Neutrophil-endothelial interactions and barrier function in sepsis

描述（由申请人提供）：脓毒症仍然是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。血管损伤部分是由于不受控制的白细胞与内皮的相互作用。设计以免疫为中心的干预措施的挑战是避免完全抑制。尽管全身性炎症过度，使用皮质类固醇的试验失败了。需要采取更有针对性和更慎重的办法。脓毒症期间过度炎症反应的共同特征是激活的嗜中性粒细胞在器官如肝、肾、脑、脾和肺的微脉管系统内的积累，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系统中积聚并随后损害屏障功能的潜在机制尚不清楚。总体假设是，保护血管内皮免受活化的中性粒细胞诱导的损伤将促进血管稳态的恢复，进而保护实质免受过度侵入性炎症反应的影响。我们将（1）确定脓毒症期间内皮糖萼层调节嗜酸性粒细胞-内皮细胞相互作用的机制，（2）研究嗜酸性粒细胞衍生的微粒是否保护内皮屏障功能，以及（3）研究 中性粒细胞渗出是否有助于血管基底膜的损伤，是否与由于屏障功能丧失引起的血管通透性有关。如果中性粒细胞的移行和脱颗粒活性得到控制而不被消除，那么对感染/损伤的生理反应将随之而来。因此，了解如何通过操纵中性粒细胞外渗来控制血管损伤在许多急性/慢性炎症环境（包括脓毒症）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.