脓毒症是ICU患者最主要的死亡原因，主要特点是炎症刺激下的微循环功能障碍，其病理生理过程分成两部分：由于高凝状态导致的血栓形成和血管内皮细胞功能障碍。脓毒症时内皮细胞发生活化，生成促凝及抑制纤溶物质增多，且白细胞和血小板滚动并粘附到受损的内皮细胞表面，从而炎症和凝血相互作用，并形成恶性循环，最终导致微血管栓塞和组织循环状态恶化，因此血管内皮细胞在脓毒症的发生发展过程中起到关键作用。近年研究表明早期血栓形成参与机体防御病原菌的免疫过程，使病原菌局限于感染部位，称为免疫血栓，其中NET起到关键作用，但免疫血栓大量形成导致微循环功能障碍。肝素具有抗炎和抗凝作用，但是否对NET及免疫血栓有作用，以及具体应用时机并不清楚。因此，本研究以脓毒症实验小鼠为研究对象，并进行细胞研究，从分子水平探讨脓毒症过程中NET及组蛋白对肺脏炎症和凝血的影响，以及肝素的作用机制和时机，旨在为脓毒症患者救治提供理论依据。

Sepsis is the main cause of death in the ICU and microvascular dysfunction plays a pivotal role in the development of multiple organ dysfunction syndrome in sepsis. The basic pathogenesis of microcirculatory dysfunction can be divided into two parts: microthrombi formation and endothelial dysfunction.When infectious bacteria invade the bloodstream, systemic activation of inflammation leads to cytokine release and endothelial activation and dysfunction, resulting in production of pro-coagulant mediators and platelet adhesion to the subendothelial surface. Thus, the close interplay between inflammation and coagulation results in microvascular occlusion and tissue microcirculatory failure. Thus endothelial cells play a central role in the poor prognosis of sepsis. Recent studies indicate that thrombosis plays a major role in early immune defense against invading pathogens in sepsis. This defensive role of thrombosis is now referred as immunothrombosis which limits invading pathogen to local site. Although NET-mediated immunothrombosis plays a role in early host defense against bacterial dissemination, uncontrolled immunothrombosis may lead to microcirculatory dysfunction. Heparin has the combined effects of anticoagulation and anti-inflammation for the treatment of sepsis, but whether it has effects on NET and immunothrombosis is not clear. And what's the proper initiation time for heparin in sepsis needs to be evaluated. Thus, we investigated the toxic effects of NET and histone on pulmonary endothelial cells in septic mice in vivo and in vitro. We also examined the mechanism of protective effects of heparin and the proper initiation time to provide theoretical basis for the treatment of septic patients.