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）：自从希波克拉底最初描述“腐败”以来，败血症已被认为是人类痛苦和死亡的主要原因。尽管在了解感染引起的全身炎症反应方面取得了重大进展，但败血症治疗的临床试验却一再令人失望。这些失败凸显了对脓毒症器官损伤的发生、进展和解决采取新的多学科视角的必要性。内皮糖萼是血管表面内衬的一层糖胺聚糖和相关蛋白聚糖。在体内，糖萼形成实质的内皮表面层（ESL），影响炎症、内皮通透性和与脓毒症病理生理学高度相关的血管张力生物过程。我们最近发现，肺 ESL 通过调节内皮表面粘附分子的暴露，发挥着控制中性粒细胞转运到肺的看门功能。响应感染刺激，激活的内皮细胞裂解肺 ESL，允许中性粒细胞粘附并随后外渗。从目的上讲，这种把关功能还需要对 ESL 重建进行精确的细胞控制，从而限制肺部炎症的严重程度。尽管这些 ESL 修复过程与脓毒症患者具有治疗相关性，但尚未得到探索。我们假设，在其他方面健康的小鼠中，退化的肺 ESL 会迅速重建，从而维持肺血管稳态。在脓毒症期间，ESL 重建被延迟，导致脓毒症肺损伤的过度肺部炎症和水肿特征。使用最先进的肺活体显微镜（E. Schmidt，肺/重症监护，科罗拉多大学）和糖组学（R. Linhardt，化学，伦斯勒理工学院）方法，我们建议（1）确定潜在的机制肺部 ESL 重建，(2) 确定这些机制在脓毒症期间如何受到抑制，(3) 治疗性操纵这些机制以加速 ESL 重建并减轻脓毒性肺损伤。这些多学科研究代表了脓毒症领域的高度新颖的合作，将得到脓毒症肺损伤动物模型以及对从严重脓毒症患者身上获得的生物样本的分析的补充。总之，该提案为脓毒症提供了一个新的、多学科的视角：ESL 完整性是脓毒症器官损伤发生和进展的关键决定因素。因此，研究 ESL 重建过程可能会确定危重疾病的新治疗靶点，尽管进行了数千年的研究，但仍然缺乏临床有效的、病理生理学靶向的治疗方法。