© 2004 American Thoracic Society doi: 10.1164/rccm.2408008
Lung InjurySphingosine-1-Phosphate to the RescueSt. Luke's-Roosevelt Hospital Center College of Physicians and Surgeons, Columbia University New York, New York Recent interest in the immunodulatory features of sphingomyelin metabolism products establishes a beachhead in pulmonary science. For many years sphingomyelin, which is abundant in the cell membrane, was essentially considered a structural lipid. It is now clear that through the sequential actions of sphingomyelinase, ceramidase, and sphingosine kinase, sphingomyelin is degraded to ceramide and then sphingosine to form the lysophospholipid, sphingosine-1-phosphate (S1P), a potent inducer of cell signaling. Acting as an extracellular ligand, S1P binds several G protein–coupled cell surface receptors (GPCRs), previously called Edg (endothelial differentiation gene) receptors, but now renamed S1P receptors (S1PR). Expression of S1PR in both the lung vasculature as well as the airway suggests that S1P could induce a wide variety of responses in the lung. Pulmonary interest in S1P stems from two sets of novel findings. First, S1P as well as the drug FTY720, an S1P analog that binds S1PR in its phosphorylated form, have immunosuppressive properties, in that they block T cell egress from lymph nodes and Peyer's patches. This finding now forms the basis of stage III clinical trials for FTY720 as therapy of organ rejection after kidney transplantation (1). It is exciting to think that the drug may be applicable to therapeutic management of lung transplantation, because FTY720 given in combination with other agents prevented obliterative airway disease resulting from cross-strain lung transplantation in mice (2). One hopes that there is more research to come in this area. Second, a landmark paper from the Hla laboratory shows that S1P promotes endothelial adherens junction assembly (3). This finding is relevant to the hyperpermeability issues associated with lung injury and pulmonary edema. The adherens junction critically determines endothelial barrier properties. Enhanced adherens junction assembly in lung endothelial cells augments barrier function and blocks pulmonary edema formation induced by intratracheal acid instillation (4, 5). The question of whether the Hla data (3), which were obtained in umbilical vein endothelial cells, are relevant to the lung has been settled by Garcia and colleagues, who showed that S1P not only enhanced barrier properties in cultured lung endothelial cells but also abrogated the hyperpermeability effect of thrombin (6, 7). In this issue of the Journal (pp. 987–993), McVerry and coworkers report that S1P has protective effects against lung injury caused by high-volume mechanical ventilation and intratracheal endotoxin installation in animal models (8). Importantly, the S1P effect was tested in a large animal model of lung injury. Because of issues relevant to the height-dependent distribution of microvascular filtration and blood flow in lung, the pattern of pulmonary edema formation in a large animal suitably replicates the human disease. These experiments show that S1P blocks exudation into the alveolar space when given concomitantly with endotoxin and also abrogates pathologic patterns of pulmonary edema formation, as detected through computer tomographic analyses. These findings bring the S1P story full circle, giving translational credence to what was previously shown only for cultured endothelial cells (3, 6) Despite the fact that S1P was given as a single intravenous injection, McVerry and colleagues found that the protective effect persisted for several hours, indicating that barrier-enhancing processes activated by S1PR are robustly sustained over prolonged periods. This intriguing result raises several mechanistic considerations regarding the dynamics of S1PR ligation. The duration over which GPCR-mediated effects remain effective depends on multiple factors including receptor-recycling time, interrelationships among activated signaling pathways, and the extent of ligand internalization. These issues require clarification for S1PR. Moreover, it should be noted that S1P is secreted by several cell types, but most abundantly by platelets. This results in steady state plasma S1P levels of approximately 400 nM, an order of magnitude higher than S1PR binding affinity (Kd) values (9), suggesting that the receptors are tonically ligated by endogenously secreted S1P. Hence, the efficacy of exogenous S1P binding to available S1PR needs to be defined. These mechanisms remain inadequately understood for S1P–S1PR interactions, but are clearly important for the therapeutic evaluation of this agent. A number of SIP-related issues are relevant to its therapeutic use. By activating Akt and increasing cellular calcium levels, S1P induces NO production (10). Although lung NO production may be hemodynamically advantageous, NO potentially mediates the generation of nitration products that might promote injury. S1P's actions in the airway also demand attention. These effects may be proinflammatory because S1P induces the secretion of interleukin-8, a neutrophil chemoattractant, from bronchial epithelial cells (11). By modifying the alveolar pool of sphingomyelin hydrolysis products, S1P impairs the biophysical properties of alveolar surfactant (12). Because mast cells express S1PR, S1P may act as an inflammatory mediator in the airway (13, 14). From the standpoint of clinical therapy, an important question relates to the efficacy of post hoc treatment with S1P. To what extent would the barrier strengthening effects of S1P be curative rather than preventive in a lung injury scenario? Despite these questions, the Garcia group has shown that S1P must be seriously considered as a candidate for the smart therapy of lung injury. FOOTNOTES Conflict of Interest Statement: J.B. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. REFERENCES
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