title: Heparins attenuated histone-mediated cytotoxicity in vitro and improved the survival in a rat model of histone-induced organ dysfunction.
abstract: BACKGROUND
  The beneficial effects of heparin in the treatment of severe sepsis, septic shock, and sepsis-associated disseminated intravascular coagulation (DIC) have recently been reported. However, the mechanisms underlying the therapeutic benefits of heparin in these conditions have not yet been clearly elucidated. The purpose of this study was to confirm the effect of heparin of neutralizing histone toxicity.
  
  
  METHODS
  Rat models of histone H3-induced organ dysfunction were administered in a low or high dose of unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), or argatroban, and the therapeutic effects of each anticoagulant were examined. In another series, the survival of the histone H3-administered animals was evaluated. Furthermore, the effect of each of the aforementioned anticoagulants on cell death induced by histone H3 was examined in cultured vascular endothelial cells and leukocytes.
  
  
  RESULTS
  Although UFH, LMWH, and argatroban significantly suppressed the histone-induced decrease of the WBC and platelet counts in the animal models of organ dysfunction, only UFH and LMWH attenuated hepatic and renal dysfunction. In addition, the mortality was significantly reduced only by high-dose UFH and LMWH. The in vitro study revealed that both vascular endothelial cell death and leukocyte cell death were significantly attenuated by UFH and LMWH but not by argatroban.
  
  
  CONCLUSIONS
  The histone-neutralizing effect of heparin may contribute to the beneficial effects of heparins observed in the animal study. The results of the in vitro study further confirmed the above contention and suggested that heparin binds to histones to attenuate the cytotoxic actions of the latter. Since heparin has been demonstrated to protect animals from the organ damage induced by histones and consequently reduce the mortality, administration of heparin could become a treatment of choice for patients suffering from severe sepsis.
authors.affiliation: Department of Emergency and Disaster Medicine, Graduate School of Medicine, Juntendo University, 2-1-1 Hongo Bunkyo-ku, Tokyo, 113-8421, Japan. toshiiba@juntendo.ac.jp.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Iba
authors.affiliation: Department of Emergency and Disaster Medicine, Graduate School of Medicine, Juntendo University, 2-1-1 Hongo Bunkyo-ku, Tokyo, 113-8421, Japan.
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Hashiguchi
authors.affiliation: Department of Host Defense and Biochemical Research, Graduate School of Medicine, Juntendo University, 2-1-1 Hongo Bunkyo-ku, Tokyo, 113-8421, Japan. nagaokai@juntendo.ac.jp.
authors.forename: Isao
authors.initials: I
authors.lastname: Nagaoka
authors.affiliation: Department of Clinical Laboratory Medicine, Graduate School of Medicine, Juntendo University, 2-1-1 Hongo Bunkyo-ku, Tokyo, 113-8421, Japan. tabe@juntendo.ac.jp.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Tabe
authors.affiliation: Department of Emergency and Disaster Medicine, Graduate School of Medicine, Juntendo University, 2-1-1 Hongo Bunkyo-ku, Tokyo, 113-8421, Japan.
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Kadota
authors.affiliation: Department of Surgery, Juntendo Shizuoka Hospital, Graduate School of Medicine, Juntendo University, 129 Izunokuni, Shizuoka, 410-2295, Japan. kou-sato@chive.ocn.ne.jp.
authors.forename: Koichi
authors.initials: K
authors.lastname: Sato
keywords: Argatroban; Histone; Low-molecular weight heparin; Unfractionated heparin