Thrombomodulin improves rat survival after extensive hepatectomy

Abstract Background Recombinant human soluble thrombomodulin (rTM) protects against disseminated intravascular coagulopathy by inhibiting coagulation, inflammation, and apoptosis. This study tests the hypothesis that rTM is hepatoprotective after extensive hepatectomy (Hx) and investigates the mecha...

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Published in:The Journal of surgical research 2015-04, Vol.194 (2), p.375-382
Main Authors: Ota, Yohei, MD, Kumamoto, Takafumi, MD, PhD, Ishibe, Atsushi, MD, PhD, Watanabe, Kazuteru, MD, PhD, Mori, Ryutarou, MD, PhD, Taniguchi, Koichi, MD, PhD, Matsuyama, Ryusei, MD, PhD, Makino, Hirochika, MD, PhD, Ueda, Michio, MD, PhD, Kubota, Toru, MD, PhD, Akiyama, Hirotoshi, MD, PhD, Tanaka, Kuniya, MD, PhD, Ichikawa, Yasushi, MD, PhD, Endo, Itaru, MD, PhD
Format: Article
Language:English
Subjects:
Alanine Transaminase - blood
Animals
Apoptosis
Apoptosis - drug effects
Blotting, Western
Drug Evaluation, Preclinical
Hepatectomy - adverse effects
Hepatectomy - mortality
Hepatocytes - drug effects
Hepatoprotective effect
Immunohistochemistry
Liver Failure - etiology
Liver Failure - prevention & control
Liver regeneration
Liver Regeneration - drug effects
Male
Ninety-five percent hepatectomy
Postoperative Complications - etiology
Postoperative Complications - prevention & control
Protease-activator receptor 1
Rats, Wistar
Receptor, PAR-1 - metabolism
Reverse Transcriptase Polymerase Chain Reaction
Surgery
Thrombomodulin
Thrombomodulin - therapeutic use
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Summary:Abstract Background Recombinant human soluble thrombomodulin (rTM) protects against disseminated intravascular coagulopathy by inhibiting coagulation, inflammation, and apoptosis. This study tests the hypothesis that rTM is hepatoprotective after extensive hepatectomy (Hx) and investigates the mechanisms underlying this effect. Materials and methods Experiment 1: rats (15 per group) were injected with rTM (1.0 or 2.0 mg/kg) or saline just before 95% Hx and their 7-d survival assessed. Experiment 2: rats were assigned to either a treated (2.0 mg/kg rTM just before Hx) or control group ( n  = 5 per group). Five rats per group were euthanized immediately after surgery, and at 1, 3, 6, 12, and 24 h postoperatively; serum and liver remnant samples were collected for biochemical and histologic analysis, as well as reverse-transcription polymerase chain reaction and Western blotting. Results All saline-injected rats died within 52 h of Hx, whereas injection of 2.0 mg/kg rTM prolonged survival ( P  = 0.003). rTM increased the number of Ki67-positive cells and reduced the number of terminal deoxynucleotidyl transferase dUTP nick-end labeling-positive cells. The number of myeloperoxidase-positive cells and the expression of high-mobility group box 1 protein did not differ. Reverse-transcription polymerase chain reaction revealed that rTM significantly enhanced protease-activated receptor-1 and sphingosine kinase 1 messenger RNA expression and significantly reduced plasminogen activator inhibitor-1 and Bax messenger RNA expression. Immunohistochemistry and Western blotting demonstrated that protease-activated receptor-1 expression 24 h after Hx was significantly higher in rTM-treated than in control rats. Conclusions rTM may improve survival after extensive Hx by inhibiting apoptosis and promoting liver regeneration.
ISSN:0022-4804
1095-8673
DOI:10.1016/j.jss.2014.10.048