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88 EFFECT OF THE S1P1 GENE KO ON LIPOPOLYSACCHARIDE-INDUCED MURINE ACUTE LUNG INJURY.
  1. S. Sammani,
  2. T. Mirzapoiazova,
  3. L. Moreno,
  4. R. Proia,
  5. C. Evenoski,
  6. J. Moitra,
  7. V. Natarajan,
  8. P. Singleton,
  9. J. G. Garcia
  1. University of Chicago, Chicago, IL; Bethesda, MD.

Abstract

Acute lung injury ALI/ARDS, a significant cause of morbidity and mortality, is characterized by a diffuse inflammatory parenchymal process with pulmonary EC vascular leak and alveolar flooding. This syndrome remains a significant cause of intensive care unit mortality, and more effective therapeutic interventions are needed. Our in vitro studies indicate that sphingosine 1-phosphate (S1P), a phospholipid angiogenic factor and a major barrier-protective product of platelets, produces endothelial cell barrier enhancement through ligation of the S1P family of receptors, especially S1P1, a G protein-coupled receptor expressed on vascular endothelial cells. Our previous data show that S1P, via S1P1, has impressive protective effects in both murine and canine models of ALI (McVerry et al, 2004). To better understand S1P receptors in barrier regulation, we examined LPS-induced ALI in S1P1 receptor heterozygous (S1P1R+/−) mice. Our data demonstrate that the S1P1-R+/− mice exhibit increased barrier disruption compared with wild-type mice, reflected by an increase in protein (25%) and inflammatory cell count (20%) in bronchoalveolar lavage (BAL) fluid. To confirm the role of S1P1R on the S1P barrier-protective effect, we administered S1P (UM final blood concentration, iv) simultaneously with LPS (2.5 mg/kg) and evaluated lung inflammation 18 hours later. LPS-treated wild-type mice treated with S1P demonstrated profound reductions (> 50%) in BAL protein, whereas S1P1+/− mice similarly treated with S1P only exhibited only a ≈10% increase in BAL protein. In conclusion, our data using genetically engineered mice demonstrate a critical need for S1P1 receptors in vivo, particularly in conditions of endotoxemia.

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