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The short-term administration of S1P or S1P1 receptor agonists enhances endothelial monolayer barrier function in vitro, and attenuates injury-induced vascular leak in the lung and other organ systems in vivo. Although S1P1 agonists bind to and activate S1P1, several of these agents also induce receptor internalization and degradation, and may therefore act as functional antagonists of S1P1 after extended exposure. Here we report on the effects of prolonged exposure to these agents in bleomycin-induced lung injury. We demonstrate that repeated administration of S1P1 agonists dramatically worsened lung injury after bleomycin challenge, as manifested by increased vascular leak and mortality. Consistent with these results, prolonged exposure to S1P1 agonists in vitro eliminated the ability of endothelial cell monolayers to respond appropriately to the barrier-protective effects of S1P, indicating a loss of normal S1P\u2013S1P1 signaling. As bleomycin-induced lung injury progressed, continued exposure to S1P1 agonists also resulted in increased pulmonary fibrosis. These data indicate that S1P1 agonists can act as functional antagonists of S1P1 on endothelial cells in vivo, which should be considered in developing these agents as therapies for vascular leak syndromes. Our findings also support the hypothesis that vascular leak is an important component of the fibrogenic response to lung injury, and suggest that targeting the S1P\u2013S1P1 pathway may also be an effective therapeutic strategy for fibrotic lung diseases.<\/jats:p>","DOI":"10.1165\/rcmb.2009-0345oc","type":"journal-article","created":{"date-parts":[[2010,1,15]],"date-time":"2010-01-15T21:47:59Z","timestamp":1263592079000},"page":"662-673","source":"Crossref","is-referenced-by-count":145,"title":["Prolonged Exposure to Sphingosine 1\u2013Phosphate Receptor-1 Agonists Exacerbates Vascular Leak, Fibrosis, and Mortality after Lung Injury"],"prefix":"10.1093","volume":"43","author":[{"given":"Barry S.","family":"Shea","sequence":"first","affiliation":[{"name":"Pulmonary and Critical Care Unit, and"},{"name":"Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah F.","family":"Brooks","sequence":"additional","affiliation":[{"name":"Pulmonary and Critical Care Unit, and"},{"name":"Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin A.","family":"Fontaine","sequence":"additional","affiliation":[{"name":"Pulmonary and Critical Care Unit, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jerold","family":"Chun","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Helen L. 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