title: The efficacy of recombinant human soluble thrombomodulin for the treatment of shiga toxin-associated hemolytic uremic syndrome model mice.
abstract: BACKGROUND
  Recombinant human soluble thrombomodulin (rhTM) is a promising therapeutic natural anticoagulant that is comparable to antithrombin, tissue factor pathway inhibitor and activated protein C. In order to clarify the efficacy of rhTM for the treatment of typical hemolytic uremic syndrome (t-HUS), we examined changes in renal damage in t-HUS mice treated with rhTM or vehicle alone.
  
  
  METHODS
  We used severe and moderate t-HUS mice injected with shiga toxin (Stx) and lipopolysaccharide (LPS). The severe t-HUS mice were divided into two subgroups [an rhTM subgroup (Group A) and a saline subgroup (Group B)] along with the moderate t-HUS mice [an rhTM subgroup (Group C) and a saline subgroup (Group D)]. Groups E and F were healthy mice treated with rhTM or saline, respectively.
  
  
  RESULTS
  All mice in Group B died at 80-90 h post-administration of Stx2 and LPS whereas all mice in Group A remained alive. Loss of body weight, serum creatinine level, endothelial injury and mesangiolysis scores at 24 h after administration in the t-HUS mice treated with rhTM were lower than those in t-HUS mice treated with saline. The levels of hemoglobin at 6 h and platelet counts at 24 h after administration in Group A were higher than those in Group B. Serum interleukin (IL)-6, IL-1β and tumor necrotic factor (TNF)-α levels at 24 h after administration in Group A were lower than those in Group B. Serum C5b-9 levels at 24 h after the administration and serum fibrinogen degradation product (FDP) at 72 h after the administration of Stx2 and LPS were lower in Group A than in Group B.
  
  
  CONCLUSIONS
  These results indicate that rhTM might afford an efficacious treatment for t-HUS model mice via the inhibition of further thrombin formation and amelioration of hypercoagulant status.
authors.affiliation: Department of Pediatrics, Fukushima Medical University School of Medicine, Fukushima City, Fukushima, Japan.
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Suyama
authors.affiliation: Department of Pediatrics, Fukushima Medical University School of Medicine, Fukushima City, Fukushima, Japan.
authors.forename: Yukihiko
authors.initials: Y
authors.lastname: Kawasaki
authors.affiliation: Department of Pediatrics, Fukushima Medical University School of Medicine, Fukushima City, Fukushima, Japan.
authors.forename: Kyohei
authors.initials: K
authors.lastname: Miyazaki
authors.affiliation: Department of Pediatrics, Fukushima Medical University School of Medicine, Fukushima City, Fukushima, Japan.
authors.forename: Syuto
authors.initials: S
authors.lastname: Kanno
authors.affiliation: Department of Pediatrics, Fukushima Medical University School of Medicine, Fukushima City, Fukushima, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ono
authors.affiliation: Department of Pediatrics, Fukushima Medical University School of Medicine, Fukushima City, Fukushima, Japan.
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Ohara
authors.affiliation: Department of Pediatrics, Fukushima Medical University School of Medicine, Fukushima City, Fukushima, Japan.
authors.forename: Masatoki
authors.initials: M
authors.lastname: Sato
authors.affiliation: Department of Pediatrics, Fukushima Medical University School of Medicine, Fukushima City, Fukushima, Japan.
authors.forename: Mitsuaki
authors.initials: M
authors.lastname: Hosoya
mesh_terms: D000818:Animals; D015938:Complement Membrane Attack Complex; D004195:Disease Models, Animal; D006463:Hemolytic-Uremic Syndrome / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D006801:Humans; D007124:Immunoenzyme Techniques; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007668:Kidney / Q000473:pathology; D008070:Lipopolysaccharides / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011994:Recombinant Proteins / Q000627:therapeutic use*; D022621:Shiga Toxin / Q000008:administration & dosage*; D018180:Thrombomodulin / Q000235:genetics / Q000378:metabolism*; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D015938:Complement Membrane Attack Complex; D053583:Interleukin-1beta; D015850:Interleukin-6; D008070:Lipopolysaccharides; D011994:Recombinant Proteins; C546931:THBD protein, human; D018180:Thrombomodulin; D014409:Tumor Necrosis Factor-alpha; D022621:Shiga Toxin
keywords: hemolytic uremic syndrome; lipopolysaccharide; mice; recombinant human soluble thrombomodulin; verotoxin