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Our prior in vitro studies indicate that sphingosine 1-phosphate (S1P), a phospholipid angiogenic factor, produces endothelial cell barrier enhancement through ligation of endothelial differentiation gene family receptors. We hypothesized that S1P may reduce the vascular leak associated with acute lung injury and found that S1P infusion produced a rapid and significant reduction in lung weight gain (more than 50%) in the isolated perfused murine lung. The effect of S1P was next assessed in a murine model of LPS-mediated microvascular permeability and inflammation with marked increases in parameters of lung injury at both 6 and 24 hours after intratracheal LPS. Each parameter assessed was significantly reduced by intravenous S1P (1 microM final) and in selected experiments by the S1P analogue FTY720 (0.1 mg/kg, intraperitoneally) delivered 1 hour after LPS. S1P produced an approximately 40-50% reduction in LPS-mediated extravasation of Evans blue dye albumin, bronchoalveolar lavage protein content, and lung tissue myeloperoxidase activity (reflecting phagocyte infiltration). Consistent with systemic barrier enhancement, S1P significantly decreased Evans blue dye albumin extravasation and myeloperoxidase content in renal tissues of LPS-treated mice. These studies indicate that S1P significantly decreases pulmonary/renal vascular leakage and inflammation in a murine model of LPS-mediated acute lung injury and may represent a novel therapeutic strategy for vascular barrier dysfunction.

Extracorporeal perfusion of isolated sheep lungs with blood after 30 min of ischemia caused injury manifested by polymorphonuclear (PMN) leukocyte sequestration, pulmonary hypertension, thromboxane release, and increased pulmonary vascular permeability. To determine the roles of ischemia, extracorporeal perfusion, and oxygen in this injury, lungs ventilated with 28% O2-5% CO2 and subjected to 30 min of ischemia followed by 180 min of perfusion (ischemic-perfused, n = 23) were compared with lungs subjected to (1) ischemia without perfusion (ischemic, n = 7), (2) perfusion without ischemia (perfused, n = 20), or (3) both ischemia and perfusion during ventilation with 95% N2 (anoxic ischemic-perfused, n = 15). Compared with ischemic-perfused lungs, ischemic lungs had an increased reflection coefficient for albumin (sigma alb, 0.82 +/- 0.03 versus 0.54 +/- 0.05) and decreased filtration coefficient (Kf, 0.05 +/- 0.01 versus 0.11 +/- 0.03 g.min-1.mm Hg-1.100 g-1). Perfused lungs had increased pulmonary hypertension, lung PMN leukocytes, and sigma alb (0.74 +/- 0.05); Kf was not different. Anoxic ischemic-perfused lungs had decreased pulmonary hypertension and thromboxane release, but sigma alb and Kf were not altered. These results suggest that extracorporeal perfusion caused PMN leukocyte sequestration, thromboxane release, and pulmonary hypertension, whereas ischemia caused derecruitment of vascular surface area. Injury required both ischemia and perfusion, but it was not decreased by anoxia, suggesting that oxygen radicals were not involved.

flow volume loops (FVL) in some bilateral lung transplant (BLT) and heart-lung transplant (HLT) patients suggest variable extrathoracic obstruction in the absence of identifiable causes. These FVLs usually have supranormal expiratory and normal inspiratory flow rates (SUPRA pattern).characterize the relationship of the SUPRA pattern to predicted donor and recipient lung volumes, airway size, and survival.we performed a retrospective review of adult BLT/HLT patients. We defined the SUPRA FVL pattern as: (1) mid-vital capacity expiratory to inspiratory flow ratio (Ve50:Vi50)1.0, (2) absence of identifiable causes of extrathoracic obstruction, and (3) Ve50/FVC ≥ 1.5 s(-1). We calculated predicted total lung capacity (pTLC) ratio by dividing the donor pTLC by the recipient pTLC. We measured airway luminal areas on thoracic computer tomographic scans. We compared survival in patients with and without the SUPRA pattern.the SUPRA FVL pattern occurred in 56% of the 89 patients who qualified for the analysis. The pTLC ratio of SUPRA and non-SUPRA patients was 1.11 and 0.99, respectively (P = 0.004). A higher pTLC ratio was correlated with increased probability of the SUPRA pattern (P = 0.0072). Airway luminal areas were larger in SUPRA patients (P = 0.009). Survival was better in the SUPRA cohort (P = 0.009).the SUPRA FVL pattern was frequent in BLT/HLT patients. High expiratory flows in SUPRA patients could result from increased lung elastic recoil or reduced airway resistance, both of which could be caused by the pTLC mismatch. Improved survival in the SUPRA cohort suggests potential therapeutic approaches to improve outcomes in BLT/HLT patients.