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Dalteparin, a low molecular weight heparin, attenuates inflammatory responses and reduces ischemia-reperfusion-induced liver injury in rats.
Crit Care Med. 2006 Jul; 34(7):1883-91.CC

Abstract

OBJECTIVE

To examine whether dalteparin, a low molecular weight heparin, prevents hepatic damage by inhibiting leukocyte activation, we analyzed its effect on ischemia/reperfusion (I/R) injury of rat liver in which activated leukocytes play a critical role.

DESIGN

Prospective, randomized, controlled study.

SETTING

Research laboratory at a university medical center.

SUBJECTS

Male Wistar rats weighing 220-280 g.

INTERVENTIONS

Hepatic damage was evaluated by changes in serum transaminase concentrations after I/R. Coagulation abnormalities were evaluated by changes in serum concentrations of fragment E of fibrin and fibrinogen degradation products after I/R. Hepatic tissue blood flow was measured by laser-Doppler flow meter. Hepatic edema was evaluated by determination of the change in the wet/dry tissue weight ratio. Rats were intravenously injected with dalteparin or unfractionated heparin (300 units/kg) and subcutaneously injected with DX9056a, a selective inhibitor of activated factor X (3 mg/kg). To determine whether dalteparin inhibits leukocyte activation, we examined the effect of dalteparin on hepatic concentrations of interleukin-12, tumor necrosis factor-alpha, and hepatic myeloperoxidase activity after I/R in vivo. In addition, we examined increases in tumor necrosis factor-alpha production in rat monocytes and in intracellular calcium concentrations in neutrophils in vitro. We also examined the effect of dalteparin on endothelial production of prostacyclin using isolated rat hepatic sinusoidal cells in vitro.

MEASUREMENTS AND MAIN RESULTS

Intravenous administration of dalteparin inhibited increases in serum levels of both transaminases and serum concentrations of fragment E of fibrin and fibrinogen degradation products in animals subjected to hepatic I/R. Hepatic tissue blood flow after reperfusion was increased by dalteparin. Dalteparin inhibited hepatic edema, increases in hepatic tissue levels of interleukin-12 and tumor necrosis factor-alpha, and accumulation of neutrophils in animals subjected to hepatic I/R. Neither DX9065a nor unfractionated heparin showed any therapeutic effects, despite potent inhibition of increases in serum levels of fragment E of fibrin and fibrinogen degradation products. Neither monocytic tumor necrosis factor-alpha production nor neutrophil activation was inhibited by dalteparin in vitro. Dalteparin enhanced the hepatic I/R-induced increases in hepatic tissue levels of 6-keto-prostaglandin (PG) F1alpha, a stable metabolite of prostacyclin, which is capable of inhibiting monocytic tumor necrosis factor-alpha production. Pretreatment with indomethacin completely reversed both of the therapeutic effects of dalteparin, whereas pretreatment with NS-398, a selective inhibitor of cyclooxygenase-2, did not. Dalteparin did not directly increase the endothelial production of prostacyclin in vitro.

CONCLUSION

Dalteparin might reduce I/R-induced liver injury in rats by attenuating inflammatory responses. These therapeutic effects might be independent of its anticoagulant activity but dependent on its capacity to enhance endothelial production of prostacyclin via cyclooxygenase-1 activation. Furthermore, the mechanism or mechanisms by which dalteparin promotes the endothelial production of prostacyclin in vivo might involve unknown factors other than endothelial cells.

Authors+Show Affiliations

Department of Biodefense Medicine, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16641616

Citation

Harada, Naoaki, et al. "Dalteparin, a Low Molecular Weight Heparin, Attenuates Inflammatory Responses and Reduces Ischemia-reperfusion-induced Liver Injury in Rats." Critical Care Medicine, vol. 34, no. 7, 2006, pp. 1883-91.
Harada N, Okajima K, Uchiba M. Dalteparin, a low molecular weight heparin, attenuates inflammatory responses and reduces ischemia-reperfusion-induced liver injury in rats. Crit Care Med. 2006;34(7):1883-91.
Harada, N., Okajima, K., & Uchiba, M. (2006). Dalteparin, a low molecular weight heparin, attenuates inflammatory responses and reduces ischemia-reperfusion-induced liver injury in rats. Critical Care Medicine, 34(7), 1883-91.
Harada N, Okajima K, Uchiba M. Dalteparin, a Low Molecular Weight Heparin, Attenuates Inflammatory Responses and Reduces Ischemia-reperfusion-induced Liver Injury in Rats. Crit Care Med. 2006;34(7):1883-91. PubMed PMID: 16641616.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Dalteparin, a low molecular weight heparin, attenuates inflammatory responses and reduces ischemia-reperfusion-induced liver injury in rats. AU - Harada,Naoaki, AU - Okajima,Kenji, AU - Uchiba,Mitsuhiro, PY - 2006/4/28/pubmed PY - 2006/7/15/medline PY - 2006/4/28/entrez SP - 1883 EP - 91 JF - Critical care medicine JO - Crit Care Med VL - 34 IS - 7 N2 - OBJECTIVE: To examine whether dalteparin, a low molecular weight heparin, prevents hepatic damage by inhibiting leukocyte activation, we analyzed its effect on ischemia/reperfusion (I/R) injury of rat liver in which activated leukocytes play a critical role. DESIGN: Prospective, randomized, controlled study. SETTING: Research laboratory at a university medical center. SUBJECTS: Male Wistar rats weighing 220-280 g. INTERVENTIONS: Hepatic damage was evaluated by changes in serum transaminase concentrations after I/R. Coagulation abnormalities were evaluated by changes in serum concentrations of fragment E of fibrin and fibrinogen degradation products after I/R. Hepatic tissue blood flow was measured by laser-Doppler flow meter. Hepatic edema was evaluated by determination of the change in the wet/dry tissue weight ratio. Rats were intravenously injected with dalteparin or unfractionated heparin (300 units/kg) and subcutaneously injected with DX9056a, a selective inhibitor of activated factor X (3 mg/kg). To determine whether dalteparin inhibits leukocyte activation, we examined the effect of dalteparin on hepatic concentrations of interleukin-12, tumor necrosis factor-alpha, and hepatic myeloperoxidase activity after I/R in vivo. In addition, we examined increases in tumor necrosis factor-alpha production in rat monocytes and in intracellular calcium concentrations in neutrophils in vitro. We also examined the effect of dalteparin on endothelial production of prostacyclin using isolated rat hepatic sinusoidal cells in vitro. MEASUREMENTS AND MAIN RESULTS: Intravenous administration of dalteparin inhibited increases in serum levels of both transaminases and serum concentrations of fragment E of fibrin and fibrinogen degradation products in animals subjected to hepatic I/R. Hepatic tissue blood flow after reperfusion was increased by dalteparin. Dalteparin inhibited hepatic edema, increases in hepatic tissue levels of interleukin-12 and tumor necrosis factor-alpha, and accumulation of neutrophils in animals subjected to hepatic I/R. Neither DX9065a nor unfractionated heparin showed any therapeutic effects, despite potent inhibition of increases in serum levels of fragment E of fibrin and fibrinogen degradation products. Neither monocytic tumor necrosis factor-alpha production nor neutrophil activation was inhibited by dalteparin in vitro. Dalteparin enhanced the hepatic I/R-induced increases in hepatic tissue levels of 6-keto-prostaglandin (PG) F1alpha, a stable metabolite of prostacyclin, which is capable of inhibiting monocytic tumor necrosis factor-alpha production. Pretreatment with indomethacin completely reversed both of the therapeutic effects of dalteparin, whereas pretreatment with NS-398, a selective inhibitor of cyclooxygenase-2, did not. Dalteparin did not directly increase the endothelial production of prostacyclin in vitro. CONCLUSION: Dalteparin might reduce I/R-induced liver injury in rats by attenuating inflammatory responses. These therapeutic effects might be independent of its anticoagulant activity but dependent on its capacity to enhance endothelial production of prostacyclin via cyclooxygenase-1 activation. Furthermore, the mechanism or mechanisms by which dalteparin promotes the endothelial production of prostacyclin in vivo might involve unknown factors other than endothelial cells. SN - 0090-3493 UR - https://www.unboundmedicine.com/medline/citation/16641616/Dalteparin_a_low_molecular_weight_heparin_attenuates_inflammatory_responses_and_reduces_ischemia_reperfusion_induced_liver_injury_in_rats_ L2 - https://dx.doi.org/10.1097/01.CCM.0000220764.10155.03 DB - PRIME DP - Unbound Medicine ER -