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)，都是血管通透性显著增加的关键 导致发病率和死亡率增加的因素。不幸的是，目前还没有针对 缓解阿里和瑞丽持续的血管渗漏。此PPG解决了以下关键需求 这些破坏性炎症性活动性损伤的新见解、生物标记物和治疗方法 脂信号介质和血管生成因子，鞘氨醇-1-磷酸(S1P)，S1P受体(S1PR)， S1P代谢酶及S1P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：1)S1P对肺内皮细胞有很强的刺激作用；2) S1P是血清中存在的主要EC趋化物质；ILL)S1P增强肺EC单层完整性和；iv) SI P是一种有效的体内血管通透性和肺泡泛滥的抑制剂。我们的PPG涉及到4个紧密的 由最先进的核心支持的内部编织项目，并将利用系统生物学方法 将鞘磷脂定义为ALI和RILI病理生物学的关键调节器。项目1将评估 鞘磷脂代谢基因作为ALI靶点并探讨细胞内S1P在预防ALI中的作用 肺部炎症和损伤。项目2将提供有关G的不同角色的新信息 炎症性肺损伤中蛋白偶联的S1PR以及识别新的基于S1P的生物标志物和 遗传因素参与了ALI。项目3研究人员为ALI开发了新的81P类似物 并将在小鼠肺损伤模型中评估这种治疗潜力。与阿里类似，还有一个 关于电离辐射对血管的不良影响的研究很少。项目4将重点放在 S1P类似物单独或与辛伐他汀合用在降低小鼠模型RILI中的潜在作用 并将S1P靶基因与RILI的易感性联系起来。总而言之，此PPG解决了关键需求(洞察力、 生物标志物、治疗)在ALI和RILI促进药物基因组分析和基于SIP的发展 炎症性肺损伤的治疗。

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.