title: 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 mechanisms underlying this effect.
  
  
  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.
authors.affiliation: Department of Gastroenterological Surgery, Yokohama City University, Graduate School of Medicine, Kanazawa-ku, Yokohama, Japan. Electronic address: y.ota1029@gmail.com.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Ota
authors.affiliation: Department of Gastroenterological Surgery, Yokohama City University, Graduate School of Medicine, Kanazawa-ku, Yokohama, Japan.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Kumamoto
authors.affiliation: Department of Gastroenterological Surgery, Yokohama City University, Graduate School of Medicine, Kanazawa-ku, Yokohama, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ishibe
authors.affiliation: Department of Gastroenterological Surgery, Yokohama City University, Graduate School of Medicine, Kanazawa-ku, Yokohama, Japan.
authors.forename: Kazuteru
authors.initials: K
authors.lastname: Watanabe
authors.affiliation: Department of Gastroenterological Surgery, Yokohama City University, Graduate School of Medicine, Kanazawa-ku, Yokohama, Japan.
authors.forename: Ryutarou
authors.initials: R
authors.lastname: Mori
authors.affiliation: Department of Gastroenterological Surgery, Yokohama City University, Graduate School of Medicine, Kanazawa-ku, Yokohama, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Taniguchi
authors.affiliation: Department of Gastroenterological Surgery, Yokohama City University, Graduate School of Medicine, Kanazawa-ku, Yokohama, Japan.
authors.forename: Ryusei
authors.initials: R
authors.lastname: Matsuyama
authors.affiliation: Department of Gastroenterological Surgery, Yokohama City University, Graduate School of Medicine, Kanazawa-ku, Yokohama, Japan.
authors.forename: Hirochika
authors.initials: H
authors.lastname: Makino
authors.affiliation: Department of Gastroenterological Surgery, Yokohama City University, Graduate School of Medicine, Kanazawa-ku, Yokohama, Japan.
authors.forename: Michio
authors.initials: M
authors.lastname: Ueda
authors.affiliation: Department of Gastroenterological Surgery, Yokohama City University, Graduate School of Medicine, Kanazawa-ku, Yokohama, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Kubota
authors.affiliation: Department of Gastroenterological Surgery, Yokohama City University, Graduate School of Medicine, Kanazawa-ku, Yokohama, Japan.
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Akiyama
authors.affiliation: Department of Gastroenterological Surgery, Yokohama City University, Graduate School of Medicine, Kanazawa-ku, Yokohama, Japan.
authors.forename: Kuniya
authors.initials: K
authors.lastname: Tanaka
authors.affiliation: Department of Gastroenterological Surgery, Yokohama City University, Graduate School of Medicine, Kanazawa-ku, Yokohama, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Ichikawa
authors.affiliation: Department of Gastroenterological Surgery, Yokohama City University, Graduate School of Medicine, Kanazawa-ku, Yokohama, Japan.
authors.forename: Itaru
authors.initials: I
authors.lastname: Endo
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D004353:Drug Evaluation, Preclinical; D006498:Hepatectomy / Q000009:adverse effects* / Q000401:mortality; D022781:Hepatocytes / Q000187:drug effects; D007150:Immunohistochemistry; D017093:Liver Failure / Q000209:etiology / Q000517:prevention & control*; D008115:Liver Regeneration / Q000187:drug effects*; D008297:Male; D011183:Postoperative Complications / Q000209:etiology / Q000517:prevention & control*; D017208:Rats, Wistar; D044463:Receptor, PAR-1 / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018180:Thrombomodulin / Q000627:therapeutic use*
chemical_list: D044463:Receptor, PAR-1; D018180:Thrombomodulin; D000410:Alanine Transaminase
keywords: Apoptosis; Hepatoprotective effect; Liver regeneration; Ninety-five percent hepatectomy; Protease-activator receptor 1; Thrombomodulin