PMID- 31454337
OWN - NLM
STAT- MEDLINE
DCOM- 20200123
LR  - 20200123
IS  - 2163-0763 (Electronic)
IS  - 2163-0755 (Linking)
VI  - 87
IP  - 3
DP  - 2019 Sep
TI  - Unfractionated heparin attenuates histone-mediated cytotoxicity in vitro and 
      prevents intestinal microcirculatory dysfunction in histone-infused rats.
PG  - 614-622
LID - 10.1097/TA.0000000000002387 [doi]
AB  - BACKGROUND: Extracellular histones are major mediators of organ dysfunction and 
      death in sepsis, and they may cause microcirculatory dysfunction. Heparins have 
      beneficial effects in sepsis and have been reported to bind to histones and 
      neutralize their cytotoxicity. The aim of this study was to investigate the 
      impact of histones on intestinal microcirculation and the intestinal endothelium 
      and to discuss the protective effect of unfractionated heparin (UFH) on the 
      endothelial cytotoxicity and microcirculatory dysfunction induced by histones. 
      METHODS: Anesthetized rats were infused with 30 mg/kg calf thymus histones, and 
      UFH was administered intravenously at a concentration of 100 IU/kg per hour. The 
      intestinal microcirculation was visualized and measured with incident dark field 
      microscope. Plasma von Willebrand factor (vWF) and soluble thrombomodulin were 
      detected, and structural changes in the rat intestinal microvascular endothelium 
      were examined. The effects of histones and UFH on cell survival rates, vWF 
      release and calcium influx were investigated in human intestinal microvascular 
      endothelial cells (HIMECs). RESULTS: Histone infusion caused severe intestinal 
      microcirculatory dysfunction in the absence of obvious hemodynamic changes, and 
      UFH protected intestinal microcirculation in histone-infused rats. Concentrations 
      of the plasma endothelial injury markers vWF and soluble thrombomodulin were 
      elevated, and structural abnormalities were found in the intestinal microvascular 
      endothelium in the histone-infused rats. These events were attenuated by UFH. In 
      vitro, UFH significantly reduced the histone-induced cytotoxicity of HIMECs, 
      reduced the release of vWF from the cytoplasm into the culture medium, and 
      inhibited calcium influx into HIMECs. CONCLUSION: Histones induce intestinal 
      microcirculatory dysfunction followed by direct injury to the endothelial cells; 
      UFH protects the intestinal microcirculation partly by antagonizing the 
      endothelial toxicity of histones.
FAU - Zhu, Chengrui
AU  - Zhu C
AD  - From the Department of Critical Care Medicine (C.Z., Y.L., X.L., X.M.), The First 
      Affiliated Hospital, China Medical University, Liaoning Province; and Department 
      of Emergency ICU (N.C.), First Affiliated Hospital of Hainan Medical University, 
      Hainan Province, China.
FAU - Liang, Yingjian
AU  - Liang Y
FAU - Li, Xu
AU  - Li X
FAU - Chen, Ning
AU  - Chen N
FAU - Ma, Xiaochun
AU  - Ma X
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Trauma Acute Care Surg
JT  - The journal of trauma and acute care surgery
JID - 101570622
RN  - 0 (Histones)
RN  - 9005-49-6 (Heparin)
SB  - IM
MH  - Animals
MH  - Cell Survival/drug effects
MH  - Cells, Cultured
MH  - Endothelium, Vascular/cytology/drug effects/ultrastructure
MH  - Heparin/*pharmacology
MH  - Histones/*toxicity
MH  - Humans
MH  - In Vitro Techniques
MH  - Intestines/*blood supply/drug effects
MH  - Male
MH  - Microcirculation/*drug effects
MH  - Microscopy, Electron
MH  - Rats
MH  - Rats, Wistar
EDAT- 2019/08/28 06:00
MHDA- 2020/01/24 06:00
CRDT- 2019/08/28 06:00
PHST- 2019/08/28 06:00 [entrez]
PHST- 2019/08/28 06:00 [pubmed]
PHST- 2020/01/24 06:00 [medline]
AID - 01586154-201909000-00020 [pii]
AID - 10.1097/TA.0000000000002387 [doi]
PST - ppublish
SO  - J Trauma Acute Care Surg. 2019 Sep;87(3):614-622. doi: 
      10.1097/TA.0000000000002387.