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ABSTRACT: To investigate the effect of hypothermia on the function of the liver remnant (LR) after extended hepatectomy.
We performed a 75% partial hepatectomy (PH) in male C57BL/6J mice. Body temperature was measured with a rectal probe. The study mice were prospectively grouped as hypothermic (HT) or normothermic (NT) if their body temperature was < 34 °C vs ≥ 34 °C, respectively. Blood and liver samples were obtained at 24 and 48 h after 75% PH. Various factors during and after 75% PH were compared at each time point and the most important factor for a good outcome after 75% PH was determined.
At 24 and 48 h after 75% PH, LR weight was decreased in HT mice compared with that in NT mice and the assay results in the HT mice were consistent with liver failure. NT mice had normal liver regeneration. Each intra- and post-operative factor which showed statistical significance in univariate analysis was evaluated by multivariate analysis. The most important factor for a good outcome after 75% PH was body temperature at both 24 and 48 h after surgery.
Hypothermia after an extensive hepatectomy predicts impending liver failure and may be a useful clinical marker for early detection of liver failure after extended hepatectomy.
World journal of hepatology. 04/2013; 5(4):170-81.
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ABSTRACT: To investigate the reliability of massive hepatectomy models by using clip techniques.
We analyzed anatomical findings in 100 mice following massive hepatectomy induced by liver reduction > 70%. The impact of various factors in the different models was also analyzed, including learning curves, operative time, survival curves, and histopathological findings.
According to anatomical results, models with 75%, 80%, and 90% hepatectomy produced massive hepatectomy. Learning curves and operative times were most optimal with the clip technique. Each hepatectomy performed using the clip technique produced a reasonable survival curve, and there were no differences in histopathological findings between the suture and clip techniques.
Massive hepatectomy by the clip technique is simple and can provide reliable and relevant data.
World Journal of Gastroenterology 06/2012; 18(22):2767-74. · 2.47 Impact Factor
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ABSTRACT: To investigate the effect of matrix metalloproteinase-9 (MMP-9) on the remnant liver after massive hepatectomy in the mouse.
Age-matched, C57BL/6 wild-type (WT), MMP-9(-/-), and tissue inhibitors of metalloproteinases (TIMP)-1(-/-) mice were used. The mice received 80%-partial hepatectomy (PH). Samples were obtained at 6 h after 80%-PH, and we used histology, immunohistochemical staining, western blotting analysis and zymography to investigate the effect of PH on MMP-9. The role of MMP-9 after PH was investigated using a monoclonal antibody and MMP inhibitor.
We examined the remnant liver 6 h after 80%-PH and found that MMP-9 deficiency attenuated the formation of hemorrhage and necrosis. There were significantly fewer and smaller hemorrhagic and necrotic lesions in MMP-9(-/-) remnant livers compared with WT and TIMP-1(-/-) livers (P < 0.01), with no difference between WT and TIMP-1(-/-) mice. Serum alanine aminotransaminase levels were significantly lower in MMP-9(-/-) mice compared with those in TIMP-1(-/-) mice (WT: 476 ± 83 IU/L, MMP-9(-/-): 392 ± 30 IU/L, TIMP-1(-/-): 673 ± 73 IU/L, P < 0.01). Western blotting and gelatin zymography demonstrated a lack of MMP-9 expression and activity in MMP-9(-/-) mice, which was in contrast to WT and TIMP-1(-/-) mice. No change in MMP-2 expression was observed in any of the study groups. Similar to MMP-9(-/-) mice, when WT mice were treated with MMP-9 monoclonal antibody or the synthetic inhibitor GM6001, hemorrhagic and necrotic lesions were significantly smaller and fewer than in control mice (P < 0.05). These results suggest that MMP-9 plays an important role in the development of parenchymal hemorrhage and necrosis in the small remnant liver.
Successful MMP-9 inhibition attenuates the formation of hemorrhage and necrosis and might be a potential therapy to ameliorate liver injury after massive hepatectomy.
World Journal of Gastroenterology 05/2012; 18(19):2320-33. · 2.47 Impact Factor
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ABSTRACT: Mechanisms of brain edema in acute liver failure (ALF) are not completely understood. We recently demonstrated that matrix metalloproteinase 9 (MMP-9) induces significant alterations to occludin in brain endothelial cells in vitro and in brains of mice with experimental ALF (Hepatology 2009;50:1914). In this study we show that MMP-9-induced transactivation of epidermal growth factor receptor (EGFR) and p38 MAPK/NFκB (mitogen-activated protein kinase/nuclear factor-kappa B) signals participate in regulating brain endothelial occludin level. Mouse brain endothelial bEnd3 cells were exposed to MMP-9 or p38 MAPK up-regulation in the presence and absence of EGFR inhibitor, p38 MAPK inhibitor, NFκB inhibitor, and/or appropriate small interfering RNA. Reverse-transcription polymerase chain reaction (RT-PCR) and western blotting were used for messenger RNA and protein expression analyses. Immunohistochemical staining and confocal microscopy were used to demonstrate cellular EGFR activation. Intraperitoneal azoxymethane was use to induce ALF in mice. Brains of comatose ALF mice were processed for histological and biochemical analyses. When bEnd3 cells were exposed to MMP-9, EGFR was significantly transactivated, followed by p38 MAPK activation, I-kappa B alpha (IκBα) degradation, NFκB activation, and suppression of occludin synthesis and expression. Similar EGFR activation and p38 MAPK/NFκB activation were found in the brains of ALF mice, and these changes were attenuated with GM6001 treatment. CONCLUSION: EGFR activation with p38 MAPK/NFκB signaling contributes to the regulation of tight junction integrity in ALF. EGFR activation may thus play an important role in vasogenic brain edema in ALF.
Hepatology 04/2011; 53(4):1294-305. · 11.66 Impact Factor
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Tomohide Hori,
Justin H Nguyen,
Xiangdong Zhao,
Yasuhiro Ogura,
Toshiyuki Hata,
Shintaro Yagi,
Feng Chen,
Ann-Marie T Baine, Norifumi Ohashi,
Christopher B Eckman, [......],
Kagemasa Kuribayashi,
Takuma Kato,
Kanako Saito,
Linan Wang,
Mie Torii,
Naruhiko Sahara,
Naoko Kamo,
Tomoko Sahara,
Motohiko Yasutomi,
Shinji Uemoto
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ABSTRACT: To investigate our learning curves of orthotopic liver transplantation (OLT) in rats and the most important factor for successful surgery.
We describe the surgical procedures for our rat OLT model, and determined the operator learning curves. The various factors that contributed to successful surgery were determined. The most important surgical factors were evaluated between successful and unsuccessful surgeries.
Learning curve data indicated that 50 cases were required for operator training to start a study. Operative time, blood loss, warm ischemic time, anhepatic phase, unstable systemic hemodynamic state, and body temperature after surgery significantly affected surgery success by univariate analysis, while the anhepatic phase was the most critical factor for success by multivariate analysis.
OLT in rats is the only liver transplantation model that provides clinically relevant and reliable results. Shortened anhepatic phase is key to success in this model.
World Journal of Gastroenterology 07/2010; 16(25):3120-32. · 2.47 Impact Factor
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ABSTRACT: Brain edema in acute liver failure (ALF) remains lethal. The role of vasogenic mechanisms of brain edema has not been explored. We previously demonstrated that matrix metalloproteinase-9 (MMP-9) contributes to the pathogenesis of brain edema. Here, we show that MMP-9 mediates disruptions in tight junction (TJ) proteins in vitro and in brains of mice with ALF. We transfected murine brain endothelial cells (ECs) with MMP-9 complementary DNA (cDNA) using pc DNA3.1 (+)/Myc-His A expression vector. Tissue inhibitor of matrix metalloproteinases (TIMP-1) cDNA transfection or GM6001 was used to inhibit MMP-9. ALF was induced in mice with azoxymethane. Endogenous overexpression of MMP-9 in brain ECs resulted in significant degradation of the TJ proteins occludin and claudin-5. The alterations in TJ proteins correlated with increased permeability to fluorescein isothiocyanate-dextran molecules. The degradation of TJ proteins and the increased permeability were reversed by TIMP-1 and GM6001. Similar results were found when MMP-9 was exogenously added to brain ECs. We also found that TJ protein degradation was reversed with GM6001 in the brains of mice with ALF. Conclusion: TJ proteins are significantly perturbed in brains of mice with ALF. These data corroborate the important role of MMP-9 in the vasogenic mechanism of brain edema in ALF.
Hepatology 08/2009; 50(6):1914-23. · 11.66 Impact Factor
