S1P Deficiency Prolongs Endothelial Barrier Recovery After Fontan Operation

S1P 缺乏可延长 Fontan 手术后内皮屏障的恢复

• 批准号: 8444397
• 负责人: KELLEY M ARGRAVES
• 金额: $ 17.55万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8444397
• 关键词: Acute Lung Injury; Address; Aftercare; Anabolism; Animal Model; Blood Vessels; Blood capillaries; Blood specimen; Canis familiaris; Cardiopulmonary Bypass; Child; Clinical; Clinical Markers; Common Ventricle; Edema; Endothelial Cells; Enzymes; Exposure to; Extravasation; Fontan Procedure; Functional disorder; G-Protein-Coupled Receptors; Goals; High Density Lipoproteins; In Vitro; Infant; Inflammatory; Investigation; Lead; Lipids; Lipopolysaccharides; Lung; Maintenance; Mediating; Mus; Patients; Permeability; Phospholipids; Physiology; Plasma; Play; Pleural effusion disorder; Postoperative Period; Recovery; Research; Role; SPHK1 enzyme; Sampling; Secondary to; Severities; Sphingolipids; Testing; Time; Vascular Permeabilities; base; capillary; experience; improved; in vivo; intravenous administration; programs; response; sphingosine 1-phosphate; therapeutic target; treatment strategy

DESCRIPTION (provided by applicant): The overall goal of this proposal is to address a widespread clinical problem occurring after the Fontan operation, persistent pleural effusions, through the investigation of vascular endothelial barrier function. The foundational hypothesis of this proposal is that children with single ventricle physiology who undergo the Fontan operation experience derangements in vascular permeability secondary to the profound inflammatory effects of cardiopulmonary bypass (CPB). Therefore, identifying therapeutic targets that restore vascular endothelial barrier may be critical to improving post-operative care after the Fontan operation. Sphingosine 1-phosphate (S1P) is a phospholipid that interacts with G protein coupled receptors on endothelial cells and mediates enhancement of endothelial barrier function, thus reducing vascular permeability. The critical role of S1P in regulating vascular permeability in vivo has been illustrated in animal models. For example, mice deficient in one of the two enzymes responsible for S1P biosynthesis, sphingosine kinase-1, display increased pulmonary microvessel permeability and greater levels of edema formation in response to an inflammatory insult induced with lipopolysaccharide (LPS) or PAR-1 activation. Importantly, intravenous administration of S1P in mice and dogs has been shown to play a protective role in acute lung injury by reducing pulmonary vascular leakage and intrapulmonary shunting. Our preliminary analysis of plasma from Fontan patients has revealed a reduction in postoperative plasma levels of HDL, the principle carrier of the endothelial barrier- promoting sphingolipid, sphingosine-1-phosphate (S1P). Based on these findings we hypothesize that plasma HDL-S1P levels are lowered in children after exposure to CPB and are predictive of persistent pleural effusions and longer post-operative recovery time. Additionally, we hypothesize that blood samples from children with persistent pleural effusions will display evidence of either propensity to disrupt barrier or a lack of ability to promote barrier either of which can be overcome by exogenous administration of S1P. To address these inter-related hypotheses there are two specific aims: 1) to determine whether plasma levels of S1P correlate with clinical markers of prolonged postoperative recovery (i.e., persistent pleural effusions) after the Fontan operation, and 2) to determine the level of barrier integrity induced by plasma samples from Fontan operation patients and determine if this correlates with S1P levels and/or severity of post-operative pleural effusions. These later studies will also determine whether exogenous administration of S1P can increase the capacity of the samples to enhance barrier in vitro to levels achieved using preoperative samples. The aims of the application may lead to new S1P based strategies for treatment of derangements in vascular permeability in Fontan patients and other infants and children undergoing CPB.

描述（由申请人提供）：该提案的总体目标是通过研究血管内皮屏障功能来解决 Fontan 手术后出现的广泛临床问题，即持续性胸腔积液。该提议的基本假设是，接受 Fontan 手术的单心室生理学儿童会因心肺旁路 (CPB) 的严重炎症影响而出现血管通透性紊乱。因此，确定恢复血管内皮屏障的治疗靶点可能对于改善 Fontan 手术后的术后护理至关重要。 1-磷酸鞘氨醇 (S1P) 是一种磷脂，可与内皮细胞上的 G 蛋白偶联受体相互作用，介导内皮屏障功能的增强，从而降低血管通透性。 S1P 在调节体内血管通透性方面的关键作用已在动物模型中得到证实。例如，缺乏负责 S1P 生物合成的两种酶之一（鞘氨醇激酶-1）的小鼠，在响应脂多糖 (LPS) 或 PAR-1 激活诱导的炎症损伤时，会表现出肺微血管通透性增加和更高水平的水肿形成。重要的是，对小鼠和狗静脉注射 S1P 已被证明可以通过减少肺血管渗漏和肺内分流，在急性肺损伤中发挥保护作用。我们对 Fontan 患者血浆的初步分析显示，术后血浆 HDL 水平降低，HDL 是促进内皮屏障的鞘脂、1-磷酸鞘氨醇 (S1P) 的主要载体。基于这些发现，我们假设儿童在接受 CPB 后血浆 HDL-S1P 水平降低，并且预示着持续性胸腔积液和较长的术后恢复时间。此外，我们假设患有持续性胸腔积液的儿童的血液样本将显示出破坏屏障的倾向或缺乏促进屏障的能力的证据，这两种情况都可以通过外源性施用 S1P 来克服。为了解决这些相互关联的假设，有两个具体目标：1）确定 S1P 血浆水平是否与 Fontan 手术后长时间术后恢复（即持续性胸腔积液）的临床标志物相关，2）确定 Fontan 手术患者血浆样本诱导的屏障完整性水平，并确定这是否与 S1P 水平和/或严重程度相关。 术后胸腔积液。这些后续研究还将确定外源性给予 S1P 是否可以提高样品的能力，以将体外屏障增强至使用术前样品达到的水平。该应用的目的可能会产生基于 S1P 的新策略，用于治疗 Fontan 患者和其他接受 CPB 的婴儿和儿童的血管通透性紊乱。