Neutrophil-endothelial interactions and barrier function in sepsis

描述(由申请人提供)：败血症仍然是ICU死亡的主要原因。死亡的根本原因可以直接追溯到多系统器官衰竭，这是由供应这些器官的血管系统受损引起的。血管损伤的部分原因是白细胞与内皮细胞的相互作用不受控制。设计一种以免疫为中心的干预措施的挑战是避免完全抑制。尽管出现了全身炎症，但使用皮质类固醇的试验都失败了。需要一种更有针对性和更深思熟虑的方法。脓毒症时炎症反应过度的一个共同特征是中性粒细胞在肝、肾、脑、脾和肺等器官的微血管内积聚，导致细胞介导的组织损伤和器官衰竭。导致中性粒细胞在血管中积聚，进而损害屏障功能的潜在机制尚不清楚。最重要的假设是，保护血管内皮细胞免受中性粒细胞激活引起的损伤将促进血管内稳态的恢复，进而保护实质免受过度侵袭性炎症反应的影响。我们将(1)确定脓毒症时内皮细胞糖帽层调节中性粒细胞-内皮细胞相互作用的机制，(2)研究中性粒细胞衍生的微粒是否保护内皮屏障功能，以及(3)研究 中性粒细胞滞留是否有助于血管基底膜的损伤，以及是否与屏障功能丧失所致的血管通透性有关。如果中性粒细胞的迁移和脱颗粒活动得到控制而不被排除，就会对感染/损伤产生更具生理性的反应。因此，了解如何通过控制中性粒细胞外溢来控制血管损伤在包括脓毒症在内的许多急/慢性炎症环境中具有潜在的应用。

DESCRIPTION (provided by applicant): Sepsis continues to be a leading cause of mortality in the ICU. The root cause of mortality can be traced directly to multisystem organ failure caused by damage to the vasculature that supplies these organs. Vascular damage is due in part to uncontrolled leukocyte interaction with endothelium. The challenge in designing an immuno-centric intervention is to avoid complete suppression. In spite of systemic hyper-inflammation, trials using corticosteroids have failed. A more targeted and deliberate approach is needed. A common feature of the exaggerated inflammatory response during sepsis is the accumulation of activated neutrophils within the microvasculature of organs such as liver, kidney, brain, spleen and lung leading to cell mediated tissue damage and organ failure. The underlying mechanisms that lead to the accumulation of neutrophils in the vasculature with ensuing damage to barrier function are not known. The overarching hypothesis is that protection of the vascular endothelium from the damage induced by the activated neutrophils will facilitate a return to vascular homeostasis and in turn protect the parenchyma from an excessive invasive inflammatory response. We will (1) determine the mechanisms by which the endothelial glycocalyx layer regulates neutrophil-endothelial cell interaction during sepsis, (2) investigate whether neutrophil-derived microparticles protect endothelial barrier function, and (3) investigate whether neutrophil diapedesis contributes to damage of the vascular basement membrane and is associated vascular permeability due to a loss of barrier function. If transmigration and degranulatory activities of neutrophils were controlled without being obviated, a more physiological response to infection/injury would ensue. Thus, understanding how to control vascular damage through manipulation of neutrophil extravasation has potential applications in many acute/chronic inflammatory settings including sepsis.