Abstract
Introduction
Levels of extracellular histones are highly increased in sepsis and may facilitate
microcirculatory dysfunction. Unfractionated heparin (UFH) binds histones and neutralizes
their cytotoxicity. We investigated the effect of UFH on microcirculatory dysfunction
by interacting with extracellular histones in endotoxemic rats.
Methods
Twenty-four Wistar rats were randomly divided into three groups: control, lipopolysaccharide
(LPS) group, and LPS + UFH group. In the LPS and LPS + UFH groups, 10 mg/kg LPS was
injected to induce endotoxemia, and 100 IU/kg/h UFH was administered intravenously
in the LPS + UFH group. The rats underwent midline laparotomy, and then intestinal
microcirculation was evaluated using an incident dark field microscope. Circulating
histones and microstructures of the rat intestinal microvascular endothelium were
also detected. Additionally, the antagonistic effect of UFH on histone-induced cytotoxicity
was investigated in human intestinal microvascular endothelial cells.
Results
UFH protected the microcirculation of the intestinal serosa and mucosa in endotoxemic
rats, as evidenced by increased total vessel density, perfused vessel density, and
proportion of perfused vessels of both the serosa and mucosa, and increased microcirculatory
flow index of the mucosa in the LPS + UFH group. UFH treatment decreased the levels
of circulating histones and alleviated intestinal microvascular endothelial injuries
in endotoxemic rats. Furthermore, UFH inhibited histone cytotoxicity in vitro.
Conclusions
UFH attenuated microcirculatory dysfunction in endotoxemic rats by antagonizing extracellular
histones, thereby providing a potential therapeutic strategy for sepsis.
Keywords
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Article info
Publication history
Published online: October 15, 2022
Accepted:
September 3,
2022
Received in revised form:
August 11,
2022
Received:
May 12,
2022
Identification
Copyright
© 2022 Elsevier Inc. All rights reserved.
