Endothelial glycocalyx reconstitution during sepsis

脓毒症期间的内皮糖萼重建

基本信息

批准号：
8803172
负责人：
ROBERT J LINHARDT
金额：
$ 69.7万
依托单位：
UNIVERSITY OF COLORADO DENVER
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/8803172
关键词：
Address Adhesions Animal Model Animals Attenuated Binding Blood Vessels Cell Adhesion Molecules Cells Characteristics Chemistry Cleaved cell Clinical Trials Collaborations Colorado Complement Complex Critical Care Critical Illness Data EXT1 protein Endothelial Cells Endothelium Etiology Extravasation FGFR2 gene Failure Fibroblast Growth Factor Fibroblast Growth Factor 2 Fibroblast Growth Factor Receptor 2 Fibroblast Growth Factor Receptors Figs - dietary Functional disorder Future Gatekeeping Gene Silencing Genetic Glycobiology Glycocalyx Glycosaminoglycans Goals Grant Heparitin Sulfate Homeostasis Human In Vitro Infection Inflammation Inflammatory Response Injury Institutes Intervention Investigation Kidney Laboratories Ligation Lipopolysaccharides Lung Maintenance Mediating Mus National Heart, Lung, and Blood Institute Organ Pathogenesis Patients Plasma Pneumonia Process Property Proteoglycan Pulmonary Circulation Pulmonary Edema Puncture procedure Recovery Resolution Respiratory physiology Sampling Sepsis Signal Transduction Stimulus Surface Techniques Testing Therapeutic Universities Vascular Permeabilities base effective therapy glycosyltransferase in vivo intravital imaging intravital microscopy lung injury mortality mouse model multidisciplinary neutrophil new therapeutic target novel novel therapeutic intervention overexpression prevent reconstitution repaired response septic sugar transcription factor

项目摘要

DESCRIPTION (provided by applicant): Since the original descriptions of "putrefaction" by Hippocrates, sepsis has been recognized as a major cause of human suffering and mortality. Despite major advances made in understanding the systemic inflammatory response to infection, clinical trials of sepsis therapeutics have been repeatedly disappointing. These failure highlight the need for new, multidisciplinary perspectives into the onset, progression, and resolution of septic organ injury. The endothelial glycocalyx is a layer of glycosaminoglycans and associated proteoglycans lining the vascular surface. In vivo, the glycocalyx forms a substantial endothelial surface layer (ESL) that influences inflammation, endothelial permeability, and vascular tone-biologic processes highly relevant to sepsis pathophysiology. We have recently identified that the pulmonary ESL, by regulating exposure of endothelial surface adhesion molecules, serves a gatekeeping function controlling neutrophil transit into the lung. In response to an infectious stimulus, activated endothelial cells cleave the pulmonary ESL, allowing neutrophil adhesion and subsequent extravasation. Teleologically, this gatekeeping function would additionally require precise cellular control of ESL reconstitution, thereby limiting the magnitude of pulmonary inflammation. These processes of ESL repair, despite therapeutic relevance to patients with sepsis, have been unexplored. We hypothesize that a degraded pulmonary ESL is rapidly reconstituted in otherwise-healthy mice, allowing for maintenance of pulmonary vascular homeostasis. During sepsis, ESL reconstitution is delayed, contributing to the excessive pulmonary inflammation and edema characteristic of septic lung injury. Using state-of-the-art pulmonary intravital microscopy (E. Schmidt, Pulmonary/Critical Care, University of Colorado) and glycomic (R. Linhardt, Chemistry, Rensselaer Polytechnic Institute) approaches, we propose to (1) determine the mechanisms underlying pulmonary ESL reconstitution, (2) identify how these mechanisms are suppressed during sepsis, and (3) therapeutically manipulate these mechanisms to accelerate ESL reconstitution and attenuate septic lung injury. These multidisciplinary investigations, representing a highly novel collaboration within the field of sepsis, will be complemented by animal models of septic lung injury as well as analyses of biologic samples obtained from humans with severe sepsis. In summary, this proposal offers a new, multidisciplinary perspective on sepsis: that ESL integrity is a critical determinant of the onset and progression of septic organ injury. Investigating processes of ESL reconstitution may therefore identify novel therapeutic targets in a critical illness that, despite millennia of study, still lacks a clinically-efficacious, pathophysiology-targeted treatment.

描述（由申请人提供）：由于希波克拉底对“腐烂”的原始描述，败血症被认为是人类痛苦和死亡的主要原因。尽管在理解了对感染的系统性炎症反应方面取得了重大进展，但败血症治疗剂的临床试验反复令人失望。这些失败凸显了对化粪池损伤的发作，进展和解决方案的新的，多学科的观点的需求。内皮糖卵形是糖胺聚糖和血管表面衬里的相关蛋白聚糖的一层。在体内，糖脂形成了一个实质性的内皮表面层（ESL），影响炎症，内皮渗透性和血管张力生物学过程与脓毒症病理生理非常相关。我们最近已经确定，通过调节内皮表面粘附分子的暴露，肺ESL具有控制嗜中性粒细胞转移到肺部的栅极功能。为了响应传染性刺激，活化的内皮细胞裂解肺ESL，从而使中性粒细胞粘附和随后的渗出。从目的论上讲，该守门功能还需要精确的ESL重建的细胞控制，从而限制了肺部炎症的大小。尽管与败血症患者的治疗性相关，但ESL修复的这些过程尚未探索。我们假设降解的肺ESL在原本健康的小鼠中迅速重构，从而维持肺血管稳态。在败血症期间，ESL的重构被延迟，导致脓毒肺损伤的过度肺部炎症和水肿特征。我们使用最先进的肺浸没显微镜（E. schmidt，肺/重症监护，科罗拉多大学）和糖糖（R. Linhardt，伦斯勒化学，伦斯勒理工学院研究所）的方法，我们建议（1）确定这些机械的抑制作用，（2）确定这些机械的抑制作用（2）加速ESL重建并减轻化脓性肺损伤的机制。这些多学科研究代表了败血症领域中高度新颖的合作，将由化粪池损伤的动物模型以及对从患有严重败血症的人类获得的生物样品的分析进行补充。总而言之，该提案为败血症提供了一种新的多学科观点：ESL完整性是化粪池损伤发作和进展的关键决定因素。因此，调查ESL重建过程的过程可能会确定危重疾病中的新型治疗靶标，尽管研究了几千年，但仍然缺乏临床有效的，病理生理学的治疗方法。