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, Inhaltsverzeichnis

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

Authors

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

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

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Referenzen

References
1 Fujishima Y, Yokota K, Sukamoto T. The effect of danaparoid sodium (danaparoid) on endotoxin-induced experimental disseminated intravascular coagulation (DIC) in rats. Thromb Res 1998; 91: 221-7.
2 Ishida M, Nakada Y, Horiuchi M. et al Pharmacokinetics of danaparoid sodium, dalteparin sodium and heparin determined by inhibitory effect on the activated coagulation factor X activity after single intravenous administration in rabbits. Arzneimittelforschung 1998; 48: 818-21.
3 Okajima K, Sakamoto Y, Uchiba M. Heterogeneity in the incidence and clinical manifestations of disseminated intravascular coagulation: a study of 204 cases. Am J Hematol 2000; 65: 215-22.
4 Okajima K. Regulation of inflammatory responses by natural anticoagulants. Immunol Rev 2001; 184: 258-74.
5 Hasselgren PO. Prevention and treatment of ischemia of the liver. Surg Gynecol Obstet 1987; 164: 187-96.
6 Keller GA, West MA, Cerra FB. et al Macrophagemediated modulation of hepatic function in multi-system failure. J Surg Res 1985; 39: 555-63.
7 Campbell EJ, Senior RM, McDonald JA. et al Proteolysis by neutrophils. Relative importance of cellsubstrate contact and oxidative inactivation of proteinase inhibitors in vitro. J Clin Invest 1982; 70: 845-52.
8 Carlos TM, Harlan JM. Leukocyte-endothelial adhesion molecules. Blood 1994; 84: 2068-101.
9 Okajima K, Harada N, Kushimoto S. et al Role of microthrombus formation in the development of ischemia/ reperfusion-induced liver injury in rats. Thromb Haemost 2002; 88: 473-80.
10 Okajima K, Harada N, Uchiba M. et al Neutrophil elastase contributes to the development of ischemiareperfusion-induced liver injury by decreasing endothelial production of prostacyclin in rats. Am J Physiol Gastrointest Liver Physiol 2004; 287: G1116-23.
11 Harada N, Okajima K, Kushimoto S. et al Antithrombin reduces ischemia/reperfusion injury of rat liver by increasing the hepatic level of prostacyclin. Blood 1999; 93: 157-64.
12 Hayashi H, Chaudry IH, Clemens MG. et al Hepatic ischemia models for determining the effects of ATP-MgCl2 treatment. J Surg Res 1986; 40: 167-75.
13 Harada N, Okajima K, Kushimoto S. Gabexate mesilate, a synthetic protease inhibitor, reduces ischemia/ reperfusion injury of rat liver by inhibiting leukocyte activation. Crit Care Med 1999; 27: 1958-64.
14 Kushimoto S, Okajima K, Uchiba M. et al Role of granulocyte elastase in ischemia/reperfusion injury of rat liver. Crit Care Med 1996; 24: 1908-12.
15 Shito M, Wakabayashi G, Ueda M. et al Interleukin 1 receptor blockade reduces tumor necrosis factor production, tissue injury, and mortality after hepatic ischemia-reperfusion in the rat. Transplantation 1997; 63: 143-8.
16 Warren JS, Yabroff KR, Remick DG. et al Tumor necrosis factor participates in the pathogenesis of acute immune complex alveolitis in the rat. J Clin Invest 1989; 84: 1873-82.
17 Akiyoshi H, Gonda T, Terada T. A comparative histochemical and immunohistochemical study of aminergic, cholinergic and peptidergic innervation in rat, hamster, guinea pig, dog and human livers. Liver 1998; 18: 352-9.
18 Harada N, Okajima K, Yuksel M. et al Contribution of capsaicin-sensitive sensory neurons to antithrombin-induced reduction of ischemia/reperfusion-induced liver injury in rats. Thromb Haemost 2005; 93: 48-56.
19 Watanabe K, Konishi K, Fujioka M. et al The neutrophil chemoattractant produced by the rat kidney epitheloid cell line NRK-52E is a protein related to the KV/gro protein. J Biol Chem 1989; 264: 19559-63.
20 Nakajima K, Powers JC, Ashe BM. et al Mapping the extended substrate binding site of cathepsin G and human leukocyte elastase. Studies with peptide substrates related to the alpha 1-protease inhibitor reactive site. J Biol Chem 1979; 254: 4027-32.
21 Molor-Erdene P, Okajima K, Isobe H. et al Urinary trypsin inhibitor reduces LPS-induced hypotension by suppressing tumor necrosis factor-? production through inhibition of Egr-1 expression. Am J Physiol Heart Circ Physiol 2005; 288: H1265-71.
22 Eisenhut T, Sinha B, Grottrup-Wolfers E. et al Prostacyclin analogs suppress the synthesis of tumor necrosis factor-? in LPS-stimulated human peripheral blood mononuclear cells. Immunopharmacology 1993; 26: 259-64.
23 Kainoh M, Imai R, Umetsu T. et al Prostacyclin and beraprost sodium as suppressors of activated rat polymorphonuclear leukocytes. Biochem Pharmacol 1990; 39: 477-84.
24 Harada N, Okajima K, Uchiba M. et al Ischemia/ reperfusion-induced increase in the hepatic level of prostacyclin is mainly mediated by activation of capsaicin-sensitive sensory neurons in rats. J Lab Clin Med 2002; 139: 218-26.
25 Tognetto M, Amadesi S, Harrison S. et al Anandamide excites central terminals of dorsal root ganglion neurons via vanilloid receptor-1 activation. J Neurosci 2001; 21: 1104-1109.
26 Sedgwick JD, Riminton DS, Cyster JG. et al Tumor necrosis factor: a master-regulator of leukocyte movement. Immunol Today 2000; 21: 110-3.
27 Okajima K, Harada N. Regulation of inflammatory responses by sensory neurons: molecular mechanism (s) and possible therapeutic applications. Curr Med Chem 2006; 13: 2241-51.
28 Okajima K, Harada N, Uchiba M. Microthrombus formation enhances tumor necrosis factorα production in the development of ischemia/reperfusion-induced liver injury in rats. J Thromb Haemost 2003; 1: 1316-7.