Neutrophil-endothelial interactions and barrier function in sepsis

脓毒症中中性粒细胞-内皮相互作用和屏障功能

基本信息

批准号：
8799334
负责人：
Minsoo Kim
金额：
$ 78.63万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-15 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8799334
关键词：
Acute Adhesions Adrenal Cortex Hormones Adult Apical Authorship Basement membrane Biochemical Biological Blood Platelets Blood Vessels Brain Cell Communication Cell Survival Cells Cellular biology Child Chronic Critical Care Data Deposition Dimensions Endothelial Cells Endothelium Event Extravasation Failure Functional disorder Funding Glycocalyx Homeostasis Host Defense Human Individual Infection Infiltration Inflammation Inflammatory Inflammatory Response Injury Integrin alpha3beta1 Integrins Intervention Kidney Laboratories Lead Leukocytes Liver Lung Measures Mediating Membrane Modeling Molecular Morbidity - disease rate Mus Neutrophil Infiltration Organ Organ failure Pathogenesis Patients Penetration Permeability Phenotype Physiological Plant Roots Plasma Cells Principal Investigator Process Regulation Research Personnel Role Sepsis Side Spleen Stimulus Stretching Subendothelial Layer System Testing Therapeutic Time Tissues Vascular Endothelium Vascular Permeabilities body system cell growth combinatorial design experience insight migration monolayer mortality neutrophil new therapeutic target novel physical property response seal septic

项目摘要

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.

描述（由申请人提供）：败血症仍然是ICU死亡率的主要原因。死亡率的根本原因可以直接追溯到由供应这些器官的脉管系统损坏引起的多系统器官故障。血管损伤部分是由于与内皮的不受控制的白细胞相互作用。设计以免疫为中心的干预措施的挑战是避免完全抑制。尽管有全身性高炎症，但使用皮质类固醇的试验仍失败了。需要采取更有针对性和故意的方法。败血症期间夸张的炎症反应的一个共同特征是肝脏，肾脏，脑，脑，脾脏和肺等器官微举行的中性粒细胞的积累，导致细胞介导的组织损伤和器官衰竭。尚不清楚导致中性粒细胞在脉管系统中积累并随之而来的屏障功能损害的基本机制。总体假设是，保护血管内皮免受激活中性粒细胞造成的损害的保护将有助于恢复血管稳态，进而保护实质免受过度浸润性炎症反应。我们将（1）确定内皮糖脂层调节败血症期间中性粒细胞 - 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（3）中性粒细胞二尿作用是否有助于血管基底膜的损害，并且由于屏障功能的丧失而与血管渗透性相关。如果控制中性粒细胞的迁移和递增活性而没有被消除，则会对感染/损伤产生更生理的反应。因此，了解如何通过操纵中性粒细胞渗出来控制血管损伤具有潜在的应用在包括败血症在内的许多急性/慢性炎症环境中。