Treatment with unfractionated heparin attenuates coagulation and inflammation in endotoxemic mice

摘要

Introduction: In the pathogenesis of sepsis, inflammation and coagulation play a pivotal role. In addition to the anticoagulant activity, unfractionated heparin (UFH) has important immunomodulatory properties. However, different studies have reported conflicting effects on sepsis in association with heparin. The objective of this study is to determine whether UFH is able to reduce endotoxin-induced inflammation and coagulation in mice or produce improved outcome. Methods: C57BL/6 J mice were randomly divided into two groups. Experimental mice were given intravenous injection of 8 units/20 g body weight UFH (heparin sodium) diluted in 20 μl sterile saline while the control mice received vehicle sterile saline only. They were injected with LPS (30 mg/kg, i.p.) 0.5 h later. Blood was collected and Livers were harvested at 3 and 6 h for analysis. In survival studies, a separate group of mice were treated with 8 units/20 g UFH (n = 20) or sterile saline (n = 20) given intravenously at 1, 12, 24 and 36 hours after LPS injection. Mice were monitored every 12 hours for a maximum of 72 hrs. Results: 1) Pretreatment of mice with UFH strongly reduced the levels of TNF-α, IL-1β and TAT in plasma at 3 and 6 h; 2) Pretreatment of mice with UFH inhibited the expression of TNF-α, IL-1β and tissue factor genes in blood cells at 3 h; 3) UFH pretreatment dramatically diminished LPS-induced neutrophil sequestration (at 3 and 6 h), thrombi formation and fibrin(ogen) deposition in the liver (at 6 h). 4) The UFH-pretreated group exhibited significantly lower levels of ALT and CRE at 6 h. 5) Treatment with UFH could prevent mortality associated with endotoxin challenge. Conclusion: These data suggest that UFH attenuates inflammation and coagulation and prevents lethality in endotoxemic mice.