Danaparoid sodium reduces ischemia/reperfusion-induced liver injury in rats by attenuating inflammatory responses

Naoaki Harada; Kenji Okajima; Hidefumi Kohmura; Mitsuhiro Uchiba; Tsutomu Tomita

doi:10.1160/TH06-04-0226

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2007; 97(01): 81-87
DOI: 10.1160/TH06-04-0226

Wound Healing and Inflammation / Infection

Schattauer GmbH

Danaparoid sodium reduces ischemia/reperfusion-induced liver injury in rats by attenuating inflammatory responses

Naoaki Harada

¹Department of Biodefense Medicine, Nagoya City University Graduate School of Medical Sciences, Nagoya

,

Kenji Okajima

¹Department of Biodefense Medicine, Nagoya City University Graduate School of Medical Sciences, Nagoya

,

Hidefumi Kohmura

²Department of Diagnostic Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto

,

Mitsuhiro Uchiba

²Department of Diagnostic Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto

,

Tsutomu Tomita

³Cine-Science Laboratory Co., Ltd., Tokyo; Japan

› Author Affiliations

Abstract

Summary

This study was undertaken to examine the mechanism by which danaparoid sodium (DS), a heparinoid that contains mainly heparan sulfate, prevents reperfusion-induced hepatic damage in a rat model of ischemia/reperfusion (I/R)-induced liver injury. Administration of DS significantly reduced liver injury and inhibited the decrease in hepatic tissue blood flow in rats. DS attenuated hepatic I/R-induced increases in hepatic tissue levels of tumor necrosis factor (TNF) and myeloperoxidase (MPO) in vivo. In contrast, neither monocytic TNF production nor neutrophil activation was inhibited by DS in vitro. DS enhanced I/R-induced increases in levels of calcitonin-gene related peptide (CGRP), a neuropeptide released from sensory neurons, and of 6-ketoprostaglandin (PG) F_1α, a stable metabolite of PGI₂, in liver tissues. The therapeutic effects of DS were not seen in animals pretreated with capsazepine, an inhibitor of sensory neuron activation. The distribution of heparan sulfate in the perivascular area was significantly increased by DS administration in this rat model. DS significantly increased CGRP release from isolated rat dorsal root ganglion neurons (DRG) in vitro, while DX-9065a, a selective inhibitor of activated factor X, did not. DS enhanced anandamide-induced CGRP release from DRG in vitro. These observations strongly suggested that DS might reduce I/R-induced liver injury in rats by attenuating inflammatory responses. These therapeutic effects of DS might be at least partly explained by its enhancement of sensory neuron activation, leading to the increase the endothelial production of PGI₂.

Keywords

Capsaicin-sensitive sensory neurons - Calcitonin-gene related peptide - TNF

Full Text

References

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