Targeting Sphingosine-1-Phosphate Receptor 1 Protects Pulmonary Vascular Endothelial Integrity During Human Ex Vivo Lung Perfusion

BACKGROUND: Pulmonary edema due to vascular endothelial injury in donor lungs reduces organ utilization and exacerbates ischemia/reperfusion injury, resulting in poor posttransplant outcomes. Sphingosine-1-phosphate (S1P) improves vascular integrity through S1P receptor 1 (S1PR1) signaling. This study assessed whether S1PR1 agonism during ex vivo lung perfusion (EVLP) reduces vascular permeability and edema formation in human donor lungs. METHODS: S1PR1 agonist CYM5442 was administered to human donor lungs declined for transplant, during 6 h of EVLP, using a paired split-lung model with one lung treated and the other acting as an internal control. Lung physiology, organ weight, vascular endothelial permeability to Evan's blue dye, and direCt Lung Ultrasound Evaluation score for lung water were assessed. Sequential perfusate and tissue samples were collected to evaluate gene and protein expression. RESULTS: During EVLP (n = 7 paired sets), CYM5442 reduced Evan's blue accumulation in bronchoalveolar lavage ( P = 0.0260) and tissue ( P = 0.0476). Increases in lung weight were ameliorated and direCt Lung Ultrasound Evaluation scores reduced in the CYM5442-treated group post-EVLP ( P = 0.0135 and P = 0.0482, respectively), leading to reduced pulmonary artery and peak airway pressures (interaction P = 0.0038 and P < 0.0001). CYM5442 maintained vascular endothelial cadherin expression and reduced interleukin-6 ( P = 0.0130, 360 min), interleukin-1 beta ( P = 0.0214, 240 min), and soluble intercellular adhesion molecule-1 ( P = 0.0067, 360 min) release compared with untreated during EVLP. CONCLUSIONS: Agonism of S1PR1 during EVLP ameliorates pulmonary vascular leak and may be used to reduce the risk of edema formation in donor lungs.