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Soto G, Rodríguez MJ, Fuentealba R, Treuer AV, Castillo I, González DR, Zúñiga-Hernández J. Maresin 1, a Proresolving Lipid Mediator, Ameliorates Liver Ischemia-Reperfusion Injury and Stimulates Hepatocyte Proliferation in Sprague-Dawley Rats. Int J Mol Sci 2020; 21:ijms21020540. [PMID: 31952110 PMCID: PMC7014175 DOI: 10.3390/ijms21020540] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Revised: 12/12/2019] [Accepted: 12/12/2019] [Indexed: 12/12/2022] Open
Abstract
Maresin-1 (MaR1) is a specialized pro-resolving mediator, derived from omega-3 fatty acids, whose functions are to decrease the pro-inflammatory and oxidative mediators, and also to stimulate cell division. We investigated the hepatoprotective actions of MaR1 in a rat model of liver ischemia-reperfusion (IR) injury. MaR1 (4 ng/gr body weight) was administered prior to ischemia (1 h) and reperfusion (3 h), and controls received isovolumetric vehicle solution. To analyze liver function, transaminases levels and tissue architecture were assayed, and serum cytokines TNF-α, IL-6, and IL-10, mitotic activity index, and differential levels of NF-κB and Nrf-2 transcription factors, were analyzed. Transaminase, TNF-α levels, and cytoarchitecture were normalized with the administration of MaR1 and associated with changes in NF-κB. IL-6, mitotic activity index, and nuclear translocation of Nrf-2 increased in the MaR1-IR group, which would be associated with hepatoprotection and cell proliferation. Taken together, these results suggest that MaR1 alleviated IR liver injury, facilitated by the activation of hepatocyte cell division, increased IL-6 cytokine levels, and the nuclear localization of Nrf-2, with a decrease of NF-κB activity. All of them were related to an improvement of liver injury parameters. These results open the possibility of MaR1 as a potential therapeutic tool in IR and other hepatic pathologies.
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Affiliation(s)
- Gonzalo Soto
- Escuela de Tecnología Medica, Facultad de Ciencias de la Salud, Universidad de Talca, Talca 3460000, Chile;
| | - María José Rodríguez
- Programa de Doctorado en Ciencias mención Investigación y Desarrollo de Productos Bioactivos, Instituto de Química de los Recursos Naturales, Universidad de Talca, Talca 3460000, Chile; (M.J.R.); (R.F.)
- Escuela de Medicina, Universidad de Talca, Talca 3460000, Chile
| | - Roberto Fuentealba
- Programa de Doctorado en Ciencias mención Investigación y Desarrollo de Productos Bioactivos, Instituto de Química de los Recursos Naturales, Universidad de Talca, Talca 3460000, Chile; (M.J.R.); (R.F.)
- Departamento de Ciencias Básicas Biomédicas, Facultad de Ciencias de la Salud, Universidad de Talca, Talca 3460000, Chile; (A.V.T.); (D.R.G.)
| | - Adriana V. Treuer
- Departamento de Ciencias Básicas Biomédicas, Facultad de Ciencias de la Salud, Universidad de Talca, Talca 3460000, Chile; (A.V.T.); (D.R.G.)
- Centro de Bioinformática, Simulación y Modelado, Facultad de Ingeniería, Universidad de Talca, Talca 3460000, Chile
| | - Iván Castillo
- Unidad de Anatomía Patológica, Hospital Regional de Talca, Talca 3460001, Chile;
- Centro Oncológico, Facultad de Medicina, Universidad Católica del Maule, Talca 3466706, Chile
| | - Daniel R. González
- Departamento de Ciencias Básicas Biomédicas, Facultad de Ciencias de la Salud, Universidad de Talca, Talca 3460000, Chile; (A.V.T.); (D.R.G.)
| | - Jessica Zúñiga-Hernández
- Escuela de Medicina, Universidad de Talca, Talca 3460000, Chile
- Correspondence: ; Tel.: +56-71-2201667
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Hiratani S, Mori R, Ota Y, Matsuyama R, Kumamoto T, Nagashima Y, Morioka D, Endo I. A Simple and Easily Reproducible Model of Reversible Obstructive Jaundice in Rats. In Vivo 2019; 33:699-706. [PMID: 31028186 PMCID: PMC6559921 DOI: 10.21873/invivo.11528] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2019] [Revised: 02/06/2019] [Accepted: 02/08/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND/AIM Cholangiocarcinoma and pancreatic carcinoma are major malignancies that cause obstructive jaundice (OJ). This study aimed to develop a simple and easily reproducible rat model of reversible OJ (ROJ). MATERIALS AND METHODS OJ was induced by clamping the common bile duct (CBD) using a U-shaped titanium hemoclip and its base was attached by ligation using 2-cm long 4-0 polypropylene suture. An anti-adhesive sheet was placed around the CBD. OJ was mitigated by pulling the suture to remove the clip under laparotomy 3 days later. Serum chemistry and liver histopathology were compared between the ROJ group and sham surgery (SH) groups. RESULTS Three days after inducing OJ, serum total bilirubin, aspartate aminotransferase, and alanine aminotransferase were remarkably elevated in the ROJ group and thereafter reduced significantly after mitigating OJ. Similar findings were confirmed by histopathology. CONCLUSION Our rat model of reversible OJ was considered simple and easily reproducible.
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Affiliation(s)
- Seigo Hiratani
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Ryutaro Mori
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Yohei Ota
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Ryusei Matsuyama
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Takafumi Kumamoto
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Yoji Nagashima
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Daisuke Morioka
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Itaru Endo
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan
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Dho SH, Deverman BE, Lapid C, Manson SR, Gan L, Riehm JJ, Aurora R, Kwon KS, Weintraub SJ. Control of cellular Bcl-xL levels by deamidation-regulated degradation. PLoS Biol 2013; 11:e1001588. [PMID: 23823868 PMCID: PMC3692414 DOI: 10.1371/journal.pbio.1001588] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2012] [Accepted: 05/07/2013] [Indexed: 02/07/2023] Open
Abstract
Deamidation of two asparagines activates a conditional PEST sequence to target Bcl-xL for degradation. The cellular concentration of Bcl-xL is among the most important determinants of treatment response and overall prognosis in a broad range of tumors as well as an important determinant of the cellular response to several forms of tissue injury. We and others have previously shown that human Bcl-xL undergoes deamidation at two asparaginyl residues and that DNA-damaging antineoplastic agents as well as other stimuli can increase the rate of deamidation. Deamidation results in the replacement of asparginyl residues with aspartyl or isoaspartyl residues. Thus deamidation, like phosphorylation, introduces a negative charge into proteins. Here we show that the level of human Bcl-xL is constantly modulated by deamidation because deamidation, like phosphorylation in other proteins, activates a conditional PEST sequence to target Bcl-xL for degradation. Additionally, we show that degradation of deamidated Bcl-xL is mediated at least in part by calpain. Notably, we present sequence and biochemical data that suggest that deamidation has been conserved from the simplest extant metazoans through the human form of Bcl-xL, underscoring its importance in Bcl-xL regulation. Our findings strongly suggest that deamidation-regulated Bcl-xL degradation is an important component of the cellular rheostat that determines susceptibility to DNA-damaging agents and other death stimuli. Cellular levels of the pro-survival protein Bcl-xL are an important determinant of cellular susceptibility to many death stimuli, including most cancer therapies. We previously showed that human Bcl-xL undergoes deamidation – the conversion of two neutral asparaginyl side-chains into negatively charged aspartyl side-chains – a process that occurs spontaneously but is accelerated by the treatment of tumor cells with DNA-damaging agents. Here, we show that deamidation activates a hitherto undetected signal sequence within Bcl-xL that targets it for degradation by a pathway involving the proteolytic enzyme calpain. This increased degradation of Bcl-xL, and the consequent enhanced cellular susceptibility to programmed cell death, may contribute to the ability of DNA-damaging agents to kill tumors. We also demonstrate that deamidation of Bcl-xL has likely been conserved from the simplest metazoans to humans, underscoring the importance of deamidation in the regulation of Bcl-xL.
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Affiliation(s)
- So Hee Dho
- Division of Urology and The Alvin J. Siteman Cancer Center, Washington University School of Medicine, Saint Louis, Missouri, United States of America
- Laboratory of Cell Signaling, Aging Research Center, Korea Research Institute of Bioscience and Biotechnology, Yusong, Daejeon, Korea
| | - Benjamin E. Deverman
- Division of Urology and The Alvin J. Siteman Cancer Center, Washington University School of Medicine, Saint Louis, Missouri, United States of America
| | - Carlo Lapid
- Department of Biology, Washington University, Saint Louis, Missouri, United States of America
| | - Scott R. Manson
- Division of Urology and The Alvin J. Siteman Cancer Center, Washington University School of Medicine, Saint Louis, Missouri, United States of America
| | - Lu Gan
- Division of Urology and The Alvin J. Siteman Cancer Center, Washington University School of Medicine, Saint Louis, Missouri, United States of America
| | - Jacob J. Riehm
- Division of Urology and The Alvin J. Siteman Cancer Center, Washington University School of Medicine, Saint Louis, Missouri, United States of America
| | - Rajeev Aurora
- Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, Saint Louis, Missouri, United States of America
| | - Ki-Sun Kwon
- Laboratory of Cell Signaling, Aging Research Center, Korea Research Institute of Bioscience and Biotechnology, Yusong, Daejeon, Korea
- * E-mail: (K-SK); (SJW)
| | - Steven J. Weintraub
- Division of Urology and The Alvin J. Siteman Cancer Center, Washington University School of Medicine, Saint Louis, Missouri, United States of America
- Department of Internal Medicine, Washington University School of Medicine, Saint Louis, Missouri, United States of America
- Department of Internal Medicine, St. Louis VA Medical Center–John Cochran Division, Saint Louis, Missouri, United States of America
- * E-mail: (K-SK); (SJW)
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Amano H, Hino H, Tateno C, Emoto K, Imaoka Y, Yamasaki C, Itamoto T, Tashiro H, Asahara T, Ohdan H, Yoshizato K. Therapeutic Potential of Propagated Hepatocyte Transplantation in Liver Failure. J Surg Res 2011; 167:e29-37. [DOI: 10.1016/j.jss.2010.12.008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2010] [Revised: 11/23/2010] [Accepted: 12/07/2010] [Indexed: 12/22/2022]
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Makino H, Shimada H, Morioka D, Kunisaki C, Morita T, Matsuyama R, Kubota T, Shimizu D, Ichikawa Y, Tanaka K, Matsuo K, Togo S, Endo I, Nagashima Y, Okazaki Y, Hayashizaki Y. Analysis of gene expression profiles in fatal hepatic failure after hepatectomy in mice. J Surg Res 2010; 169:36-43. [PMID: 20444472 DOI: 10.1016/j.jss.2009.11.722] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2009] [Revised: 09/17/2009] [Accepted: 11/19/2009] [Indexed: 11/29/2022]
Abstract
BACKGROUND We developed 90%-hepatectomized mice that were the fatal model, and analyzed the gene expression profiles using a complementary DNA (cDNA) microarray to clarify the mechanisms of hepatic failure after excessive hepatectomy. MATERIALS AND METHODS Ribonucleic acid (RNA)s from the remnant hepatic tissue of 70%- and 90%-hepatectomized mice were labeled with fluorescent dyes, and hybridized to the Riken set of 39,168 full-length enriched mouse cDNA arrays. The gene expression profiles in 90%- and 70%-hepatectomized mice were analyzed by scanning date for fluorescent dye signals. RESULTS The down-regulated genes in 90%-hepatectomized mice were genes activating extracellular matrix (ECM) remodeling (matrix metalloproteinases, laminins, and integrins), genes related to cytokines (tumor necrosis factor α converting enzyme, and Janus kinase 3) that were related to the priming, genes related to growth factor (heparin-binding epidermal growth factor-like growth factor and others), and genes promoting cell cycle progression (cyclin D1, D2, and E2) that were related to the progression of hepatocytes. The up-regulated genes were genes inhibiting ECM remodeling [plasminogen activator inhibitors (PAIs)]. CONCLUSIONS Hepatic failure after hepatectomy was characterized by the inhibition of hepatic cell cycle priming and progression both induced by ECM remodeling in liver regeneration. Particularly, the overexpression of PAIs was thought to play the major role in the first step of inhibition of ECM remodeling.
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Affiliation(s)
- Hirochika Makino
- Department of Gastroenterological Surgery, Yokohama City University School Graduate of Medicine, Yokohama, Japan.
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Honda K, Tohyama T, Kotegawa H, Kojima Y, Kushihata F, Watanabe J, Kobayashi N. Protective Effect of Adeno-Mediated Human Bcl-xL Gene Transfer to the Mouse Liver in a Partial Ischemia/Reperfusion Model. J Surg Res 2009; 157:e107-16. [DOI: 10.1016/j.jss.2008.10.019] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2008] [Revised: 10/10/2008] [Accepted: 10/22/2008] [Indexed: 10/21/2022]
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Ishibe A, Togo S, Kumamoto T, Watanabe K, Takahashi T, Shimizu T, Makino H, Matsuo K, Kubota T, Nagashima Y, Shimada H. Prostaglandin E1 prevents liver failure after excessive hepatectomy in the rat by up-regulating Cyclin C, Cyclin D1, and Bclxl. Wound Repair Regen 2009; 17:62-70. [PMID: 19152652 DOI: 10.1111/j.1524-475x.2008.00442.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Prostaglandin E1 (PGE1) has wide-ranging effects on cytoprotection and may play a role in preventing liver failure following excessive hepatectomy. We examined the effect of PGE1 on hepatocyte apoptosis and liver regeneration after 95% hepatectomy in a rat model. PGE1 or vehicle was intravenously administered 30 minutes before and during hepatectomy. The extent of hepatocyte injury was evaluated by serum alanine aminotransferase and aspartate aminotransferase levels. To evaluate hepatocyte apoptosis and liver regeneration, terminal deoxynucleotidyl transferase dUTP nick end labeling staining and Ki67 labeling were performed. The expression levels of Bcl-xL, Bcl-2, Bax, Cyclin C, Cyclin D1, Cyclin E, p21, transforming growth factor-beta, plasminogen activator inhibitor-1, and glyceraldehyde-2-phosphate dehydrogenase mRNA were also examined by reverse transcription-polymerase chain reaction. Survival was improved in the PGE1 group (26.6%), whereas all rats in the vehicle group died within 60 hours. PGE1 significantly suppressed the release of alanine aminotransferase and aspartate aminotransferase at 12 hours postoperatively. Pretreatment with PGE1 significantly increased the Ki67-positive cell count and decreased the terminal deoxynucleotidyl transferase dUTP nick end labeling positive cell count after hepatectomy, and also significantly increased the expression levels of Bcl-xL, Cyclin C, and Cyclin D1. Our results suggest that pretreatment with PGE1 may increase survival following hepatectomy by salvaging the remaining liver tissue, which it does by inhibiting apoptosis and stimulating hepatocyte proliferation.
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Affiliation(s)
- Atsushi Ishibe
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan
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Wang Y, Zhang B, Peng X, Perpetua M, Harbrecht BG. Bcl-xL prevents staurosporine-induced hepatocyte apoptosis by restoring protein kinase B/mitogen-activated protein kinase activity and mitochondria integrity. J Cell Physiol 2008; 215:676-83. [PMID: 18163394 DOI: 10.1002/jcp.21350] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Our study reports that staurosporine induces apoptosis in cultured rat hepatocytes in a dose- and time-dependent fashion. Staurosporine induced apparent cleavage of caspase-8, caspase-9, and caspase-3. The release of cytochrome c from mitochondria, and Bid activation were also detected in staurosporine-treated primary hepatocytes. These results suggest that mitochondria-mediated cell death signaling may be involved in staurosporine-induced hepatocyte apoptosis. Bcl-x(L) overexpression protected from "loss of" mitochondrial transmembrane potential and prevented staurosporine-induced caspase-3 and caspase-8 cleavage. Overexpression of constitutively active ERK and PKB inhibited staurosporine-induced caspase-3 activation and hepatocyte death. PI3K inhibitor (LY294002) and ERK inhibitor (PD98059) significantly reversed the protective effects of Bcl-x(L) on staurosporine-induced hepatocyte death. Our data suggest that Bcl-x(L) prevents staurosporine-induced hepatocyte apoptosis by modulating protein kinase B and p44/42 mitogen-activated protein kinase activity and disrupts mitochondria death signaling.
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Affiliation(s)
- Yinna Wang
- Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
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Yoshida N, Iwata H, Yamada T, Sekino T, Matsuo H, Shirahashi K, Miyahara T, Kiyama S, Takemura H. Improvement of the survival rate after rat massive hepatectomy due to the reduction of apoptosis by caspase inhibitor. J Gastroenterol Hepatol 2007; 22:2015-21. [PMID: 17559362 DOI: 10.1111/j.1440-1746.2007.04960.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND AND AIM Acute liver failure after massive hepatectomy is caused by both necrosis and apoptosis in the remnant liver. We investigate the protective effect of the caspase inhibitor on apoptosis after massive hepatectomy in rats. METHODS Benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethylketone (ZVAD-fmk) is a general inhibitor of the caspase. Male Wister rats weighing 200-300 g were divided into three groups: 90Hx group undergoing 90% hepatectomy, 95Hx group undergoing 95% hepatectomy, 95Hx + ZVAD group undergoing 95% hepatectomy and administration of ZVAD-fmk. The 7-day survival rate was studied, and the rats were sacrificed at the 1, 2, 3, 5, and 7th day after hepatectomy. The remnant liver tissues were stained with hematoxylin-eosin, and with proliferating cell nuclear antigen (PCNA) for evaluation of liver regeneration, and with TdT-mediated dUTP-biotin nick end labeling (TUNEL) and in situ oligo ligation method (ISOL) for evaluation of apoptosis. RESULTS The 7-day survival rates were 100%, 0%, and 30%, in the 90Hx, 95Hx, and 95Hx + ZVAD groups, respectively. There was no significant difference in PCNA labeling index (LI) between the 95Hx and 95Hx + ZVAD groups. TUNEL and ISOL LI of 95Hx + ZVAD group were significantly lower than those of 95Hx group. Fatal liver failure after massive hepatectomy was characterized by more apoptosis and less mitosis of hepatocytes. ZVAD-fmk could significantly attenuate apoptosis of hepatocytes in the remnant liver and improve the survival rate after 95% hepatectomy in rats. CONCLUSION Caspase inhibitors such as ZVAD-fmk may provide a new adjuvant therapy to treat liver failure after massive hepatectomy.
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Affiliation(s)
- Naomasa Yoshida
- Department of Advanced Surgery, Graduate School of Medicine, Gifu University, Gifu, Japan.
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Watanabe K, Togo S, Takahashi T, Matsuyama R, Yamamoto H, Shimizu T, Makino H, Matsuo K, Morioka D, Kubota T, Nagashima Y, Shimada H. PAI-1 plays an important role in liver failure after excessive hepatectomy in the rat. J Surg Res 2007; 143:13-9. [PMID: 17655862 DOI: 10.1016/j.jss.2007.04.041] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2006] [Revised: 04/25/2007] [Accepted: 04/30/2007] [Indexed: 12/25/2022]
Abstract
BACKGROUND/AIMS Well-organized turnover of the extracellular matrix is important in liver regeneration, which is regulated by the plasminogen activating system. The aim of this study was to investigate the role of plasminogen activator inhibitor-1 (PAI-1) after excessive hepatectomy and to ascertain whether angiotensin-converting enzyme (ACE) inhibitors, which are PAI-1 inhibitors as well, successfully improve the survival rate of rats that have undergone 95% partial hepatectomy (PHx). METHODS Using liver tissues sampled after 90% or 95% PHx, the expression of PAI-1 mRNA was evaluated using reverse transcription polymerase chain reaction. Hepatic PAI-1 protein and urokinase-type plasminogen activator (uPA) levels were determined by enzyme-linked immunosorbent assay. Survival study and cytodynamic analysis by 5-bromo-2'-deoxyuridine staining were performed to evaluate the effects of ACE inhibition. RESULTS The levels of PAI-1 mRNA and hepatic PAI-1 protein in the 95% PHx group peaked and were then maintained. By contrast, the uPA level fell relative to the 90% PHx group. Additionally, the hepatic PAI-1 protein level decreased and the survival rate improved in the 95% PHx rats that had undergone ACE inhibition. CONCLUSIONS Our experimental results suggest that PAI-1 plays a role in the occurrence of liver failure after excessive hepatectomy via accelerated maturation of pro-uPA and fibrinolytic factors. These are potential molecular therapeutic targets for liver failure after excessive hepatectomy.
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Affiliation(s)
- Kazuteru Watanabe
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan
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Abstract
OBJECTIVE Based on the 3-dimensional visualization of vascular supply and drainage, a vessel-oriented resection technique was optimized. The new surgical technique was used to determine the maximal reduction in liver mass enabling a 50% 1-week survival rate. BACKGROUND DATA Determination of the minimal liver mass is necessary in clinical as well as in experimental liver surgery. In rats, survival seems to depend on the surgical technique applied. Extended hepatectomy with removal of 90% of the liver mass was long regarded as a lethal model. Introduction of a vessel-oriented approach enabled long-term survival in this model. METHODS The lobar and vascular anatomy of rat livers was visualized by plastination of the whole organ, respectively, by corrosion casts of the portal vein, hepatic artery and liver veins. The three-dimensional models were used to extract the underlying anatomic structure. In 90% partial hepatectomy, the liver parenchyma was clamped close to the base of the respective liver lobes (left lateral, median and right, liver lobe). Piercing sutures were placed through the liver parenchyma, so that the stem of portal vein and the accompanying hepatic artery but also the hepatic vein were included. RESULTS A 1-week survival rate of 100% was achieved after 90% hepatectomy. Extending the procedure to 95% resection by additional removal of the upper caudate lobe led to a 1-week survival rate of 66%; 97% partial hepatectomy, accomplished by additional resection of the lower caudate lobe only leaving the paracaval parts of the liver behind, resulted in 100% lethality within 4 days. CONCLUSIONS Using a anatomically based, vessel-oriented, parenchyma-preserving surgical technique in 95% liver resections led to long-term survival. This represents the maximal reduction of liver mass compatible with survival.
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Affiliation(s)
- Nodir Madrahimov
- Department of General, Visceral and Transplantation Surgery, University Hospital Essen, Essen, Germany
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Ijichi H, Taketomi A, Yoshizumi T, Uchiyama H, Yonemura Y, Soejima Y, Shimada M, Maehara Y. Hyperbaric oxygen induces vascular endothelial growth factor and reduces liver injury in regenerating rat liver after partial hepatectomy. J Hepatol 2006; 45:28-34. [PMID: 16513203 DOI: 10.1016/j.jhep.2005.12.021] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2005] [Revised: 12/13/2005] [Accepted: 12/15/2005] [Indexed: 12/04/2022]
Abstract
BACKGROUND/AIMS The aim of this study was to investigate the effect and the mechanism of hyperbaric oxygen treatment on regenerating rat liver after partial hepatectomy (PH). METHODS Wistar rats underwent a 70% PH, followed by treatment with hyperbaric oxygen starting 8 h after PH. The regenerated liver weight and serum parameters were compared. Proliferation of both hepatocytes and sinusoidal endothelial cell (SEC) was also monitored by evaluating the proliferating cell nuclear antigen (PCNA) labeling index. Furthermore, the hepatic adenosine triphosphate levels and vascular endothelial growth factor (VEGF) protein expression were analyzed at different times. RESULTS Hyperbaric oxygen treatment significantly reduced the serum alanine aminotransferase levels at 24 h, total bilirubin and total bile acid levels at 48 and 72 h, respectively. No significant differences in the hepatic adenosine triphosphate levels, the restitution of liver weight, or PCNA positive hepatocytes were observed between the two groups. The PCNA positive SEC, in contrast, was significantly increased in the hyperbaric oxygen group at 48h, furthermore, the hyperbaric oxygen treatment significantly increased the expression of VEGF protein in the regenerating liver at 24 and 48 h. CONCLUSIONS Hyperbaric oxygen treatment can be considered as a therapeutic modality after massive PH.
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Affiliation(s)
- Hideki Ijichi
- The Department of Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan. hiditi@
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Morioka D, Watanabe K, Makino H, Saito S, Ueda M, Kubota T, Sekido H, Matsuo KI, Ichikawa Y, Endo I, Togo S, Shimada H. Safety limit of the extent of hepatectomy for rats with moderately fatty liver: experimental study concerning living liver donor safety. J Gastroenterol Hepatol 2006; 21:367-73. [PMID: 16509860 DOI: 10.1111/j.1440-1746.2005.03972.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
INTRODUCTION The aim of the present study was to determine whether rats with moderately fatty liver could withstand a 90% hepatectomy, which rats with normal livers can survive. MATERIAL AND METHODS Nine-week-old male Wistar rats were used. Normal rat chow was fed to the normal liver group, and fat-enriched rat chow was fed to the fatty liver group for 4 weeks to induce a moderately fatty liver. The authors have previously reported that this fatty liver rat model can cause fatal liver dysfunction after reduced-size-liver transplantation. A 90% and 95% hepatectomy were performed using rats of both groups to evaluate posthepatectomized liver function. RESULTS All rats undergoing a 90% hepatectomy were still alive 30 days after the hepatectomy, but the rats that underwent a 95% hepatectomy were all dead within 4 days regardless of group. Increases in the liver remnant wet weight measured until 7 postoperative days after 90% hepatectomy were almost similar among the two groups. Alanin aminotransferase measured at 24, 48, 72, and 168 h after a 90% hepatectomy were significantly higher in the fatty liver group than in the normal liver group. Similarly, at up to 72 h postoperatively, the serum hyarulonic acids were significantly higher in the fatty liver group. CONCLUSION A moderately fatty liver did not cause mortality in 90% hepatectomized rats. However, it caused a higher degree of hepatic parenchymal as well as sinusoidal injury.
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Affiliation(s)
- Daisuke Morioka
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Fukuura, Kanazawa, Yokohama, Japan.
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Makino H, Togo S, Kubota T, Morioka D, Morita T, Kobayashi T, Tanaka K, Shimizu T, Matsuo K, Nagashima Y, Shimada H. A good model of hepatic failure after excessive hepatectomy in mice. J Surg Res 2005; 127:171-6. [PMID: 15916769 DOI: 10.1016/j.jss.2005.04.029] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2004] [Revised: 03/07/2005] [Accepted: 04/12/2005] [Indexed: 02/07/2023]
Abstract
AIMS This study was intended to establish in mice: 1) a safety limit for the extent of hepatectomy and 2) the extent of hepatectomy invariably causing fatal hepatic failure, to facilitate gene expression analysis. MATERIALS AND METHODS In 70%-hepatectomy, the left lateral and median lobes were removed, and in 90%-hepatectomy, all lobes except the caudate were resected. One-week survival rates, serum concentrations of aspartate aminotransferase, alanine aminotransferase and total bilirubin were measured. Histological examinations were performed using hematoxylin and eosin staining, and immunohistochemical tests were done with antibody against Ki-67 antigen. RESULTS All of the 70%-hepatectomized mice were alive at 1 week, but the 90%-hepatectomized mice all died within 24 h after hepatectomy. Serum aminotransferase and total bilirubin levels were significantly higher in the 90%-hepatectomized mice than in the 70%-hepatectomized mice. Liver histology revealed more prominent vacuolar degeneration in the former. Ki67-positive hepatocytes appeared and proliferated immediately after 70%-hepatectomy, but few were observed in the 70%-hepatectomized mice. CONCLUSION We established 90%-hepatectomy as the safety limit for murine hepatectomy and as a model for liver regeneration, and 90%-hepatectomy as a "fatal hepatic failure level."
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Affiliation(s)
- Hirochika Makino
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan
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Akcali KC, Dalgic A, Ucar A, Haj KB, Guvenc D. Expression of bcl-2 gene family during resection induced liver regeneration: comparison between hepatectomized and sham groups. World J Gastroenterol 2004; 10:279-83. [PMID: 14716839 PMCID: PMC4717020 DOI: 10.3748/wjg.v10.i2.279] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2003] [Revised: 10/05/2003] [Accepted: 10/12/2003] [Indexed: 12/15/2022] Open
Abstract
AIM During liver regeneration cellular proliferation and apoptosis result in tissue remodeling to restore normal hepatic mass and structure. Main regulators of the apoptotic machinery are the Bcl-2 family proteins but their roles are not well defined throughout the liver regeneration. We aimed to analyze the expression levels of bcl-2 gene family members during resection induced liver regeneration. METHODS We performed semi-quantitative RT-PCR to examine the expression level of bak, bax, bcl-2 and bcl-xL in 70% hepatectomized rat livers during the whole regeneration process and compared to that of the sham and normal groups. RESULTS The expression of bak and bax was decreased whereas that of bcl-2 and bcl-xL was increased in hepatectomized animals compared to normal liver at most time points. We also reported for the first time that sham group of animals had statistically significant higher expression of bak and bax than hepatectomized animals. In addition, the area under the curve (AUC) values of these genes was larger in sham groups than the hepatectomized groups. CONCLUSION The expression changes of bak, bax, bcl-2 and bcl-xL genes are altered not only due to regeneration, but also due to effects of surgical operations.
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Affiliation(s)
- Kamil Can Akcali
- Department of Molecular Biology and Genetics, Bilkent University, Bilkent, Ankara 06800, Turkey.
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