| Anticoagulant protein C (PC) is an important serine protease that down-regulates thrombin generation by proteolytic cleavage of coagulation factors (F)VIIIa and FVa, cofactors that participate in the Xase and prothrombinase complexes, respectively. To analyze whether an additional deficiency in a procoagulant such as FXI alleviates the hypercoagulable state induced by a PC deficiency and hence improves the viability of these mice, PC +/- mice were crossbred with FXI-/- mice in successive rounds.; Unfortunately, only a small fraction of PC-/- FXI-/- mice survived birth which rendered them unsuitable for inflammatory-challenge studies. Subsequently, systemic and focal inflammatory responses were studied in mice with heterozygous deficiencies in PC. For this purpose, we chose the cecal ligation and puncture (CLP) model of sepsis, a systemic inflammatory response syndrome, and the copper/silicone cuff model of arterial injury and inflammation.; In the sepsis studies, a partial deficiency in protein C conferred CLP-treated mice increased mortality in comparison with treated WT mice. Plasma cytokine levels as well as cytokine expression in liver, kidney and lung were more elevated in PC+/- mice compared to WT mice at 24 hours post-CLP surgery. Additionally, renal and hepatic damage were more severe in PC+/- treated mice relative to similar WT mice.; Considering these observations and the evidence of increased granulocyte activation in FXI-/- cattle, we decided to include FXI-/- mice in the study of copper-induced arterial inflammation. As a result, arterial inflammation and cell proliferation were remarkably more elevated in FXI-/- arteries, compared to similar WT arteries, at early and late time points. However, the areas of arterial transversal sections were larger in FXI-/- arteries than in WT arteries, only in the earlier time point. These observations suggest that the initial condition of the arteries as well as the favorable pro-inflammatory state in FXI -/- arteries was important in the initiation of the arterial damage and repair. (Abstract shortened by UMI.)... |
