Unfractionated Heparin Protects the Protein C System Against Lipopolysaccharide-induced Damage and

Overview

Journal Exp Ther Med

Specialty Pathology

Date 2017 Dec 30

PMID 29285085

Citations 2

Authors

Dongmei Zhao

Renyu Ding

Yina Liu

Xiaohan Yin

Zhidan Zhang

Xiaochun Ma

Affiliations

Soon will be listed here.

Abstract

Activation of protein C is greatly enhanced by the presence of thrombomodulin (TM) and endothelial protein C receptor (EPCR) on the endothelial surface. Impairment of the anticoagulant protein C system occurs during endotoxemia and contributes to sepsis-associated hypercoagulability. Previous studies have demonstrated that unfractionated heparin (UFH) can attenuate coagulation in endotoxemic mice. However, whether UFH has an effect on the protein C system remains to be elucidated. The current study evaluated the therapeutic effect of UFH on the protein C system in a mouse model of lipopolysaccharide (LPS)-induced sepsis, and further investigated the effect of UFH on the expression of TM and EPCR using human umbilical vein endothelial cells (HUVECs). The data indicated that UFH preconditioning attenuated the decline in circulating activated protein C following LPS administration, and also reduced LPS-induced shedding of TM and EPCR. In HUVECs, LPS stimulation led to the downregulation of TM and EPCR expression, and UFH dose-dependently restored the mRNA and protein levels of TM and EPCR. In addition, UFH inhibited the LPS-induced activation of mitogen-activated protein kinase 14, proto-oncogene tyrosine-protein kinase Src and nuclear factor κB signaling in HUVECs. In summary, these results suggest that UFH has a protective effect on the protein C system during sepsis. Thus, UFH may be a candidate therapeutic agent for the treatment of patients with sepsis.

Citing Articles

Un-fractionated heparin counteracts the systemic inflammatory responses and multiple organ damages caused by endotoxaemia in sheep.

Ashareyoun H, Chalmeh A, Pourjafar M Vet Med Sci. 2022; 8(3):1187-1196.

PMID: 34978390 PMC: 9122390. DOI: 10.1002/vms3.720.

Both UFH and NAH alleviate shedding of endothelial glycocalyx and coagulopathy in LPS-induced sepsis.

Huang X, Han S, Liu X, Wang T, Xu H, Xia B Exp Ther Med. 2020; 19(2):913-922.

PMID: 32010252 PMC: 6966138. DOI: 10.3892/etm.2019.8285.

References

Ding R, Zhao D, Guo R, Zhang Z, Ma X . Treatment with unfractionated heparin attenuates coagulation and inflammation in endotoxemic mice. Thromb Res. 2011; 128(6):e160-5. DOI: 10.1016/j.thromres.2011.07.044. View

Li X, Zheng Z, Mao Y, Ma X . Unfractionated heparin promotes LPS-induced endothelial barrier dysfunction: a preliminary study on the roles of angiopoietin/Tie2 axis. Thromb Res. 2012; 129(5):e223-8. DOI: 10.1016/j.thromres.2012.03.003. View

Faioni E, Fontana G, Razzari C, Avagliano L, Bulfamante G, Calvi E . Activation of Protein C in Human Trophoblasts in Culture and Downregulation of Trophoblast Endothelial Protein C Receptor by TNF-α. Reprod Sci. 2015; 22(8):1042-8. DOI: 10.1177/1933719115570904. View

Schouten M, Wiersinga W, Levi M, van der Poll T . Inflammation, endothelium, and coagulation in sepsis. J Leukoc Biol. 2007; 83(3):536-45. DOI: 10.1189/jlb.0607373. View

Lo I, Lin T, Chou L, Liu S, Wu L, Shi G . Ets-1 mediates platelet-derived growth factor-BB-induced thrombomodulin expression in human vascular smooth muscle cells. Cardiovasc Res. 2008; 81(4):771-9. DOI: 10.1093/cvr/cvn351. View

Terada Y, Eguchi Y, Nosaka S, Toba T, Nakamura T, Shimizu Y . Capillary endothelial thrombomodulin expression and fibrin deposition in rats with continuous and bolus lipopolysaccharide administration. Lab Invest. 2003; 83(8):1165-73. DOI: 10.1097/01.lab.0000080606.96797.a5. View

Livak K, Schmittgen T . Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2002; 25(4):402-8. DOI: 10.1006/meth.2001.1262. View

Ishii H, Uchiyama H, Kazama M . Soluble thrombomodulin antigen in conditioned medium is increased by damage of endothelial cells. Thromb Haemost. 1991; 65(5):618-23. View

Esmon C . The protein C pathway. Chest. 2003; 124(3 Suppl):26S-32S. DOI: 10.1378/chest.124.3_suppl.26s. View

10.

Gao X, Xu X, Pan R, Li Y, Luo Y, Xia Y . Saponin fraction from Astragalus membranaceus roots protects mice against polymicrobial sepsis induced by cecal ligation and puncture by inhibiting inflammation and upregulating protein C pathway. J Nat Med. 2009; 63(4):421-9. DOI: 10.1007/s11418-009-0348-2. View

11.

Fowler R, Hill-Popper M, Stasinos J, Petrou C, Sanders G, Garber A . Cost-effectiveness of recombinant human activated protein C and the influence of severity of illness in the treatment of patients with severe sepsis. J Crit Care. 2003; 18(3):181-91. DOI: 10.1016/j.jcrc.2003.08.009. View

12.

Annane D, Bellissant E, Cavaillon J . Septic shock. Lancet. 2005; 365(9453):63-78. DOI: 10.1016/S0140-6736(04)17667-8. View

13.

Cohen J . The immunopathogenesis of sepsis. Nature. 2002; 420(6917):885-91. DOI: 10.1038/nature01326. View

14.

Levi M, van der Poll T, Buller H . Bidirectional relation between inflammation and coagulation. Circulation. 2004; 109(22):2698-704. DOI: 10.1161/01.CIR.0000131660.51520.9A. View

15.

Li X, Zheng Z, Li X, Ma X . Unfractionated heparin inhibits lipopolysaccharide-induced inflammatory response through blocking p38 MAPK and NF-κB activation on endothelial cell. Cytokine. 2012; 60(1):114-21. DOI: 10.1016/j.cyto.2012.06.008. View

16.

Marti-Carvajal A, Sola I, Gluud C, Lathyris D, Cardona A . Human recombinant protein C for severe sepsis and septic shock in adult and paediatric patients. Cochrane Database Syst Rev. 2012; 12:CD004388. PMC: 6464614. DOI: 10.1002/14651858.CD004388.pub6. View

17.

Song D, Ye X, Xu H, Liu S . Activation of endothelial intrinsic NF-{kappa}B pathway impairs protein C anticoagulation mechanism and promotes coagulation in endotoxemic mice. Blood. 2009; 114(12):2521-9. PMC: 2746475. DOI: 10.1182/blood-2009-02-205914. View

18.

Cornet A, Smit E, Beishuizen A, Groeneveld A . The role of heparin and allied compounds in the treatment of sepsis. Thromb Haemost. 2007; 98(3):579-86. View

19.

Zarychanski R, Abou-Setta A, Kanji S, Turgeon A, Kumar A, Houston D . The efficacy and safety of heparin in patients with sepsis: a systematic review and metaanalysis. Crit Care Med. 2014; 43(3):511-8. DOI: 10.1097/CCM.0000000000000763. View

20.

Mu E, Ding R, An X, Li X, Chen S, Ma X . Heparin attenuates lipopolysaccharide-induced acute lung injury by inhibiting nitric oxide synthase and TGF-β/Smad signaling pathway. Thromb Res. 2011; 129(4):479-85. DOI: 10.1016/j.thromres.2011.10.003. View