungbuk 27850, Korea
| | - Jae-Dong Lee
- Department of Internal Medicine, School of Medicine, Konkuk University, Chungju, Chungbuk 27376, Korea
| | - MinDong Song
- Department of Biotechnology, College of Biomedical and Health Sciences, Konkuk University, 268 Chungwon-daero, Chungju-si, Chungbuk 27478, Korea
- Department of Applied Life Science, Graduate School of Konkuk University, 268 Chungwon-daero, Chungju-si, Chungbuk 27478, Korea
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Amirtharaj GJ, Natarajan SK, Pulimood A, Balasubramanian KA, Venkatraman A, Ramachandran A. Role of Oxygen Free Radicals, Nitric Oxide and Mitochondria in Mediating Cardiac Alterations During Liver Cirrhosis Induced by Thioacetamide. Cardiovasc Toxicol 2017; 17:175-184. [PMID: 27131982 DOI: 10.1007/s12012-016-9371-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Thioacetamide (TAA) administration is widely used for induction of liver cirrhosis in rats, where reactive oxygen radicals (ROS) and nitric oxide (NO) participate in development of liver damage. Cardiac dysfunction is an important complication of liver cirrhosis, but the role of ROS or NO in cardiac abnormalities during liver cirrhosis is not well understood. This was investigated in animals after TAA-induced liver cirrhosis and temporal changes in oxidative stress, NO and mitochondrial function in the heart evaluated. TAA induced elevation in cardiac levels of nitrate before development of frank liver cirrhosis, without gross histological alterations. This was accompanied by an early induction of P38 MAP kinase, which is influenced by ROS and plays an important signaling role for induction of iNOS. Increased nitrotyrosine, protein oxidation and lipid peroxidation in the heart and cardiac mitochondria, suggestive of oxidative stress, also preceded frank liver cirrhosis. However, compromised cardiac mitochondrial function with a decrease in respiratory control ratio and increased mitochondrial swelling was seen later, when cirrhosis was evident. In conclusion, TAA induces elevations in ROS and NO in the heart in parallel to early liver damage. This leads to later development of functional deficits in cardiac mitochondria after development of liver cirrhosis.
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Affiliation(s)
- G Jayakumar Amirtharaj
- The Wellcome Trust Research Laboratory, Division of Gastrointestinal Sciences, Christian Medical College, Ida Scudder Road, Vellore, 632004, India
| | - Sathish Kumar Natarajan
- The Wellcome Trust Research Laboratory, Division of Gastrointestinal Sciences, Christian Medical College, Ida Scudder Road, Vellore, 632004, India
| | - Anna Pulimood
- The Wellcome Trust Research Laboratory, Division of Gastrointestinal Sciences, Christian Medical College, Ida Scudder Road, Vellore, 632004, India
| | - K A Balasubramanian
- The Wellcome Trust Research Laboratory, Division of Gastrointestinal Sciences, Christian Medical College, Ida Scudder Road, Vellore, 632004, India
| | - Aparna Venkatraman
- Center for Stem Cell Research, Christian Medical College, Ida Scudder Road, Vellore, 632004, India
| | - Anup Ramachandran
- The Wellcome Trust Research Laboratory, Division of Gastrointestinal Sciences, Christian Medical College, Ida Scudder Road, Vellore, 632004, India.
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Ismail A, Hassan E, Seleem MI, Hassan M, ElDeen FZ, Salah A, Selim AA. Migration of human umbilical cord blood cells into rat liver. Int J Stem Cells 2014; 3:154-60. [PMID: 24855553 DOI: 10.15283/ijsc.2010.3.2.154] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/03/2010] [Indexed: 11/09/2022] Open
Abstract
BACKGROUND AND OBJECTIVES Cell therapy provides an effective strategy for the treatment of an impaired liver. Human umbilical cord blood progenitor cells have the potential to differentiate into hepatocytes. Progenitor cells transplanted into the spleen could migrate directly into the liver through portal circulation. To track migration of human umbilical cord blood progenitor cells in cirrhotic rat liver after intrasplenic transplantation and to prove the possibility similar behavior of human umbilical cord blood nucleated cells in humans. METHODS AND RESULTS Umbilical cord blood samples from full-term deliveries will be collected after obtaining an informed consent from the mother. The collection procedure will be conducted after completion of delivery and will not interfere with the normal obstetric procedures. Adult male Sprague Dawley rats were subjected to liver cirrhosis by intraperitoneal injection of thioacetamide. Cirrhotic rats were treated with human umbilical cord blood nucleated cells by intra-splenic transplantation. Migration of intrasplenic transplanted human umbilical cord blood cells to the liver was successfully documented with Immunohistochemistry. The liver and spleen from recipient animals were removed. Histopathological and immunohistochemical analysis were performed 20 weeks after intrasplenic injection of the cells. Intrasplenically injected cells migrate to the liver of recipient animals. CONCLUSIONS Human cord blood nucleated cells have the potential to differentiate into hepatocytes and substantially improve the histology and function of the cirrhotic liver in rats. Relocation into liver after intrasplenic transplantation could be detected by immunohistochemistry. Transdifferentiated cells could be efficiently stained with antihuman hepatocytes.
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Affiliation(s)
- Alaa Ismail
- Surgery Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Ehsan Hassan
- Pathology Department, National Hepatology and Tropical Medicine Research Institute, Cairo, Egypt
| | - Mohamed I Seleem
- Surgery Department, National Hepatology and Tropical Medicine Research Institute, Cairo, Egypt
| | - Medhat Hassan
- Surgery Department, National Hepatology and Tropical Medicine Research Institute, Cairo, Egypt
| | - Firas Z ElDeen
- Surgery Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Ahmed Salah
- Surgery Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
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Kadir FA, Kassim NM, Abdulla MA, Yehye WA. Hepatoprotective Role of Ethanolic Extract of Vitex negundo in Thioacetamide-Induced Liver Fibrosis in Male Rats. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2013; 2013:739850. [PMID: 23762157 PMCID: PMC3671533 DOI: 10.1155/2013/739850] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/23/2012] [Revised: 04/09/2013] [Accepted: 04/29/2013] [Indexed: 12/21/2022]
Abstract
The hepatoprotective activity of ethanolic extract from the leaves of Vitex negundo (VN) was conducted against thioacetamide- (TAA-) induced hepatic injury in Sprague Dawley rats. The therapeutic effect of the extract was investigated on adult male rats. Rats were divided into seven groups: control, TAA, Silymarin (SY), and VN high dose and low dose groups. Rats were administered with VN extract at two different doses, 100 mg/kg and 300 mg/kg body weight. After 12 weeks, the rats administered with VN showed a significantly lower liver to body weight ratio. Their abnormal levels of biochemical parameters and liver malondialdehyde were restored closer to the normal levels and were comparable to the levels in animals treated with the standard drug, SY. Gross necropsy and histopathological examination further confirmed the results. Progression of liver fibrosis induced by TAA in rats was intervened by VN extract administration, and these effects were similar to those administered with SY. This is the first report on hepatoprotective effect of VN against TAA-induced liver fibrosis.
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Affiliation(s)
- Farkaad A. Kadir
- Department of Anatomy, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Federal Territory, Malaysia
| | - Normadiah M. Kassim
- Department of Anatomy, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Federal Territory, Malaysia
| | - Mahmood A. Abdulla
- Department of Biomedical Science, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Federal Territory, Malaysia
| | - Wageeh A. Yehye
- Nanotechnology & Catalysis Research Centre (NANOCAT), Block 3A, Institute of Postgraduate Studies Building, University of Malaya, 50603 Kuala Lumpur, Federal Territory, Malaysia
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Shirin H, Sharvit E, Aeed H, Gavish D, Bruck R. Atorvastatin and rosuvastatin do not prevent thioacetamide induced liver cirrhosis in rats. World J Gastroenterol 2013; 19:241-8. [PMID: 23345947 PMCID: PMC3547559 DOI: 10.3748/wjg.v19.i2.241] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2012] [Revised: 08/31/2012] [Accepted: 09/19/2012] [Indexed: 02/06/2023] Open
Abstract
AIM: To examine whether the administration of atorvastatin and rosuvastatin would prevent experimentally-induced hepatic cirrhosis in rats.
METHODS: Liver cirrhosis was induced by injections of thioacetamide (TAA). Rats were treated concurrently with TAA alone or TAA and either atorvastatin (1,10 and 20 mg/kg) or rosuvastatin (1, 2.5, 5, 10 and 20 mg/kg) given daily by nasogastric gavage.
RESULTS: Liver fibrosis and hepatic hydroxyproline content, in the TAA-treated group was significantly higher than those of the controls [11.5 ± 3.2 vs 2.6 ± 0.6 mg/g protein (P = 0.02)]. There were no differences in serum aminotransferase levels in the TAA controls compared to all the groups treated concomitantly by statins. Both statins used in our study did not prevent liver fibrosis or reduce portal hypertension, and had no effect on hepatic oxidative stress. Accordingly, the hepatic level of malondialdehyde was not lower in those groups treated by TAA + statins compared to TAA only. In vitro studies, using the BrdU method have shown that atorvastatin had no effect of hepatic stellate cells proliferation. Nevertheless, statin treatment was not associated with worsening of liver damage, portal hypertension or survival rate.
CONCLUSION: Atorvastatin or rosuvastatin did not inhibit TAA-induced liver cirrhosis or oxidative stress in rats. Whether statins may have therapeutic applications in hepatic fibrosis due to other etiologies deserve further investigation.
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Foo NP, Lin SH, Lee YH, Wu MJ, Wang YJ. α-Lipoic acid inhibits liver fibrosis through the attenuation of ROS-triggered signaling in hepatic stellate cells activated by PDGF and TGF-β. Toxicology 2011; 282:39-46. [PMID: 21251946 DOI: 10.1016/j.tox.2011.01.009] [Citation(s) in RCA: 91] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2010] [Revised: 01/03/2011] [Accepted: 01/10/2011] [Indexed: 12/13/2022]
Abstract
Reactive oxygen species (ROS) have been implicated in hepatic stellate cell activation and liver fibrosis. We previously reported that α-lipoic acid (LA) and its reduced form dihydrolipoic acid (DHLA) inhibited toxicant-induced inflammation and ROS generation. In the present study, we further examined the effects of LA/DHLA on thioacetamide (TAA)-induced liver fibrosis in rats and the possible underlying mechanisms in hepatic stellate cells in vitro. We found that co-administration of LA to rats chronically treated with TAA inhibited the development of liver cirrhosis, as indicated by reductions in cirrhosis incidence, hepatic fibrosis, and AST/ALT activities. We also found that DHLA inhibited TGF-β/PDGF-stimulated HSC-T6 activation and ROS generation. These effects could be mediated by the MAPK and PI3K/Akt pathways. According to our current results, LA may have a beneficial role in the treatment of chronic liver diseases caused by ongoing hepatic damage.
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Affiliation(s)
- Ning-Ping Foo
- Department of Environmental and Occupational Health, National Cheng Kung University Medical College, Tainan, Taiwan
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Evaluation of the 13C-octanoate breath test as a surrogate marker of liver damage in animal models. Dig Dis Sci 2010; 55:1589-98. [PMID: 19731033 DOI: 10.1007/s10620-009-0913-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2009] [Accepted: 07/09/2009] [Indexed: 12/13/2022]
Abstract
BACKGROUND Octanoate (also known as sodium octanoate), a medium-chain fatty acid metabolized in the liver, is a potential substrate for non-invasive breath testing of hepatic mitochondrial beta-oxidation. METHODS We evaluated the 13C-octanoate breath test (OBT) for assessing injury in acute hepatitis and two rat models of liver cirrhosis, first testing octanoate absorption (per os or intraperitoneally (i.p.)) in normal rats. We then induced acute hepatitis with thioacetamide (300 mg/kg/i.p., 24-h intervals). Liver injury end points were serum aminotransferase levels and 13C-OBT (24 and 48 h following initial injection). Thioacetamide (200 mg/kg/i.p., twice per week, 12 weeks) was used to induce liver cirrhosis. OBT and liver histological assessment were performed every 4 weeks. Bile duct ligation (BDL) was used to induce cholestatic liver injury. We completed breath tests with 13C-OBT and 13C-methacetin (MBID), liver biochemistry, and liver histology in BDL and sham-operated rats (baseline, 6, 14, 20 days post-BDL). RESULTS Octanoate absorbs well by either route. Peak amplitudes and cumulative percentage dose recovered at 30 and 60 min (CPDR30/60), but not peak time, correlated with acute hepatitis. Fibrosis stage 3 at week 8 significantly correlated with each OBT parameter. Cholestatic liver injury (serum bilirubin, ALP, gamma-GT, liver histology) was associated with significant suppression of the maximal peak values and CPDR30/60, respectively (P<0.05),using MBID but not 13C-octanoate. CONCLUSIONS OBT is sensitive for potentially evaluating liver function in rat models of acute hepatitis and thioacetamide-induced liver cirrhosis but not in cholestatic liver injury. The MBID test may be better for evaluation of cholestatic liver disease in this model.
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Natarajan SK, Amirtharaj GJ, Ramachandran A, Pulimood AB, Balasubramanian KA. Retinoid metabolism in the small intestine during development of liver cirrhosis. J Gastroenterol Hepatol 2009; 24:821-9. [PMID: 19226378 DOI: 10.1111/j.1440-1746.2008.05771.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND AND AIMS Retinoids are important mediators of cellular differentiation and proliferation in various epithelia of the body including the small intestine. Though alterations in intestinal epithelial cell proliferation have been noted in liver cirrhosis, mechanisms involved in the process are not well understood. This study examined the levels of various retinoids and retinoid-metabolizing enzymes in the small intestine during development of liver cirrhosis. METHODS Four groups of animals were used (control, phenobarbitone control, thioacetamide and carbon tetrachloride treatment). Twice-weekly intragastric or i.p. administration of carbon tetrachloride or thioacetamide, respectively, produced liver cirrhosis after 3 months, which was confirmed through histology and serum markers. Retinoid levels were measured by high-performance liquid chromatography. RESULTS A decrease in the levels of retinal, retinoic acid and retinol was evident in the intestine by 3 months, when cirrhosis was evident histologically, and these remained low until 6 months. A decrease in the activities of retinaldehyde oxidase, retinaldehyde reductase and retinol dehydrogenase was also seen in intestine from cirrhotic rats. CONCLUSION These results suggest that altered retinoid metabolism in the intestine of cirrhotic rats might have an influence on changes in intestinal epithelial cell differentiation, seen in liver cirrhosis.
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Affiliation(s)
- Sathish Kumar Natarajan
- The Wellcome Trust Research Laboratory, Department of Gastrointestinal Sciences, Christian Medical College, Vellore, India
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Aller M, Vara E, García C, Méndez M, Méndez-López M, Mejía I, López L, Arias J, Arias J. Prehepatic portal hypertension worsens the enterohepatic redox balance in thioacetamide-cirrhotic rats. PATHOPHYSIOLOGY 2008; 15:233-42. [DOI: 10.1016/j.pathophys.2008.09.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2008] [Accepted: 09/19/2008] [Indexed: 02/07/2023] Open
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Méndez M, Méndez-López M, López L, Aller MA, Arias J, Arias JL. Associative learning deficit in two experimental models of hepatic encephalopathy. Behav Brain Res 2008; 198:346-51. [PMID: 19056427 DOI: 10.1016/j.bbr.2008.11.015] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2008] [Revised: 11/04/2008] [Accepted: 11/09/2008] [Indexed: 01/26/2023]
Abstract
People with hepatic insufficiency can develop hepatic encephalopathy (HE), a complex neuropsychological syndrome covering a wide range of neurological and cognitive and motor alterations. The cognitive deficits include disturbances in intellectual functions such as memory and learning. In spite of its high prevalence in western societies, the causes of HE have not yet been clearly established. For this reason, experimental models of HE are used to study this condition. In this work, two experimental models were used, one Type B HE (portacaval shunt) and the other Type C HE (cirrhosis by intoxication with thioacetamide), to evaluate its effect on two tasks of associative learning: two-way active avoidance and step-through passive avoidance. The results show an impediment both in acquisition and retention of active avoidance in both models of HE. However, in passive avoidance, only the rats with portacaval shunt presented a memory deficit for the aversive event. In our opinion, these results can be explained by alterations in the neurotransmission system presented by animals with hepatic insufficiency, which are mainly caused by a rise in cerebral histamine and a dysfunction of the glutamatergic system.
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Affiliation(s)
- Marta Méndez
- Laboratorio de Neurociencias, Departamento de Psicología, Universidad de Oviedo, Plaza Feijoo s/n, 33003 Oviedo, Spain
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Shirin H, Aeed H, Shalev T, Sorin V, Stavinski S, Shahmurov M, Ilan Y, Avni Y. Utility of a 13C-methacetin breath test in evaluating hepatic injury in rats. J Gastroenterol Hepatol 2008; 23:1762-8. [PMID: 19120861 DOI: 10.1111/j.1440-1746.2008.05431.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
BACKGROUND AND AIM Methacetin is thought to be a good substrate for the evaluation of different cytochrome P450 enzymatic systems of liver microsomes because of its rapid metabolism and lack of toxicity in small doses. Recent studies indicate that a methacetin breath test may be a non-invasive alternative for the evaluation of liver function since it correlates well with the severity of liver damage. It may also discriminate between different stages of liver cirrhosis and correlates with the Child-Pugh score. The application of this test in experimental liver damage in animal models has not yet been examined. This study aimed to evaluate the efficacy of the (13)C-methacetin breath test in assessing the extent of hepatic injury in models of acute liver failure, liver cirrhosis, and fatty liver in rats. METHODS Absorption of methacetin given per os or intraperitoneally in normal rats was evaluated. The association between liver mass and (13)C-methacetin breath test results was assessed in a 70% hepatectomy rat model. Fulminant hepatic failure was induced by three consecutive intraperitoneal injections of thioacetamide, 300 mg/kg, at 24 h intervals. For induction of liver cirrhosis, rats were given intraperitoneal injections of thioacetamide, 200 mg/kg, twice a week for 12 weeks. A methionine-choline deficient diet was used for the induction of fatty liver. Rats were analyzed for (13)C-methacetin by BreathID (MBID) using molecular correlation spectrometry. BreathID continuously sampled the animal's breath for 60 min and displayed the results on the BreathID screen in real-time. RESULTS Methacetin was absorbed well irrespective of the administration method in normal rats. Liver mass was associated with peak amplitude, complete percent dose recovery (CPDR) at 30 and 60 min and MBID peak time. A high degree of association was also demonstrated with MBID results in acute hepatitis (peak amplitude, 19.6 +/- 3.4 vs 6.3 +/- 1.63.4; CPDR30, 6.0 +/- 3.3 vs 1.2 +/- 0.5; CPDR60, 13.3 +/- 4.5 vs 3.2 +/- 1.4; and peak time, 31.0 +/- 14.9 vs 46.9 +/- 10.8 min) and liver cirrhosis (peak amplitude, 24.4 +/- 2.3 vs 15.6 +/- 6.4; CPDR30, 7.9 +/- 1.2 vs 2.7 +/- 1.0; CPDR60, 17.8 +/- 2.6 vs 8.8 +/- 2.1; and peak time, 30.2 +/- 1.5 vs 59.6 +/- 14.5 min), but not with grade of liver steatosis. CONCLUSIONS Methacetin is well absorbed and exclusively metabolized in the liver. MBID is a sensitive test and may be a useful tool for the evaluation of functional liver mass in animal models of acute liver failure and cirrhosis. However, MBID could not distinguish between fatty liver and normal liver in rats.
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Affiliation(s)
- Haim Shirin
- Department of Gastroenterology, The E. Wolfson Medical Center and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
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14
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Mammillary body alterations and spatial memory impairment in Wistar rats with thioacetamide-induced cirrhosis. Brain Res 2008; 1233:185-95. [DOI: 10.1016/j.brainres.2008.07.040] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2008] [Revised: 07/03/2008] [Accepted: 07/07/2008] [Indexed: 11/23/2022]
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15
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NF-κB-activated tissue transglutaminase is involved in ethanol-induced hepatic injury and the possible role of propolis in preventing fibrogenesis. Toxicology 2008; 246:148-57. [DOI: 10.1016/j.tox.2008.01.009] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2007] [Revised: 01/04/2008] [Accepted: 01/07/2008] [Indexed: 12/29/2022]
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16
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Bruck R, Weiss S, Traister A, Zvibel I, Aeed H, Halpern Z, Oren R. Induced hypothyroidism accelerates the regression of liver fibrosis in rats. J Gastroenterol Hepatol 2007; 22:2189-94. [PMID: 18031379 DOI: 10.1111/j.1440-1746.2006.04777.x] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIM It has been shown in previous studies that hypothyroidism prevents the development of liver fibrosis in bile duct ligated rats and in rats chronically treated with thioacetamide (TAA). In recent years, regression of liver fibrosis (occurring spontaneously or during treatment) has been demonstrated in rodent models such as bile duct ligation and CCl(4) administration. Therefore, in the present study, the potential therapeutic effect of hypothyroidism on liver fibrosis was investigated. METHODS Liver fibrosis was induced in rats by administration of TAA (200 mg/kg, i.p., twice weekly) for 12 weeks. Hypothyroidism was then induced by either methimazole (0.04%) or propylthiouracil (0.05%) administered in drinking water for 8 weeks. Control euthyroid rats received normal drinking water. Hypothyroidism was confirmed by a significant elevation of serum thyroid-stimulating hormone levels. RESULTS Eight weeks after the cessation of TAA administration, spleen weight, histological score of liver fibrosis, and hepatic hydroxyproline content were significantly lower in both groups of hypothyroid rats as compared to euthyroid controls (P < 0.001). In vitro studies using the rat hepatic stellate cell line HSC-T6 using northern blot analysis and zymography, respectively, showed that high concentrations of triiodotyronine (T(3)) enhanced transforming growth factor (TGF)-beta-induced collagen I gene expression, and reduced metalloproteinase (MMP)-2 secretion, implying that reducing the levels of T(3) may contribute to resolution of fibrosis. Additionally, low T(3) concentration inhibited HSC-T6 proliferation. CONCLUSION Pharmacologically induced hypothyroidism accelerates the resolution of liver fibrosis in rats. This beneficial effect may in part be due to prevention of T(3)-induced stimulation of collagen synthesis and reduction of MMP-2 secretion.
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Affiliation(s)
- Rafael Bruck
- Department of Gastrointestinal and Liver Diseases, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel.
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17
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Reynaert H, van Rossen E, Uyama N, Chatterjee N, Kumar U, Urbain D, Geerts A. Expression of somatostatin receptors in splanchnic blood vessels of normal and cirrhotic rats. Liver Int 2007; 27:825-31. [PMID: 17617126 DOI: 10.1111/j.1478-3231.2007.01503.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
Abstract
BACKGROUND/AIMS Somatostatin has been used for over two decades to treat acute variceal bleeding. Although it is assumed that somatostatin lowers portal pressure by constriction of the splanchnic arteries, little is known about the expression of somatostatin receptors (SSTR) in splanchnic blood vessels. In this study we investigated SSTR expression in splanchnic blood vessels from normal and cirrhotic rats. METHODS/RESULTS Cirrhosis was induced by intraperitoneal injection of 50 mg thioacetamide twice a week for 14 weeks. In portal vein, mesenteric artery and aorta of normal and cirrhotic rats, mRNA for the five known SSTR was measured by quantitative reverse transcriptase-polymerase chain reaction. SSTR subtypes 1, 2, 3 and 4 were expressed, but subtype 5 was undetectable. In the portal vein of cirrhotic animals, SSTR1 was significantly down-regulated as compared with controls. Otherwise, no major differences in receptor expression between normal and cirrhotic animals were observed. Using immunohistochemistry, we identified all five receptors, although the staining of receptor 5 was very weak. CONCLUSION All five SSTR are expressed in splanchnic blood vessels. Our results suggest that cirrhosis reduces expression of SSTR1 in portal vein. In other vessels, no major differences between the normal and cirrhotic state were noted.
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Affiliation(s)
- Hendrik Reynaert
- Department of Cell Biology, Vrije Universiteit Brussel (VUB), Brussels, Belgium.
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18
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Bruck R, Ashkenazi M, Weiss S, Goldiner I, Shapiro H, Aeed H, Genina O, Helpern Z, Pines M. Prevention of liver cirrhosis in rats by curcumin. Liver Int 2007; 27:373-83. [PMID: 17355460 DOI: 10.1111/j.1478-3231.2007.01453.x] [Citation(s) in RCA: 92] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
BACKGROUND AND AIM Curcumin, the major polyphenolic compound in turmeric, has been shown to attenuate hepatic damage in several animal models of liver injury. The aim of the present study was to examine the efficacy of curcumin in preventing thioacetamide-induced cirrhosis and to unravel the mechanism of curcumin's effect on hepatic fibrosis in rats. METHODS Liver cirrhosis was induced by thioacetamide (TAA; 200 mg/kg, i.p.) twice weekly for 12 weeks. One group of rats concomitantly received curcumin (300 mg/kg/day, by gavage for 12 weeks); the control group received the solvent at identical amounts and duration. RESULTS TAA administration induced liver cirrhosis, which was inhibited by curcumin. Liver histopathology, hydroxyproline levels and spleen weights were significantly lower in the rats treated with TAA+curcumin compared with TAA only (P<0.001). Immunohistochemical studies and in situ hybridization demonstrated inhibition of hepatic stellate cell (alpha smooth muscle actin-positive) activation and collagen alpha1 (I) gene expression in the livers of the TAA+curcumin-treated rats. Curcumin reduced oxidative stress as shown by the decreased hepatic nitrotyrosine staining in the curcumin+TAA-treated rats. Curcumin treatment had no effect on pre existing liver cirrhosis. As determined by in vitro studies using the rat HSC-T6 cell line, curcumin had no direct inhibitory effect on collagen alpha1 (I) messenger RNA expression. Further studies in these cells using reverse transcriptase-polymerase chain reaction demonstrated that curcumin had no effect on the expression of PDGF-induced TIMP-1 and TIMP-2, TGFbeta1, TGFbeta2 and MCP-1 but significantly inhibited tumor necrosis factor alpha expression. Curcumin had no effect on hepatic stellate cells proliferation. Zymography showed that curcumin had no effect on matrix metalloproteinase-2 activity. CONCLUSIONS Curcumin inhibited the development of TAA-induced liver cirrhosis mainly due to its anti-inflammatory activities and not by a direct anti-fibrotic effect. As curcumin ingestion is safe in humans, it may be reasonable to assess in clinical studies the beneficial effect of curcumin in slowing the development of liver cirrhosis.
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Affiliation(s)
- Rafael Bruck
- The Department of Gastroenterology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel.
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19
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Goldani HAS, Matte US, Ramos ARL, Costa TG, Winkelmann LV, Meurer L, Vieira SMG, Kieling CO, Silveira TR. The role of food restriction on CCl4-induced cirrhosis model in rats. ACTA ACUST UNITED AC 2007; 58:331-7. [PMID: 17275271 DOI: 10.1016/j.etp.2006.11.007] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2006] [Accepted: 11/11/2006] [Indexed: 12/14/2022]
Abstract
Effects of food restriction on susceptibility to the toxic effect of some chemicals are controversial. In order to identify an exposure model that could maximize cirrhosis and minimize mortality rate, this study aimed to evaluate the effect of food restriction on tetrachloride carbon (CCl(4))-induced cirrhosis model in rats. Fifty-three male Wistar rats received CCl(4) 0.25 ml/kg weekly intragastrically once a week. Thirty-three had 44% food restriction (group 1); 10 rats had 25% food restriction (group 2); and 10 rats received ad libitum food (group 3). After 10 weeks, the animals were sacrificed and liver sections were collected for histology. Of the 53 animals enrolled for the study, 22 (41.5%) died before completing 10-week CCl(4). Mortality rate was significantly higher in group 1 compared to other groups (p<0.05). Cirrhosis was significantly more prevalent in group 1 than in group 3 (p<0.01), but without significant difference between groups 1 and 2 (p=0.624). We concluded that food restriction is an important issue to be considered when establishing a CCl(4)-induced cirrhosis model in rats. Moreover, there is an ideal range of food intake that predisposes to liver damage without increasing mortality leading to a more effective model.
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Affiliation(s)
- Helena A S Goldani
- Laboratório de Hepatologia Experimental, Centro de Pesquisas do Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos 2350, 90035-003 Porto Alegre-RS, Brazil.
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20
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Méndez-López M, Méndez M, Sánchez-Patán F, Casado I, Aller MA, López L, Corcuera MT, Alonso MJ, Nava MP, Arias J, Arias JL. Partial portal vein ligation plus thioacetamide: a method to obtain a new model of cirrhosis and chronic portal hypertension in the rat. J Gastrointest Surg 2007; 11:187-94. [PMID: 17390171 DOI: 10.1007/s11605-006-0063-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
To obtain a new model of chronic portal hypertension in the rat, two classical methods to produce portal hypertension, partial portal vein ligation and the oral administration of thioacetamide (TAA), have been combined. Male Wistar rats were divided into four groups: 1 (control; n = 10), 2 [triple partial portal vein ligation (TPVL); n = 9], 3 (TAA; n = 11), and 4 (TPVL plus TAA; n = 9). After 3 months, portal pressure, types of portosystemic collateral circulation, laboratory hepatic function tests (aspartate aminotransferase, alanine aminotransferase, bilirubin, alkaline phosphatase, and gamma-glutamyl transpeptidase) and liver histology were studied. The animals belonging to group 2 (TPVL) developed extrahepatic portosystemic collateral circulation, associated with mesenteric venous vasculopathy without hepatic destructurization or portal hypertension. Animals from group 3 (TAA) developed cirrhosis and portal hypertension but not extrahepatic portosystemic collateral circulation, or mesenteric venous vasculopathy. Finally, the animals from group 4 (TPVL + TAA) developed cirrhosis, portal hypertension, portosystemic collateral circulation, and mesenteric venous vasculopathy. The association of TPVL and TAA can be used to obtain a model of chronic portal hypertension in the rat that includes all the alterations that patients with hepatic cirrhosis usually have. This could, therefore, prove to be a useful tool to study the pathophysiological mechanisms involved in these alterations.
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Affiliation(s)
- Marta Méndez-López
- Psychobiology Department, Psychology School, University of Oviedo, Asturias, Spain
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21
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Abstract
Animal models have allowed detailed study of hemodynamic alterations typical of portal hypertension and the molecular mechanisms involved in abnormalities in splanchnic and systemic circulation associated with this syndrome. Models of prehepatic portal hypertension can be used to study alterations in the splanchnic circulation and the pathophysiology of the hyperdynamic circulation. Models of cirrhosis allow study of the alterations in intrahepatic microcirculation that lead to increased resistance to portal flow. This review summarizes the currently available literature on animal models of portal hypertension and analyzes their relative utility. The criteria for choosing a particular model, depending on the specific objectives of the study, are also discussed.
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Affiliation(s)
- Juan-G Abraldes
- Liver Unit, Hospital Clinic, Villarroel 170, University of Barcelona 08036, Spain.
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22
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Neef M, Ledermann M, Saegesser H, Schneider V, Reichen J. Low-dose oral rapamycin treatment reduces fibrogenesis, improves liver function, and prolongs survival in rats with established liver cirrhosis. J Hepatol 2006; 45:786-96. [PMID: 17050028 DOI: 10.1016/j.jhep.2006.07.030] [Citation(s) in RCA: 114] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2005] [Revised: 06/30/2006] [Accepted: 07/03/2006] [Indexed: 01/18/2023]
Abstract
BACKGROUND/AIMS Mammalian target of rapamycin (mTOR) signalling is central in the activation of hepatic stellate cells (HSCs), the key source of extracellular matrix (ECM) in fibrotic liver. We tested the therapeutic potential of the mTOR inhibitor rapamycin in advanced cirrhosis. METHODS Cirrhosis was induced by bile duct-ligation (BDL) or thioacetamide injections (TAA). Rats received oral rapamycin (0.5 mg/kg/day) for either 14 or 28 days. Untreated BDL and TAA-rats served as controls. Liver function was quantified by aminopyrine breath test. ECM and ECM-producing cells were quantified by morphometry. MMP-2 activity was measured by zymography. mRNA expression of procollagen-alpha1, transforming growth factor-beta1 (TGF-beta1) and beta2 was quantified by RT-PCR. RESULTS Fourteen days of rapamycin improved liver function. Accumulation of ECM was decreased together with numbers of activated HSCs and MMP-2 activity in both animal models. TGF-beta1 mRNA was downregulated in TAA, TGF-beta2 mRNA was downregulated in BDL. 28 days of rapamycin treatment entailed a survival advantage of long-term treated BDL-rats. CONCLUSIONS Low-dose rapamycin treatment is effectively antifibrotic and attenuates disease progression in advanced fibrosis. Our results warrant the clinical evaluation of rapamycin as an antifibrotic drug.
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MESH Headings
- Administration, Oral
- Aminopyrine
- Animals
- Blotting, Western
- Breath Tests/methods
- Collagen Type I/biosynthesis
- Collagen Type I/genetics
- Collagen Type I, alpha 1 Chain
- Disease Models, Animal
- Dose-Response Relationship, Drug
- Extracellular Matrix/metabolism
- Extracellular Matrix/pathology
- Gene Expression
- Immunosuppressive Agents/administration & dosage
- Immunosuppressive Agents/therapeutic use
- Liver Cirrhosis, Experimental/drug therapy
- Liver Cirrhosis, Experimental/mortality
- Liver Cirrhosis, Experimental/pathology
- Male
- Matrix Metalloproteinase 2/metabolism
- RNA, Messenger/biosynthesis
- RNA, Messenger/genetics
- Rats
- Rats, Wistar
- Reverse Transcriptase Polymerase Chain Reaction
- Sirolimus/administration & dosage
- Sirolimus/therapeutic use
- Survival Rate/trends
- Transforming Growth Factor beta1/biosynthesis
- Transforming Growth Factor beta1/genetics
- Transforming Growth Factor beta2/biosynthesis
- Transforming Growth Factor beta2/genetics
- Treatment Outcome
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Affiliation(s)
- Markus Neef
- Institute of Clinical Pharmacology, University of Berne, Berne, Switzerland.
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23
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Abstract
Animal models have allowed detailed study of hemodynamic alterations typical of portal hypertension and the molecular mechanisms involved in abnormalities in splanchnic and systemic circulation associated with this syndrome. Models of prehepatic portal hypertension can be used to study alterations in the splanchnic circulation and the pathophysiology of the hyperdynamic circulation. Models of cirrhosis allow study of the alterations in intrahepatic microcirculation that lead to increased resistance to portal flow. This review summarizes the currently available literature on animal models of portal hypertension and analyzes their relative utility. The criteria for choosing a particular model, depending on the specific objectives of the study, are also discussed.
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Affiliation(s)
- Juan-G Abraldes
- Liver Unit, Hospital Clinic, Villarroel 170, University of Barcelona 08036, Spain.
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24
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Natarajan SK, Thomas S, Ramamoorthy P, Basivireddy J, Pulimood AB, Ramachandran A, Balasubramanian KA. Oxidative stress in the development of liver cirrhosis: a comparison of two different experimental models. J Gastroenterol Hepatol 2006; 21:947-57. [PMID: 16724977 DOI: 10.1111/j.1440-1746.2006.04231.x] [Citation(s) in RCA: 89] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
BACKGROUND/AIMS Oxidative stress has been implicated in liver cirrhosis. Carbon tetrachloride and thioacetamide are the most widely used models to develop cirrhosis in rats and the present study compares oxidative stress in the liver induced by these compounds at different stages of cirrhosis development. METHODS Twice-weekly intragastric or intraperitoneal administration of carbon tetrachloride or thioacetamide, respectively, produced liver cirrhosis after 3 months. Histology, serum markers and hepatic hydroxy proline content confirmed the cirrhosis. RESULTS An increase in oxidative stress parameters was seen in mitochondria, peroxisomes and microsomes from the liver after carbon tetrachloride or thioacetamide treatment. Oxidative stress was more severe in carbon tetrachloride treated animals than thioacetamide. Mild oxidative stress was evident at 1 and 2 months of treatment and a significant increase was seen by 3 months of treatment with either compound. By this time, frank liver cirrhosis was also observed. CONCLUSIONS These results suggest that evidence of oxygen free radicals is also found early in the development of fibrosis and cirrhosis in both models.
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Affiliation(s)
- Sathish Kumar Natarajan
- Wellcome Trust Research Laboratory, Department of Gastrointestinal Sciences, Christian Medical College, Vellore, India.
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25
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Takiguchi F, Irisawa A, Saito A, Sakamoto H, Obara K, Kasukawa R, Ohira H. EFFECT OF ISOSORBIDE DINITRATE ON GASTRIC BLOOD FLOW IN RATS WITH LIVER CIRRHOSIS DETERMINED BY ANALYZING GASTRIC BLOOD FLOW, PORTAL VEIN PRESSURE AND BLOOD GAS. Fukushima J Med Sci 2006; 52:111-24. [PMID: 17427762 DOI: 10.5387/fms.52.111] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
We investigated the effects of isosorbide dinitrate (IDN) on gastric blood flow (GBF), portal venous pressure (PVP) and blood gas of rats with liver cirrhosis (LC) accompanied by portal hypertension. Thirty male Wistar rats (LC in 17 and normal in 13) were used. Before and after IDN administration, GBF, PVP and blood gas in the femoral artery and portal vein were measured. Portal blood oxygen concentration was estimated by calculating the ratio of PO2 in portal blood and that in arterial blood (PpvO2/PaO2) of each rat. The GBF in the LC rats was significantly lower than that in the normal rats. In the LC group, IDN administration significantly increased the GBF. The PpvO2/PaO2 value in the group with LC was significantly lower after IDN administration than that before IDN administration. In the investigation whether changes in PVP or Ppv/PaO2 contributed more to the change in GBF after IDN administration, a significant correlation was found between rates of change in GBF and PpvO2/PaO2 were significantly correlated (r= -0.733, p <0.05). The effect of IDN on changes in the stomach accompanying portal hypertension is mainly attributable to a decrease in preload, which suppresses inflow to the stomach, as reflected by a decrease in PpvO2/ PaO2, rather than to a decrease in afterload on GBF, as reflected by a decrease in PVP.
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Affiliation(s)
- Fujio Takiguchi
- Department of Internal Medicine II, Fukushima Medical University, School of Medicine, Fukushima, 960-1295, Japan
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26
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Abraldes JG, García-Pagán JC. Modelos animales en el estudio de la hipertensión portal. GASTROENTEROLOGIA Y HEPATOLOGIA 2006; 29:51-9. [PMID: 16393631 DOI: 10.1157/13083254] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
Animal models allow detailed study of the hemodynamic alterations in portal hypertension syndrome and of the molecular mechanisms involved in the abnormalities in splenic and systemic circulation associated with this syndrome. Models of prehepatic portal hypertension can be used to study alterations in the splenic circulation and the physiopathology of hyperdynamic circulation. Moreover, models of cirrhosis allow the alterations in intrahepatic microcirculation that lead to increased resistance to portal flow to be studied. The present review summarizes currently available animal models of portal hypertension and analyzes their relative utility in investigating the distinct disorders associated with this entity. The criteria for the choice of a particular model, depending on the specific objectives of the study, are also discussed.
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Affiliation(s)
- J G Abraldes
- Servicio de Hepatología, ICMDiM, Hospital Clínic, IDIBAPS, Universidad de Barcelona, Barcelona, Spain
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27
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Natarajan SK, Thomas S, Ramachandran A, Pulimood AB, Balasubramanian KA. Retinoid metabolism during development of liver cirrhosis. Arch Biochem Biophys 2005; 443:93-100. [PMID: 16248980 DOI: 10.1016/j.abb.2005.09.008] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2005] [Revised: 08/30/2005] [Accepted: 09/03/2005] [Indexed: 11/29/2022]
Abstract
The changes in retinoid metabolism have been documented in liver cirrhosis. However, the dynamic alterations in levels of this vitamin between circulation and liver during development of the liver cirrhosis are not well understood. The aim of this study was to measure retinoids in the liver and circulation in parallel, during and after development of cirrhosis induced by carbon tetrachloride and thioacetamide. Retinoid levels were measured by HPLC. A decrease in retinaldehyde and total retinol, together with an increase in retinoic acid was evident in liver from both carbon tetrachloride or thioacetamide treated rats within a month after initiation of treatment. Activity of enzymes involved in retinoid metabolism such as retinaldehyde oxidase, retinaldehyde dehydrogenase, and retinaldehyde reductase were decreased in the liver. In parallel, levels of retinol and retinaldehyde in the serum were increased while retinoic acid was decreased. This study indicates that during development of cirrhosis, there is reciprocal transfer of retinoid metabolites between the circulation and the liver.
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Affiliation(s)
- Sathish Kumar Natarajan
- The Wellcome Trust Research Laboratory, Department of Gastrointestinal Sciences, Christian Medical College, Ida Scudder Road, Vellore 632004, India
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28
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Ming Z, Fan YJ, Yang X, Lautt WW. Blockade of intrahepatic adenosine receptors improves urine excretion in cirrhotic rats induced by thioacetamide. J Hepatol 2005; 42:680-6. [PMID: 15826717 DOI: 10.1016/j.jhep.2004.12.023] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2004] [Revised: 11/22/2004] [Accepted: 12/24/2004] [Indexed: 12/29/2022]
Abstract
BACKGROUND/AIMS In healthy rats, we recently showed that reduced intrahepatic portal blood flow leads to activation of hepatic adenosine receptors and a nerve-induced decrease in urine production. We hypothesize that the impaired urine excretion in liver cirrhosis is related to an increase in intrahepatic adenosine. METHODS Anesthetized normal and thioacetamide-induced cirrhotic rats were instrumented for the measurement of urine flow, hepatic portal venous blood flow, and renal arterial blood flow. 8-Phenyltheophylline was used to block adenosine receptors. RESULTS Compared to normal rats, cirrhotic rats had a lower baseline urine flow (P<0.05). In both normal and cirrhotic rats, intraportal but not intravenous administration of 8-phenyltheophylline increased urine flow. Saline overload in normal rats increased urine flow (from 6.8+/-0.6 to 42.2+/-4.6 microlmin(-1)) and this ability was impaired in cirrhotic rats (from 3.9+/-0.4 to 6.2+/-0.9 microlmin(-1)). Intraportal, but not intravenous, administration of 8-phenyltheophylline partially restored the renal ability to excrete the saline load. CONCLUSIONS Impaired renal ability to excrete urine in liver cirrhosis is related to the activation of intrahepatic adenosine receptors, and this is consistent with our previous data showing renal regulation through a hepatorenal neural mechanism activated by intrahepatic adenosine.
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Affiliation(s)
- Zhi Ming
- Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Manitoba, A210-753 McDermot Avenue, Winnipeg, Man., Canada
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29
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Abstract
AIM: To investigate the effects of cyclosporine A (CsA) on thioacetamide (TAA)-induced liver injury.
METHODS: CsA was co-administrated (7.5 μg/kg body weight per day, i.p.) into rat to investigate the role of CsA on TAA-(200 mg/kg body weight per 3 d for 30 d, i.p.)induced liver injury.
RESULTS: The data show that TAA caused liver fibrosis in rat after 30 d of treatment. CsA alleviates the morphological changes of TAA-induced fibrosis in rat liver. The blood glutamyl oxaloacetic transaminase (GOT)/glutamyl pyruvic transaminase (GPT) in the TAA-injury group is elevated compared to that of the normal rat. Compared with the TAA-injury group, the blood GOT/GPT and TGFβ1 (by RT-PCR analysis) are reduced in the CsA plus TAA-treated rat. The level of the transforming growth factor receptor I (TGFβ-R1) in the CsA plus TAA-treated group shows higher than that in the TAA only group, but shows a lower level of the fibroblast growth factor receptor 4 (FGFR4) in the CsA plus TAA-treated group, when using the Western blot analysis. After immunostaining of the frozen section, TGFβ-R1 and FGFR4 are more concentrated in rat liver after CsA plus TAA injury.
CONCLUSION: This result suggests that CsA has an alleviated effect on TAA-induced liver injury by increasing the multidrug resistance P-glycoprotein and could be through the regulation of TGFβ-R1 and FGFR4.
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Affiliation(s)
- Sabrina Fan
- Institute of Biotechnology, National Dong Hwa University, Hualien 974, Taiwan, China
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30
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Reif S, Aeed H, Shilo Y, Reich R, Kloog Y, Kweon YO, Bruck R. Treatment of thioacetamide-induced liver cirrhosis by the Ras antagonist, farnesylthiosalicylic acid. J Hepatol 2004; 41:235-41. [PMID: 15288472 DOI: 10.1016/j.jhep.2004.04.010] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2003] [Revised: 03/29/2004] [Accepted: 04/02/2004] [Indexed: 01/06/2023]
Abstract
BACKGROUND/AIMS Several studies have indicated increased expression of the Ras protooncogenes in liver cirrhosis. In a previous study in rats, we have shown that a synthetic Ras antagonist, S-farnesylthiosalicylic acid (FTS), could inhibit the development of liver cirrhosis. The aim of the current study was to examine whether FTS will accelerate the resolution of liver cirrhosis induced in rats by thioacetamide. METHODS Cirrhosis was induced in male Wistar rats by intraperitoneal (i.p.) administration of thioacetamide (200 mg/kg twice weekly for 12 weeks). In the treated group, the Ras antagonist FTS (5 mg/kg, i.p./3 times/week) was administered for 8 weeks after liver cirrhosis has already been established. Control cirrhotic rats received PBS injections for 8 weeks. RESULTS Rats treated with FTS for 8 weeks had lower histopathologic score of fibrosis (P = 0.01), lower hepatic hydroxyproline levels (P = 0.0002) and lower spleen weight (P = 0.02) than the cirrhotic rats treated with PBS. Following FTS treatment, the MMP-2 and MMP-9-induced collagenolytic activity and TIMP-2 expression, were increased in FTS-compared to PBS-treated rats. TUNEL assay of liver sections performed 8 weeks after thioacetamide withdrawal showed increased apoptotic figures in both groups (P = NS). CONCLUSIONS These results indicate that the Ras antagonist FTS accelerates the regression of experimentally-induced hepatic cirrhosis. The mechanism may involve increased collagenolytic activity.
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Affiliation(s)
- Shimon Reif
- Department of Pediatric Gastroenterology, Tel-Aviv, Souraski Medical Center, Tel-Aviv, Israel
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31
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Bruck R, Schey R, Aeed H, Hochman A, Genina O, Pines M. A protective effect of pyrrolidine dithiocarbamate in a rat model of liver cirrhosis. Liver Int 2004; 24:169-76. [PMID: 15078482 DOI: 10.1111/j.1478-3231.2004.00900.x] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
Abstract
BACKGROUND Nuclear factor kappa B (NF-kappaB) activation, proinflammatory cytokines, and reactive oxygen species have been implicated as mediators of liver injury and fibrogenesis. We have shown recently that pyrrolidine dithiocarbamate (PDTC), an antioxidant and inhibitor of NF-kappaB activation, was protective in a rat model of acute liver failure. The aim of the present study was to examine the efficacy of PDTC in a chronic rat model of thioacetamide (TAA)-induced hepatic fibrosis. METHODS Liver cirrhosis was induced by intraperitoneal injections of TAA (200 mg/kg) twice weekly for 12 weeks. Two groups of rats also received PDTC (either 20 or 60 mg/kg, i.p. for 12 weeks). RESULTS TAA administration induced liver cirrhosis, which was inhibited by PDTC in a dose-dependent manner. The histopathologic score of fibrosis, the spleen weight, and hepatic hydroxyproline were significantly lower in the rats treated with TAA+PDTC compared with TAA only (P<0.001). The hepatic levels of thiobarbituric acid reactive substances and protein carbonyls after 12 weeks of treatment were also lower in the rats treated with TAA+PDTC (P=0.02 and 0.01, respectively), indicating reduced oxidative stress. Immunohistochemical studies and in situ hybridization demonstrated inhibition of stellate cell (alpha smooth muscle actin positive) activation, tissue inhibitor of metalloproteinase-2, and collagen alpha1(I) gene expression in the livers of the PDTC-treated rats. As determined by Northern blot analysis, PDTC had no inhibitory effect on collagen alpha1(I) gene expression in the rat hepatic stellate cells-T6 cells in vitro. CONCLUSIONS PDTC inhibits the development of liver cirrhosis in TAA-treated rats. The mechanism of action is associated with decreased oxidative stress and hepatic necroinflammation.
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Affiliation(s)
- Rafael Bruck
- Department of Gastroenterology, The E. Wolfson Medical Center, Holon, Israel.
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32
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Luo B, Liu L, Tang L, Zhang J, Ling Y, Fallon MB. ET-1 and TNF-alpha in HPS: analysis in prehepatic portal hypertension and biliary and nonbiliary cirrhosis in rats. Am J Physiol Gastrointest Liver Physiol 2004; 286:G294-303. [PMID: 14715521 DOI: 10.1152/ajpgi.00298.2003] [Citation(s) in RCA: 69] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Common bile duct ligation (CBDL) triggers a molecular cascade resulting in the hepatopulmonary syndrome (HPS). Both increased hepatic endothelin-1 (ET-1) production and pulmonary vascular ET(B) receptor expression with stimulation of endothelial nitric oxide synthase and TNF-alpha mediated inducible nitric oxide synthase and heme oxygenase-1 expression in pulmonary intravascular macrophages occur. Whether biliary cirrhosis is unique in triggering ET-1 and TNF-alpha alterations and HPS is unknown. We evaluated for HPS in rat prehepatic portal hypertension [partial portal vein ligation (PVL)], biliary (CBDL) and nonbiliary [thioacetamide treatment (TAA)] cirrhosis, and assessed ET-1 infusion in normal and PVL animals. Control, PVL, CBDL, TAA-treated, and ET-1-infused PVL animals had ET-1 and TNF-alpha levels measured and underwent molecular and physiological evaluation for HPS. HPS developed only in biliary cirrhosis in association with increased plasma ET-1 and TNF-alpha levels and the development of established molecular changes in the pulmonary microvasculature. In contrast, PVL did not increase ET-1 or TNF-alpha levels and TAA treatment increased TNF-alpha levels alone, and neither resulted in the full development of molecular or physiological changes of HPS despite portal pressure increases similar to those after CBDL. Exogenous ET-1 increased TNF-alpha levels and triggered HPS after PVL. Combination of ET-1 and TNF-alpha overproduction is unique to biliary cirrhosis and associated with experimental HPS. ET-1 infusion increases TNF-alpha levels and triggers HPS in prehepatic portal hypertension. ET-1 and TNF-alpha interact to trigger pulmonary microvascular changes in experimental HPS.
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Affiliation(s)
- Bao Luo
- Department of Internal Medicine, University of Alabama at Birmingham, Birmingham, AL 35294-0005, USA
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33
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Yang W, Koti R, Glantzounis G, Davidson BR, Seifalian AM. Arterialization of the portal vein improves hepatic microcirculation and tissue oxygenation in experimental cirrhosis. Br J Surg 2003; 90:1232-9. [PMID: 14515292 DOI: 10.1002/bjs.4209] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
Abstract
Background
Arterialization of the portal vein (APV) has shown beneficial effects on liver regeneration and function in selected patients undergoing liver resection and transplantation. Whether APV improves liver perfusion and function in cirrhosis is unclear. This study investigated the effect of APV on hepatic haemodynamics and liver function in a rat model of cirrhosis.
Methods
Male Sprague–Dawley rats (250–300 g) were divided into three groups: normal controls (n = 7), cirrhosis with sham laparotomy (sham; n = 7) and cirrhosis with APV (APV; n = 9). Portal venous blood flow, portal vein pressure and hepatic parenchymal microcirculation (HPM) were measured before and after APV. Hepatic parenchymal oxygenation was assessed by near-infrared spectroscopy and hepatocellular injury by standard liver function tests. Measurements were taken at baseline, after APV and 7 days after surgery.
Results
APV increased portal blood flow and pressure in cirrhotic rats without altering intrahepatic portal resistance. APV increased the HPM in cirrhotic rats by a mean(s.e.m.) of 28·5(0·1) per cent on day 0 and 54·6(0·1) per cent by day 7 (P = 0·001). Liver tissue oxygenation was increased by APV and the plasma γ-glutamyltranspeptidase level was reduced (mean(s.e.m.) 6·0(0·5) versus 3·8(0·3) units/l before and after APV respectively; P = 0·006) at day 7.
Conclusion
APV increases portal blood flow, tissue perfusion and oxygenation in cirrhosis.
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Affiliation(s)
- W Yang
- Hepatic Haemodynamic Laboratory, University Department of Surgery and Liver Transplantation Unit, Royal Free and University College Medical School, University College London, UK
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34
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Kato N, Ihara S, Tsujimoto T, Miyazawa T. Effect of resovist on rats with different severities of liver cirrhosis. Invest Radiol 2002; 37:292-8. [PMID: 11979155 DOI: 10.1097/00004424-200205000-00007] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
RATIONALE AND OBJECTIVES Whether the degree of diffuse hepatic damage is correlated with the signal change on MR images after injection of superparamagnetic iron oxide (SPIO) particles was investigated. In addition, we investigated whether hepatic function deteriorates after injection of SPIO. METHODS Seventy-six female Sprague-Dawley rats aged 3 to 4 weeks were given drinking water containing 0.03% thioacetamide (TAA) for 4 or 12 weeks to induce two grades of liver injury. Seventeen normal rats were served as a control. Normal and model rats were administered Resovist (10 micromol Fe/kg), and signal intensities in the liver on MR images obtained at 4.7 T were measured up to 60 minutes after injection (n = 5). The model rats were injected with 10 times the envisaged dose of Resovist (100 micromol Fe/kg) or saline as a control substance, and blood parameters were measured at 4, 24, and 48 hours after injection (n = 5 or 6). At 4 hours after injection, iron and Kupffer cells in the liver were stained (n = 3). RESULTS Maximal signal reduction in the liver occurred 15 minutes after injection in all groups. The reduced signal persisted for 60 minutes after injection. However, the degree of maximal signal reduction in the model rats was significantly less than that in the normal rats (P < 0.05, 0.01). Signal reduction in the 12-week group was less than that in the 4-week group. In control rats, the number of iron-positive cells increased by 22 cells per area (0.065 mm(2)) following treatment with Resovist. In the 4-week and 12-week groups, numbers of iron-positive cells increased by 13 and 11 cells, respectively. There was no statistically significant difference in the number of Kupffer cells between control and model rats. No significant change was observed in blood parameters with Resovist. CONCLUSION The MR signal induced by Resovist depended on the degree of phagocytic activity in the liver. The safety profiles of Resovist remained unchanged even at 10 times the imaging dose.
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Affiliation(s)
- Naoki Kato
- Drug Discovery Institute, Nihon Schering K.K., Yodogawa-ku, Osaka, Japan.
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35
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Bruck R, Shirin H, Aeed H, Matas Z, Hochman A, Pines M, Avni Y. Prevention of hepatic cirrhosis in rats by hydroxyl radical scavengers. J Hepatol 2001; 35:457-64. [PMID: 11682029 DOI: 10.1016/s0168-8278(01)00163-5] [Citation(s) in RCA: 60] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
BACKGROUND/AIMS Reactive oxygen species and oxidative stress were implicated in hepatic stellate cell activation and liver fibrosis. The aim of the present study was to examine whether the administration of free radical scavengers in vivo would prevent experimentally-induced hepatic cirrhosis in rats. METHODS Cirrhosis was induced by administration of thioacetamide (TAA; 200 mg/kg, i.p.) twice/week, for 12 weeks. Rats were treated concurrently with either dimethylsulfoxide (DMSO; 4 g/kg, s.c. or p.o.) or dimethylthiourea (DMTU; 200 mg/kg i.p.) three times a week. RESULTS Liver fibrosis (histopathological score, spleen weight, and hepatic hydroxyproline) was abolished in rats treated with TAA and either DMSO or DMTU (P < 0.001). Accordingly, the hepatic expression of alpha smooth muscle actin, tissue inhibitor of metalloproteinase 2 and collagen alpha1 (I) gene were inhibited. The hepatic level of methane-sulfinic acid (produced by the interaction of DMSO with hydroxyl radicals) was increased in rats treated with TAA + DMSO (P = 0.0005) and decreased after pretreatment of these rats with DMTU (P = 0.008). However, the hepatic levels of malondialdehyde, lipid peroxides and protein carbonyls were not lower in the DMSO- and DMTU-treated groups. CONCLUSIONS The administration of free radical scavengers prevented the development of TAA-induced liver cirrhosis probably associated with decreased oxidative stress.
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Affiliation(s)
- R Bruck
- Department of Gastroenterology, The E. Wolfson Medical Center, Holon, Israel.
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36
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Nakatani Y, Fukui H, Kitano H, Nagamoto I, Tsujimoto T, Kuriyama S, Kikuchi E, Hoppou K, Tsujii T. Endotoxin clearance and its relation to hepatic and renal disturbances in rats with liver cirrhosis. LIVER 2001; 21:64-70. [PMID: 11169075 DOI: 10.1034/j.1600-0676.2001.210110.x] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
BACKGROUND/AIMS Little is known about endotoxin clearance and secretion of cytokines from macrophages in liver cirrhosis. The aims of this study were to investigate the relationship of endotoxin clearance and release of tumor necrosis factor alpha by various macrophages to hepatic and renal disturbances in liver cirrhosis. METHODS Male Sprague-Dawley rats were given 0.04% thioacetamide orally for 6 or 12 months. The organ distribution of infused [3H]-endotoxin (10 microg/kg b.w.) was analyzed at 30 min or at 24 h. Uptake of [3H]-endotoxin and secretion of tumor necrosis factor alpha by Kupffer cells, splenic macrophages and peripheral blood monocytes (1 x 10(4) cells/ml) from cirrhotic and control rats were determined. RESULTS In cirrhotic rats, more endotoxin was left in the body and more endotoxin accumulated in the spleen and kidney, and thus was related to elevation of serum total bilirubin, aspartate aminotransferase, alanine aminotransferase, blood urea nitrogen, creatinine and tumor necrosis factor alpha. Endotoxin uptake and tumor necrosis factor alpha release by the Kupffer cells were decreased and those by the splenic macrophages and peripheral blood monocytes were increased in cirrhotic rats. CONCLUSIONS In liver cirrhosis, impaired clearance of endotoxin together with increased secretion of tumor necrosis factor alpha by extrahepatic macrophages may play an important role in the progression of hepatic and renal disturbances.
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Affiliation(s)
- Y Nakatani
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Japan.
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37
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Reif S, Weis B, Aeed H, Gana-Weis M, Zaidel L, Avni Y, Romanelli RG, Pinzani M, Kloog Y, Bruck R. The Ras antagonist, farnesylthiosalicylic acid (FTS), inhibits experimentally-induced liver cirrhosis in rats. J Hepatol 1999; 31:1053-61. [PMID: 10604579 DOI: 10.1016/s0168-8278(99)80318-3] [Citation(s) in RCA: 40] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/04/2022]
Abstract
BACKGROUND/AIMS Protooncogenes may play an important role, not only in carcinogenesis, but also in the regulation of normal cellular proliferation and differentiation. Several studies have indicated increased expression of the Ras protooncogenes in the liver in animal models and in patients with liver cirrhosis. The aim of the present study was to examine whether a synthetic Ras antagonist, S-farnesylthiosalicylic acid (FTS), which specifically dislodges Ras from the membrane of Ras-transformed fibroblasts (EJ cells), can prevent experimentally-induced liver cirrhosis in rats. METHODS Cirrhosis was induced in male Wistar rats by intraperitoneal administration of thioacetamide (200 mg/kg twice weekly for 12 weeks). The Ras antagonist, farnesylthiosalicylic acid (FTS, 5 mg/kg), was administered during the study period 3 times a week. Ras expression in the liver was determined by Western blot analysis with pan anti-Ras antibodies and by immunohistochemistry. RESULTS Rats treated with thioacetamide and the Ras antagonist, farnesylthiosalicylic acid (FTS), for 12 weeks had lower histopathologic scores of fibrosis and inflammation (p-values of 0.003 and 0.008, respectively) than those treated with thioacetamide only. There were no differences between the histopathologic scores in vehicle (control) and in Ras-antagonist (FTS) only treatments. Analysis of hepatic hydroxyproline levels from the two thioacetamide-treated groups and controls confirmed the histopathologic scores (7.7+/-0.9 mg/g protein in the TAA-treated vs. 3.8+/-0.5 mg/g protein in the TAA+FTS treated group, p = 0.007). Ras levels, determined by Western blot analysis, were markedly increased in the livers treated with TAA (17-fold over control) and significantly decreased (by about 70%) in the livers of rats treated with TAA and FTS. Studies in isolated human hepatic stellate cells demonstrated that FTS inhibited both DNA synthesis and migration of those cells (p<0.05). CONCLUSION These results indicate that inhibition of Ras expression in the liver during fibrogenesis, prevents the development of experimentally-induced hepatic cirrhosis.
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Affiliation(s)
- S Reif
- Department of Pediatric Gastroenterology, Tel-Aviv, Sourasky Medical Center, Israel
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38
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Kato N, Takahashi M, Tsuji T, Ihara S, Brautigam M, Miyazawa T. Dose-dependency and rate of decay of efficacy of Resovist on MR images in a rat cirrhotic liver model. Invest Radiol 1999; 34:551-7. [PMID: 10485069 DOI: 10.1097/00004424-199909000-00001] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
RATIONALE AND OBJECTIVES To investigate the dose-dependency and half-life of decay of the signal reduction by super-paramagnetic iron oxides on three different spin-echo images in a rat model of cirrhosis. METHODS For normal and cirrhotic liver, signal intensities were measured 15 minutes after injection of Resovist (range, 1-40 mumol Fe/kg) on three different spin-echo images. Subsequently, recovery of signal intensity was monitored up to 2 weeks after injection. RESULTS The dose-dependency of efficacy was somewhat less at all doses and imaging parameters in cirrhotic liver. However, the submaximal effect was obtained at a dose of 20 mumol Fe/kg, the same as in normal liver. The rate of decay of the efficacy in cirrhotic liver was similar to or faster than that in normal liver. CONCLUSIONS The dose-dependency and rate of decay of efficacy of Resovist in cirrhosis were similar to those in normal liver, although the efficacy was less in cirrhotic liver and both the dose-dependency and rate of decay of efficacy were dependent on imaging parameters.
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Affiliation(s)
- N Kato
- Basic Research Institute, Nihon Schering K.K., Osaka, Japan
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39
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Masumi S, Moriyama M, Kannan Y, Ohta M, Koshitani O, Sawamoto O, Toyoshima S, Ishikawa K, Miyoshi M, Sugano T. Characteristics of nitrogen metabolism in rats with thioacetamide-induced liver cirrhosis. Toxicology 1999; 132:155-66. [PMID: 10433379 DOI: 10.1016/s0300-483x(98)00148-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Female Sprague-Dawley rats were given 0.03% thioacetamide (TAA) in their drinking water daily for 4 or 12 weeks, and were then given normal water for 4 weeks after the end of a 12-week TAA treatment to investigate amino acid metabolism. In the malnourished precirrhotic stage (stage 1) and the malnourished cirrhotic stage (stage 2), the aromatic amino acids (AAA), Glu, Asp, Orn, Arg and Cit increased, and the branched-chain amino acids (BCAA) decreased slightly. Because these changes normalized in the well-nourished cirrhotic stage (stage 3), they might have resulted from impairment of hepatocytes and malnutrition. The net uptake of BCAA into the liver increased in stage 2, but the AAA uptake did not exceed that in normal controls. Portal venous plasma AAA increased to the same level as arterial plasma AAA. These results suggest that the decrease in BCAA was partially due to liver uptake and that the increase in AAA was induced by reduction of liver uptake and overproduction in extrahepatic tissues. The liver contents of BCAA and AAA were unchanged in all stages, so were fully utilized in the impaired liver. The increases in Glu, Asp, Orn and Cit might have resulted from overproduction in the liver, because these contents of the liver increased in stage 2. In conclusion, the changes in amino acid metabolism in rats with cirrhosis induced by TAA closely resemble those seen in human liver cirrhosis.
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Affiliation(s)
- S Masumi
- Department of Veterinary Physiology, College of Agriculture, Osaka Prefecture University, Sakai, Japan
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40
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Hori N, Okanoue T, Sawa Y, Kashima K. Role of calcitonin gene-related peptide in the vascular system on the development of the hyperdynamic circulation in conscious cirrhotic rats. J Hepatol 1997; 26:1111-9. [PMID: 9186842 DOI: 10.1016/s0168-8278(97)80120-1] [Citation(s) in RCA: 21] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND/AIMS Calcitonin gene-related peptide (CGRP), a potent vasodilator; plays an important role in modulating vascular tone, acting as a noncholinergic nonadrenergic neurotransmitter. The aim of this study was to assess the role of CGRP, present in the vascular system, in the development of the hyperdynamic circulation observed in liver cirrhosis. METHODS Two doses of human alpha-CGRP [8-37], a specific antagonist of CGRP, were administered to cirrhotic and controls rats. Hemodynamics were evaluated using radioactive microspheres in conscious animals. To investigate the arterial depressor effect of exogenous CGRP, we constructed a dose-response curve for mean arterial pressure in cirrhotic and control rats by administering human alpha-CGRP. RESULTS The administration of high-dose human alpha-CGRP [8-37] (300 nmol.kg body weight-1.min-1) significantly increased both the mean arterial pressure (21 +/- 2 vs. 13 +/- 1%, p < 0.01) and total vascular resistance (76 +/- 5 vs. 54 +/- 5%, p < 0.01) in cirrhotic rats, compared to control rats. The splanchnic hemodynamic effects induced by human alpha-CGRP [8-37] were a significant decrease in percent change of portal venous inflow -42 +/- 3 vs. -33 +/- 3%, p < 0.05) and a significant increase in percent change of splanchnic arterial resistance (110 +/- 9 vs. 76 +/- 5%, p < 0.01) in cirrhotic rats, compared to control rats. Low-dose human alpha-CGRP [8-37] (60 nmol.kg body weight-1. min-1) caused similar hemodynamic changes, but the degree of change was much less than for the high-dose administration. The vascular response to human alpha-CGRP was significantly reduced in cirrhotic rats as compared to controls (ANOVA, p < 0.01). Plasma concentrations of CGRP were significantly elevated in cirrhotic rats. CONCLUSIONS CGRP in the vascular system was involved in the modulation of vasodilatation in rats with liver cirrhosis, as demonstrated by the administration of a selective CGRP antagonist and exogenous CGRP.
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Affiliation(s)
- N Hori
- Third Department of Internal Medicine, Kyoto Prefectural University of Medicine, Japan
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41
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Hori N, Okanoue T, Sawa Y, Mori T, Kashima K. Haemodynamic effects of combined treatment with molsidomine and propranolol on portal hypertension in conscious and unrestrained cirrhotic rats. J Gastroenterol Hepatol 1996; 11:985-92. [PMID: 8912139 DOI: 10.1111/j.1440-1746.1996.tb01858.x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
We investigated the systemic and splanchnic haemodynamic effects of combined treatment with molsidomine and propranolol on cirrhotic rats. Liver cirrhosis was produced by repeated intraperitoneal injections of thioacetamide. The blood flow of each organ was measured serially using the radioactive microsphere method in the awake state before and after the administration of each agent. Cirrhotic rats received molsidomine (0-.5 mg/kg), propranolol (0.1 or 0.2 mg/min), both agents or placebo. Combination treatment with molsidomine and 0.1 mg/min propranolol significantly reduced portal pressure compared with molsidomine or propranolol alone (21 +/- 4 vs 15 +/- 3 or 11 +/- 2% P < 0.05). Systemic haemodynamic changes with this combined treatment were mild. This combined treatment slightly inhibited the molsidomine-induced decrease in portal vascular resistance (27 +/- 9 vs 31 +/- 6; NS) and markedly inhibited the molsidomine-induced decrease in splanchnic arterial resistance (7 +/- 6 vs 27 +/- 5% P < 0.05). Compared with low-dose propranolol administration, the combined treatment was associated with a significant decrease in portal vascular resistance (27 +/- 9% decrease vs 2 +/- 2% increase; P < 0.001) and a significant decrease in splanchnic arterial resistance (7 +/- 6% decrease vs 5 +/- 4% increase P < 0.05). The combination of molsidomine and high-dose propranolol (0.2 mg/min) caused a marked reduction in portal venous inflow, mean arterial pressure and cardiac index. We conclude that propranolol enhances the molsidomine-induced decrease in portal pressure by splanchnic vasoconstriction in association with a slight decrease in portal vascular resistance. The combination therapy with molsidomine and low-dose propranolol combination had more beneficial and less harmful effects on systemic and splanchnic haemodynamics and thus appears to be a superior method for treating portal hypertension.
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Affiliation(s)
- N Hori
- Third Department of Internal Medicine, Kyoto Prefectural University of Medicine, Japan
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Bruck R, Hershkoviz R, Lider O, Aeed H, Zaidel L, Matas Z, Barg J, Halpern Z. Inhibition of experimentally-induced liver cirrhosis in rats by a nonpeptidic mimetic of the extracellular matrix-associated Arg-Gly-Asp epitope. J Hepatol 1996; 24:731-8. [PMID: 8835749 DOI: 10.1016/s0168-8278(96)80270-4] [Citation(s) in RCA: 23] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
AIMS/METHODS In the present study, we examined whether a nonpeptidic mimetic of Arg-Gly-Asp (RGD), which specifically inhibits RGD-dependent adhesion of CD4+ T lymphocytes or fibroblasts to fibronectin, can prevent thioacetamide-induced liver cirrhosis in rats. The nonpeptidic RGD mimetic, rather than the RGD peptide was utilized, since the peptide is rapidly degraded, and therefore, relatively ineffective for in vivo use. RESULTS We now report that rats treated with thioacetamide and the RGD analogue SF-6,5 for 12 weeks had lower histopathologic scores than those treated with thioacetamide alone. Further improvement in liver histology was observed after another 8 weeks of treatment with the analogue SF-6,5. Quantitative microscopic analysis by computerized imaging morphometry of liver biopsies from the three groups and controls confirmed the semi-quantitative histopathologic scores (p < 0.001). After 3 months of treatment, the spleen weights in the SF-6,5-treated rats were 30% less than those of rats that received only thioacetamide, which indicated that the analogue-treated rats were less portal hypertensive. CONCLUSIONS The observed inhibition of the progression of cirrhosis in rats by the nonpeptidic RGD analogue suggests that RGD mimetics may be useful therapeutically in inhibiting pathological processes that involve RGD recognition.
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Affiliation(s)
- R Bruck
- Department of Gastroenterology, E. Wolfson Medical Center, Holon, Israel
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Hori N, Takahashi H, Okanoue T, Sawa Y, Mori T, Takami S, Yoshimura M, Kashima K. Augmented endogenous nitric oxide production in partial portal vein-ligated rats. Clin Exp Pharmacol Physiol 1995; 22:506-11. [PMID: 7586705 DOI: 10.1111/j.1440-1681.1995.tb02058.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
1. Endothelium-derived nitric oxide (NO) is a potent vasodilator. Because the body oxidizes it to nitrate ions, NO3-, measurement of the serum concentration and the urinary excretion of NO3- may be an index for endogenous NO. We investigated the role of NO on hyperdynamic circulation in cirrhotic and partial portal vein-ligated rats by measuring NO3. 2. Liver cirrhosis was induced by administration of thioacetamide. Systemic and splanchnic haemodynamics and splenic-systemic shunting were determined by tracer microspheres. The concentration of NO3- was measured by using high-performance liquid chromatography with an anioncolumn. 3. We found that systemic and splanchnic hyperdynamic circulation existed to almost the same extent in cirrhotic and in portal vein-ligated rats as compared to the controls and shamoperated rats, respectively. Splenic-systemic shunting was markedly greater in portal vein-ligated rats than in cirrhotic rats. 4. Serum NO3- levels and urinary excretion of NO3- in cirrhotic rats tended to increase as compared to the controls. On the other hand, the levels in portal vein-ligated rats were significantly increased as compared to those of the shamoperated rats, and were significantly and negatively correlated to the splanchnic arterial resistance and total vascular resistance. The amount of urinary excretion of NO3- significantly correlated to splenic-systemic shunting (r = 0.61, P < 0.05) only in portal vein-ligated rats. 5. We suggest that these high levels of NO3- in portal vein-ligated rats relate to the extensive formation of porto-collateral vasculature or acute changes in systemic and splanchnic haemodynamics due to portal vein-ligation.(ABSTRACT TRUNCATED AT 250 WORDS)
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Affiliation(s)
- N Hori
- Third Department of Internal Medicine, Kyoto Prefectural University of Medicine, Japan
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Hori N, Takahashi H, Okanoue T, Sawa Y, Mori T, Takami S, Yoshimura M, Kashima K. Augmented endogenous nitric oxide production in partial portal vein-ligated rats. J Hepatol 1995; 22:250-1. [PMID: 7790716 DOI: 10.1016/0168-8278(95)80439-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
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Hori N, Okanoue T, Sawa Y, Itoh Y, Mori T, Takami S, Kashima K. Hemodynamic effects of combined treatment with somatostatin analogue (SMS 201-995) and low-dose isosorbide dinitrate on portal hypertension in conscious cirrhotic rats. J Gastroenterol 1994; 29:460-8. [PMID: 7951857 DOI: 10.1007/bf02361244] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
The authors investigated whether combined treatment with the somatostatin analogue, SMS 201-995, and low-dose isosorbide dinitrate enhanced the hemodynamic effects of the individual agents on rats with thioacetamide-induced cirrhosis. Four groups of cirrhotic rats received SMS 201-995 (0.1 microgram.min-1.kg-1), isosorbide dinitrate (10 micrograms.min-1.kg-1), both agents, or placebo, respectively. Hemodynamics were measured serially in conscious rats, using a radioactive microsphere method. SMS 201-995 reduced portal venous inflow 21 +/- 4% and portal pressure 17 +/- 3%. Isosorbide dinitrate decreased portal venous inflow 20 +/- 4%, by inducing splanchnic vasoconstriction mediated by low pressure baroreflexes, and this agent also decreased portal pressure, by 14 +/- 2%. Portal venous resistance rose 7.6 +/- 3% with isosorbide dinitrate alone, but decreased 18 +/- 4% with combination therapy. This effect may have been induced by the pronounced vasodilatory effect of isosorbide dinitrate on the venous vasculature, since the reflex splanchnic vasoconstriction that occurs with low-dose isosorbide dinitrate disappears when this agent is combined with SMS 201-995. The decrease in portal pressure was more marked (22 +/- 4%) and changes in systemic hemodynamics were milder with the combined treatment. It was concluded that combination therapy with SMS 201-995 and low-dose isosorbide dinitrate may be beneficial for portal hypertension in liver cirrhosis.
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Affiliation(s)
- N Hori
- Third Department of Internal Medicine, Kyoto Prefectural University of Medicine, Japan
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