Unfractionated heparin protects the protein C system against lipopolysaccharide‑induced damage in vivo and in vitro

Abstract

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 in vitro using human umbilical vein endothelial cells (HUVECs). The in vivo 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.

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

“…In the present study, in rats with LPS-induced sepsis, plasma inflammation cytokines indicated a positive correlation with coagulation parameters. Previous studies have demonstrated that heparin decreased the levels of the inflammatory cytokines TNF-α, IL-6, IL-8 and IL-1β in an LPS-induced sepsis model (15,19,22). Similar results were indicated in the present study, which demonstrated that preconditioning with NAH or UFH inhibited the LPS-induced cytokines of TNF-α and IL-6.…”

“…The primary organ affected during sepsis is the lung (14). Previous studies have demonstrated that UFH and NAH may decrease the severity of sepsis-associated acute lung injury and lethality in LPS-induced mice (17,19,22). Therefore, pulmonary histopathology was examined using hematoxylin and eosin staining and lung injury score to assess the protective effect of UFH and NAH ( Fig.…”

Sustenance of endothelial cell stability in septic mice through appropriate activation of transient receptor potential vanilloid-4

“…The expressions of TM and EPCR are almost exclusive to vascular endothelial cells, and increased levels of sTM and sEPCR serve as markers of endothelial injury in sepsis (11). In our study, the concentrations of sTM and sEPCR in LPS+2.5HC mice group were the lowest among the 12.5 mg/kg LPS-treated mice groups.…”

“…This suggests that vascular endothelial cell injury in LPS+2.5HC was milder than the degree of injury in any of the other LPS-treated mice. Furthermore, in normal situations, the endothelial cell layer provides an anticoagulant surface by expressing TM and EPCR, and supports thrombin to generate activated protein C (APC) that limits the progression of the coagulation cascade (11,12). The endothelial surface is cleaved by elastase to liberate EPCR and TM during sepsis; the resultant sTM and sEPCR can also bind APC, but they inhibit its anticoagulant activity (11).…”

Heparanized chitosans: towards the third generation of chitinous biomaterials

“…Most of its potential applications seem to be associated with its anti-inflammatory effects, 41 as well as its interactions with a multitude of proteins. 42 It also inhibits different enzymes involved in pathologic processes, such as heparanase 43 and metalloproteases, 44 and also acts as a heparan sulfate mimic.…”