Endothelial glycocalyx reconstitution during sepsis

脓毒症期间的内皮糖萼重建

• 批准号: 9066215
• 负责人: ROBERT J LINHARDT
• 金额: $ 66.67万
• 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/9066215
• 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; FGF2 gene; FGFR2 gene; Failure; Fibroblast Growth Factor; 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(申请人提供)：自从希波克拉底对“腐烂”的最初描述以来，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，但脓毒症治疗的临床试验一再令人失望。这些失败凸显了对脓毒症器官损伤的发生、进展和解决需要新的多学科视角的必要性。内皮糖萼是一层糖胺聚糖和相关的蛋白多糖，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过程。我们最近发现，肺ESL通过调节内皮细胞表面黏附分子的暴露，发挥把关功能，控制中性粒细胞进入肺内。作为对感染性刺激的反应，激活的内皮细胞裂解肺ESL，允许中性粒细胞黏附和随后的渗出。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，在其他健康的小鼠中，降解的肺ESL可以迅速重建，从而维持肺血管的动态平衡。在脓毒症期间，ESL重建延迟，导致败血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，科罗拉多大学肺/重症监护)和血糖学(R.Linhardt，化学，伦斯勒理工学院)方法，我们建议(1)确定肺ESL重建的机制，(2)确定这些机制在脓毒症期间如何被抑制，以及(3)从治疗上操纵这些机制，以加速ESL重建并减轻败血症肺损伤。这些多学科研究代表着脓毒症领域的一种高度新颖的合作，将得到败血症肺损伤的动物模型以及从患有严重脓毒症的人类获得的生物样本的分析的补充。总之，这项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发展的关键决定因素。因此，研究ESL重建的过程可能会确定这种危重疾病的新治疗靶点，尽管有数千年的研究，但仍然缺乏临床有效的病理生理学靶向治疗。