A sphingosine 1-phosphate 1 receptor agonist modulates brain death-induced neurogenic pulmonary injury

Saad Sammani, Ki Sung Park, Syed R. Zaidi, Biji Mathew, Ting Wang, Yong Huang, Tong Zhou, Yves A Lussier, Aliya N. Husain, Liliana Moreno-Vinasco, Wickii T. Vigneswaran, Joe GN Garcia

Research output: Contribution to journalArticle

3 Citations (Scopus)

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 (0.1mg/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.

Original languageEnglish (US)
Pages (from-to)1022-1027
Number of pages6
JournalAmerican Journal of Respiratory Cell and Molecular Biology
Volume45
Issue number5
DOIs
StatePublished - Nov 1 2011
Externally publishedYes

Fingerprint

Lysosphingolipid Receptors
Brain Death
Lung Injury
Brain
Pulmonary Edema
Primary Graft Dysfunction
Lung
Gene expression
Lung Transplantation
Tissue Donors
Bronchoalveolar Lavage
Grafts
CCR Receptors
Availability
Tissue
Transplantation (surgical)
Gene Expression
Weights and Measures
CC Chemokines
Pulmonary diseases

Keywords

  • Lung injury
  • Lung transplant donors
  • Neurogenic pulmonary edema
  • Sphingolipids
  • Sphingosine 1-phosphate

ASJC Scopus subject areas

  • Cell Biology
  • Pulmonary and Respiratory Medicine
  • Molecular Biology
  • Clinical Biochemistry

Cite this

A sphingosine 1-phosphate 1 receptor agonist modulates brain death-induced neurogenic pulmonary injury. / Sammani, Saad; Park, Ki Sung; Zaidi, Syed R.; Mathew, Biji; Wang, Ting; Huang, Yong; Zhou, Tong; Lussier, Yves A; Husain, Aliya N.; Moreno-Vinasco, Liliana; Vigneswaran, Wickii T.; Garcia, Joe GN.

In: American Journal of Respiratory Cell and Molecular Biology, Vol. 45, No. 5, 01.11.2011, p. 1022-1027.

Research output: Contribution to journalArticle

Sammani, Saad ; Park, Ki Sung ; Zaidi, Syed R. ; Mathew, Biji ; Wang, Ting ; Huang, Yong ; Zhou, Tong ; Lussier, Yves A ; Husain, Aliya N. ; Moreno-Vinasco, Liliana ; Vigneswaran, Wickii T. ; Garcia, Joe GN. / A sphingosine 1-phosphate 1 receptor agonist modulates brain death-induced neurogenic pulmonary injury. In: American Journal of Respiratory Cell and Molecular Biology. 2011 ; Vol. 45, No. 5. pp. 1022-1027.
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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 (0.1mg/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.",
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