Role of Sphingolipids in the Pathobiology of Lung Injury

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Joe G.N. Garcia, MD
Nati Natarajan, PhD
P01/PPG (NIH/NHLBI), 2011-2016 (Project 2, Core C, Core D)
Total Dollars: 
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.
Public Health Relevance Statement:
Acute lung injury (ALI) and radiation-induced lung injury (RILI) are devasting inflammatory lung injuries which share increased morbidity and mortality with increased lung vascular permeability as a defining feature. Sphingolipids, such as S1P, represent a novel biomarker and therapy for the vascular leak in ALI and RILI via stabilization or restoration of lung endothelial integrity. Our PPG studies will evaluate the S1P pathway as a source of novel biomarkers and genetic variants to improve management of patients with ALI and RILI.