PMID- 26715580
OWN - NLM
STAT- PubMed-not-MEDLINE
DCOM- 20151230
LR  - 20201001
IS  - 2197-425X (Print)
IS  - 2197-425X (Electronic)
IS  - 2197-425X (Linking)
VI  - 3
IP  - 1
DP  - 2015 Dec
TI  - Heparins attenuated histone-mediated cytotoxicity in vitro and improved the 
      survival in a rat model of histone-induced organ dysfunction.
PG  - 36
LID - 10.1186/s40635-015-0072-z [doi]
LID - 36
AB  - 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.
FAU - Iba, Toshiaki
AU  - Iba T
AD  - 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.
FAU - Hashiguchi, Naoyuki
AU  - Hashiguchi N
AD  - Department of Emergency and Disaster Medicine, Graduate School of Medicine, 
      Juntendo University, 2-1-1 Hongo Bunkyo-ku, Tokyo, 113-8421, Japan.
FAU - Nagaoka, Isao
AU  - Nagaoka I
AD  - 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.
FAU - Tabe, Yoko
AU  - Tabe Y
AD  - 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.
FAU - Kadota, Katsuhiko
AU  - Kadota K
AD  - Department of Emergency and Disaster Medicine, Graduate School of Medicine, 
      Juntendo University, 2-1-1 Hongo Bunkyo-ku, Tokyo, 113-8421, Japan.
FAU - Sato, Koichi
AU  - Sato K
AD  - Department of Surgery, Juntendo Shizuoka Hospital, Graduate School of Medicine, 
      Juntendo University, 129 Izunokuni, Shizuoka, 410-2295, Japan. 
      kou-sato@chive.ocn.ne.jp.
LA  - eng
PT  - Journal Article
DEP - 20151229
PL  - Germany
TA  - Intensive Care Med Exp
JT  - Intensive care medicine experimental
JID - 101645149
PMC - PMC4695463
OTO - NOTNLM
OT  - Argatroban
OT  - Histone
OT  - Low-molecular weight heparin
OT  - Unfractionated heparin
EDAT- 2015/12/31 06:00
MHDA- 2015/12/31 06:01
PMCR- 2015/12/29
CRDT- 2015/12/31 06:00
PHST- 2015/08/24 00:00 [received]
PHST- 2015/12/20 00:00 [accepted]
PHST- 2015/12/31 06:00 [entrez]
PHST- 2015/12/31 06:00 [pubmed]
PHST- 2015/12/31 06:01 [medline]
PHST- 2015/12/29 00:00 [pmc-release]
AID - 10.1186/s40635-015-0072-z [pii]
AID - 72 [pii]
AID - 10.1186/s40635-015-0072-z [doi]
PST - ppublish
SO  - Intensive Care Med Exp. 2015 Dec;3(1):36. doi: 10.1186/s40635-015-0072-z. Epub 
      2015 Dec 29.