Role of Sphingolipids in the Pathobiology of Lung Injury

急性肺损伤或ALI（由于脓毒症或呼吸机诱导的肺损伤）和亚急性肺损伤（由于 电离辐射诱导的肺损伤（RILI），共享血管通透性的深刻增加作为一个关键， 导致发病率和死亡率上升的因素。不幸的是，目前还不存在针对 减轻了在ALI和RILI中观察到的持续的血管渗漏。本PPG解决了以下关键需求： 新的见解，生物标志物，和治疗这些毁灭性的炎症liing损伤，通过重点放在 脂质信号传导介质和血管生成因子，鞘氨醇-1-磷酸（S1 P），S1 P受体（S1 PRs）， S1 P代谢酶和S1 P类似物。我们的PPG调查团队帮助创建了这个 通过初步观察发现：i）S1 P是一种有效的肺内皮细胞（EC）刺激物; ii） S1 P是存在于血清中的关键EC化学引诱物; iii）S1 P增强肺EC单层完整性; iv） SiP是一种强有力的体内血管通透性和肺泡灌流抑制剂。我们的PPG涉及4紧密 由最先进的核心支持的交织项目，并将利用系统生物学方法， 将鞘脂定义为ALI和RILI病理生物学的关键调节剂。项目#1将评估 鞘脂代谢基因作为ALI靶点，并阐明细胞内S1 P在保护ALI中的作用 肺部炎症和损伤。项目#2将提供有关G的不同作用的新信息 炎症性肺损伤中的蛋白偶联S1 PRs以及鉴定新的基于S1 P的生物标志物， 与ALI有关的遗传因素项目#3研究人员开发了用于ALI的新型81 P类似物 治疗，并将在肺损伤的鼠模型中评估这种治疗潜力。与ALI类似， 缺乏关于电离辐射对血管的不良影响的研究。项目#4将重点放在 S1 P类似物单独或与辛伐他汀联合在降低小鼠模型RILI中的潜在作用 并将S1 P靶基因与RILI易感性联系起来。总之，这个PPG解决了关键需求（见解， 促进药物基因组学测定和基于SIP的 治疗炎症性肺损伤。

Acute lung injury or ALI (due to sepsis or ventilator-induced lung injury) and subacute lung injury (due to ionizing radiation-induced lung injury (RILI), share profound increases in vascular permeability as a key element driving increased morbidity and mortality. Unfortunately, specific therapies currently do not exist for alleviating the unremitting vascular leak seen in ALI and RILI. This PPG addresses the critical need for novel insights, biomarkers, and therapies in these devasting inflammatory liing injuries via a focus on the lipid signaling mediator and angiogenic factor, sphingosine-1-phosphate (S1P), S1P receptors (S1PRs), enzymes of S1P metabolism and S1P analogues. Our PPG investigative team helped create this remarkable field by making the initial observations that: i) S1P is a potent lung endothial cell (EC) stimulus; ii) S1P is the key EC chemoattractant present in serum; ill) S1P enhances lung EC monolayer integrity and; iv) Si P is a powerful in vivo inhibitor of vascular permeability and alveolar flooding. Our PPG involves 4 tightly intenwoven Projects supported by State of the Art Cores, and will utilize a systems biology approach to define sphingolipids as key modulators of the pathobiology of ALI and RILI. Project #1 will evaluate sphingolipid metabolizing genes as ALI targets and address the role of intracellular S1P in protection against lung inflammation and injury. Project #2 will provide novel information regarding differential roles of the G protein-coupled S1PRs in inflammatory lung injury as well as identify novel S1P-based biomarkers and genetic factors involved in ALI. Project # 3 investigators have developed novel analogues of 81P for ALI treatment and will assess this therapeutic potential in murine models of lung injury. Similar to ALI, there is a paucity of studies addressing the untoward vascular effects of ionizing radiation. Project #4 will focus on the potential role of S1P analogues, alone or in combination with simvastatin, in reducing RILI in murine models and link S1P target genes to RILI susceptibility. Together, this PPG addresses critical needs (insights, biomarkers, therapies) in ALI and RILI facilitating development of pharmacogenomic assays and SIP-based therapies for inflammatory lung injury.