title: A sphingosine 1-phosphate 1 receptor agonist modulates brain death-induced neurogenic pulmonary injury.
abstract: Lung transplantation remains the only viable therapy for patients with end-stage lung disease. However, the full utilization of this strategy is severely compromised by a lack of donor lung availability. The vast majority of donor lungs available for transplantation are from individuals after brain death (BD). Unfortunately, the early autonomic storm that accompanies BD often results in neurogenic pulmonary edema (NPE), producing varying degrees of lung injury or leading to primary graft dysfunction after transplantation. We demonstrated that sphingosine 1-phosphate (S1P)/analogues, which are major barrier-enhancing agents, reduce vascular permeability via the S1P1 receptor, S1PR1. Because primary lung graft dysfunction is induced by lung vascular endothelial cell barrier dysfunction, we hypothesized that the S1PR1 agonist, SEW-2871, may attenuate NPE when administered to the donor shortly after BD. Significant lung injury was observed after BD, with increases of approximately 60% in bronchoalveolar lavage (BAL) total protein, cell counts, and lung tissue wet/dry (W/D) weight ratios. In contrast, rats receiving SEW-2871 (0.1 mg/kg) 15 minutes after BD and assessed after 4 hours exhibited significant lung protection (∼ 50% reduction, P = 0.01), as reflected by reduced BAL protein/albumin, cytokines, cellularity, and lung tissue wet/dry weight ratio. Microarray analysis at 4 hours revealed a global impact of both BD and SEW on lung gene expression, with a differential gene expression of enriched immune-response/inflammation pathways across all groups. Overall, SEW served to attenuate the BD-mediated up-regulation of gene expression. Two potential biomarkers, TNF and chemokine CC motif receptor-like 2, exhibited gene array dysregulation. We conclude that SEW-2871 significantly attenuates BD-induced lung injury, and may serve as a potential candidate to improve human donor availability.
authors: Section of Pulmonary, Critical Care, Sleep, and Allergy, Department of Medicine, University of Illinois at Chicago, 60612, USA.
authors: Saad
authors: S
authors: Sammani
authors: Ki-Sung
authors: KS
authors: Park
authors: Syed R
authors: SR
authors: Zaidi
authors: Biji
authors: B
authors: Mathew
authors: Ting
authors: T
authors: Wang
authors: Yong
authors: Y
authors: Huang
authors: Tong
authors: T
authors: Zhou
authors: Yves A
authors: YA
authors: Lussier
authors: Aliya N
authors: AN
authors: Husain
authors: Liliana
authors: L
authors: Moreno-Vinasco
authors: Wickii T
authors: WT
authors: Vigneswaran
authors: Joe G N
authors: JG
authors: Garcia
references: Am J Transplant. 2007 Jan;7(1):83-90
references: 17227559
references: Eur Respir J. 2007 Sep;30(3):429-35
references: 17537765
references: FASEB J. 2005 Oct;19(12):1646-56
references: 16195373
references: Am J Respir Cell Mol Biol. 2010 Oct;43(4):394-402
references: 19749179
references: J Heart Lung Transplant. 2006 Jul;25(7):745-55
references: 16818116
references: Eur J Pharmacol. 2008 Dec 14;600(1-3):1-9
references: 18854184
references: Chest. 1997 Mar;111(3):706-11
references: 9118712
references: J Hematother Stem Cell Res. 1999 Dec;8(6):627-34
references: 10645770
references: Am J Physiol Lung Cell Mol Physiol. 2003 Jul;285(1):L258-67
references: 12626332
references: J Clin Invest. 2001 Sep;108(5):689-701
references: 11544274
references: J Cell Biochem. 2004 Aug 1;92(5):913-22
references: 15258915
references: J Heart Lung Transplant. 2007 Oct;26(10):1040-7
references: 17919625
references: Science. 1999 Oct 15;286(5439):531-7
references: 10521349
references: Environ Health Perspect. 2008 Nov;116(11):1500-8
references: 19057703
references: Circ Res. 2001 Sep 14;89(6):496-502
references: 11557736
references: Ann Thorac Surg. 1987 Mar;43(3):288-94
references: 3827373
references: Am J Respir Crit Care Med. 2004 Jun 1;169(11):1245-51
references: 15020292
references: Am J Transplant. 2007;7(5 Pt 2):1390-403
references: 17428287
references: J Pharmacol Exp Ther. 2009 Oct;331(1):54-64
references: 19592667
references: Transplantation. 2004 Nov 15;78(9):1251-8
references: 15548960
references: Am J Transplant. 2005 Apr;5(4 Pt 1):684-93
references: 15760391
references: Chest. 1995 Nov;108(5):1358-63
references: 7587442
references: FASEB J. 2000 Nov;14(14):2255-65
references: 11053247
references: Proc Natl Acad Sci U S A. 2001 Apr 24;98(9):5116-21
references: 11309499
references: Am J Respir Crit Care Med. 2004 Nov 1;170(9):987-93
references: 15282202
references: Transl Res. 2008 Mar;151(3):141-53
references: 18279813
references: Am J Respir Cell Mol Biol. 2001 Jun;24(6):711-9
references: 11415936
references: Transplantation. 2008 Feb 27;85(4):597-606
references: 18347540