Sphingosine-1–Phosphate, FTY720, and Sphingosine-1–Phosphate Receptors in the Pathobiology of Acute Lung Injury

Abstract

Acute lung injury (ALI) attributable to sepsis or mechanical ventilation and subacute lung injury because of ionizing radiation (RILI) share profound increases in vascular permeability as a key element and a common pathway driving increased morbidity and mortality. Unfortunately, despite advances in the understanding of lung pathophysiology, specific therapies do not yet exist for the treatment of ALI or RILI, or for the alleviation of unremitting pulmonary leakage, which serves as a defining feature of the illness. A critical need exists for new mechanistic insights that can lead to novel strategies, biomarkers, and therapies to reduce lung injury. Sphingosine 1-phosphate (S1P) is a naturally occurring bioactive sphingolipid that acts extracellularly via its G protein-coupled S1P 1-5 as well as intracellularly on various targets. S1P-mediated cellular responses are regulated by the synthesis of S1P, catalyzed by sphingosine kinases 1 and 2, and by the degradation of S1P mediated by lipid phosphate phosphatases, S1P phosphatases, and S1P lyase. We and others have demonstrated that S1P is a potent angiogenic factor that enhances lung endothelial cell integrity and an inhibitor of vascular permeability and alveolar flooding in preclinical animal models of ALI. In addition to S1P, S1P analogues such as 2-amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol (FTY720), FTY720 phosphate, and FTY720 phosphonates offer therapeutic potential in murine models of lung injury. This translational review summarizes the roles of S1P, S1P analogues, S1P-metabolizing enzymes, and S1P receptors in the pathophysiology of lung injury, with particular emphasis on the development of potential novel biomarkers and S1P-based therapies for ALI and RILI.Keywords: sphingolipids; S1P receptors; sphingosine kinase; S1P lyase; sepsis Acute and subacute inflammatory lung injuries are common and devastating disorders resulting from insults such as sepsis, ventilator-induced lung injury, ischemia/reperfusion, hyperoxia, and radiation therapy for thoracic malignancies. Unfortunately, despite recent advances in our understanding of the mechanisms and pathophysiology of acute lung injury (ALI), mortality rates remain very high (30-50%) because of the dearth of specific therapies for the treatment of ALI (1, 2). The only therapy for radiation-induced pneumonitis is based on long-term treatment with a high dose of corticosteroids. However, it is encumbered by severe side effects and relatively low efficacy (3). Therefore, an urgent need exists for new mechanistic insights into the pathophysiology of ALI that are likely to reveal new potential therapeutic targets, discover novel biomarkers, and develop highly efficacious targeted therapies that will effectively reduce the morbidity and mortality associated with acute and subacute lung injury."Sphingosin," first described by J. L. W. Thudichum in 1884, derived its name from the Greek word "sphinx" meaning enigmatic, and it encompasses many compounds commonly referred to as "sphingoid bases" (4). Since thei...

Sphingosine‐1‐Phosphate is Involved in the Occlusive Arteriopathy of Pulmonary Arterial Hypertension

“…Given that physiological levels of S1P enhance endothelial barrier function, increased vascular permeability was a possible adverse effect of chronic inhibition of S1P synthesis. 49,50 However, because SphK1 inhibitors reduce circulating S1P levels by only ∼50%, we did not observe lung edema formation in the rats. 22 In contrast to our study and others 10,33,51 suggesting a role for S1P in the pathogenesis of PH, long-term exposure to an allergen exaggerated pulmonary arterial responsiveness and wall thickening in SphK1-deficient mice.…”

Lung Circulation

“…In addition to investigation of signaling pathways that worsen barrier function, there has been recent interest in upstream proteins that exert barrier protective effects, such as S1P and angiopoietins. Interactions between S1P and one of its receptors, S1P1R, are thought to strengthen the endothelial barrier through a variety of mechanisms, including stabilization of the adherens junction and rearrangement of the actin cytoskeleton in a protective configuration [reviewed in (452,640,668)]. Consistent with these suppositions, S1P administration attenuated LPSinduced increases in bronchoalveolar lavage fluid protein and Evans blue dye extravasation in a murine model of endotoxininduced lung injury (493) and attenuated high tidal volume induced increases in bronchoalveolar lavage fluid protein in a canine model of lung injury (608).…”

Novel concepts of acute lung injury and alveolar-capillary barrier dysfunction

“…Imai et al (106) were the first to suggest that the signals impacting on the balance between angiotensin converting enzymes (ACE) 1 and 2 modulate the degree of inflammatory lung injury after sepsis, and ACE I/D polymorphism was recently associated with mortality risk of ALI/ ARDS in patients (152). Angiogenic factors such as sphingosine-1-phosphate (S1P), Robo4 signaling, or angiopoietin-1 have been attributed a central role in preventing loss of or restoring endothelial barrier function (1,18,66,142,164). S1P is a lipid binding to G protein-coupled receptors expressed on endothelial cells (S1Prs), which induces actin cytoskeletal reorganization, activation of Rac, relocalization of VE-cadherin and catenin to junctional regions, and reassembly of adherens junctions in vitro (135,172).…”