Endothelial glycocalyx reconstitution during sepsis

脓毒症期间的内皮糖萼重建

• 批准号: 8927683
• 负责人: ROBERT J LINHARDT
• 金额: $ 65.85万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 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/8927683
• 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; 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; Process; Property; Proteoglycan; Pulmonary Circulation; Pulmonary Edema; Pulmonary Inflammation; Puncture procedure; Recovery; Resolution; Respiratory physiology; Sampling; Sepsis; Signal Transduction; Stimulus; Surface; Techniques; Testing; Therapeutic; Universities; Vascular Permeabilities; base; effective therapy; genetic approach; 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; targeted treatment; transcription factor

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“腐烂”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一再令人失望。这些失败强调需要新的、多学科的视角来研究败血性器官损伤的发生、进展和解决。内皮糖萼是一层糖胺聚糖和相关蛋白聚糖排列在血管表面。在体内，糖萼形成一个实质性的内皮表面层（ESL），影响炎症、内皮通透性和与脓毒症病理生理高度相关的血管张力生物学过程。我们最近发现，肺ESL通过调节内皮表面粘附分子的暴露，起着控制中性粒细胞进入肺的把关功能。作为对感染刺激的反应，活化的内皮细胞分裂肺ESL，允许中性粒细胞粘附和随后的外渗。从目的论上讲，这种守门人功能还需要精确的细胞控制ESL重建，从而限制肺部炎症的程度。这些ESL修复过程，尽管与脓毒症患者的治疗相关，但尚未被探索。我们假设，退化的肺ESL在其他健康小鼠中迅速重建，允许维持肺血管稳态。脓毒症期间，ESL重建延迟，导致脓毒性肺损伤特征的过度肺部炎症和水肿。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glycomic （R. Linhardt，化学，伦斯勒理工学院）的方法，我们提出(1)确定肺ESL重建的机制，(2)确定这些机制在败血症期间是如何被抑制的，(3)治疗性地控制这些机制以加速ESL重建和减轻脓毒性肺损伤。这些多学科研究代表了脓毒症领域内的一种高度新颖的合作，将通过脓毒症肺损伤动物模型以及从严重脓毒症患者身上获得的生物样本分析来补充。总之，这一建议为脓毒症提供了一个新的多学科视角：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重建过程可能会在一种危重疾病中发现新的治疗靶点，尽管经过数千年的研究，仍然缺乏临床有效的病理生理靶向治疗。