Hemostasis System in Acute Inflammation-Sepsis

炎症和止血之间有很强的关系，这是基于对促炎环境也是促凝剂的理解。导致在急性炎症状态下产生因子(F) vla /组织因子（TF）复合物的事件，如革兰氏阴性脓毒症，始于内毒素介导的白细胞和内皮细胞活化，以及这些改变细胞的细胞因子和趋化因子上调，以及TF的表达。随后产生的促凝剂，凝血酶和FXa，通过这些蛋白酶与蛋白酶激活的细胞受体的相互作用启动信号通路，从而介导进一步的细胞（如血小板、内皮细胞、白细胞）反应，这些反应涉及血液凝固、炎症和血管形成。这些细胞的活化也导致其表面粘附分子的表达，因此

There is a strong relationship between inflammation and hemostasis that is based on the understanding that a proinflammatory environment is also procoagulant. Events that lead to the generation of the Factor (F) Vlla/Tissue Factor (TF) complex in an acute inflammatory state, such as gram-negative sepsis, begin with endotoxin-mediated activation of ieukocytes and endothelial cells, and cytokine and chemokine upregulation from these altered cells, along with expression of TF. The consequent generation of the procoagulants, thrombin and FXa, initiates signaling pathways via interactions of these proteases with protease activated cellular receptors, and thus mediate further cellular (e.g., platelet, endothelial cell, leukocyte) responses that are involved in blood coagulation, as well as inflammation and vessel formation. The activation of these cells also results in the expression of adhesion molecules on their surfaces, thereby facilitating leukocyte binding to the endothelium. This interaction is the first step in ultimate extravasation of neutrophils and macrophages into organs, thereby causing severe organ damage in the advanced septic state. Thus, it is our basic hypothesis that attenuation of inflammation may result from inhibition of coagulation and vice versa, and sepsis models using appropriate gene-targeted mice will allow an understanding of these relationships in vivo at the level of the gene. The overall goal of this proposal is to dissect the in vivo relationships between individual genes of hemostasis and inflammation that occur in an acute model of the serious inflammatory disease, gram-negative sepsis, with its progression to severe sepsis and septic shock. Mice with single and combined genetic alterations in the pathways of hemostasis will be employed with endotoxin (LPS)-mediated models of sepsis in order to monitor the relationships between hemostasis and inflammation in the progression of the disease. Specifically, 5 highly interconnected specific aims are proposed: (1) to employ mice (and isolated endothelial cells and adherent macrophages) with genetic alterations of specific hemostasis-related genes in examining the progression of induced sepsis to severe sepsis and septic shock, and ultimate survival; (2) to assess temporal responses, after injection of LPS, of the systemic coagulation, anticoagulation, and fibrinolytic systems in these genotypically-distinct mice; (3) to measure in these same mice, the temporal plasma and organ responses of specific cytokines, chemokines, soluble adhesion proteins, and other inflammatory mediators; (4) to determine the temporal nature of organ and cell damage in tissue slices in these mice after LPS administration; and (5) to employ additional mice with combined deficiencies of hemostasis- and inflammation-related genes to further understand the in vivo mechanisms involved in their sepsis-related effects. It is expected that the results of this study will allow an in vivo evaluation of the roles of specific hemostasis- and inflammation-related genes in the development and course of this model of acute inflammatory disease, and will provide groundwork for therapeutic interventions to attenuate the morbidity and mortality associated with its downward progression.