Sphingosine-1-phosphate Receptor-1 Agonist Averts the De Novo Generation of Autoreactive T-cells in Murine Acute Graft-versus-Host Disease.
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ABSTRACT:
SUBMITTER: Vollmer M
PROVIDER: S-EPMC8274799 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description: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.
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Project description:Lung transplantation remains the only viable therapy for patients with end-stage lung disease; however, full utilization of this treatment strategy is severely compromised by the lack of donor lung availability. For example, the vast majority of donor lungs available for transplantation are obtained from brain death (BD) individuals. Unfortunately, the autonomic storm which accompanies BD often results in neurogenic pulmonary edema (NPE), thereby either producing irreversible lung injury or leading to primary graft dysfunction following lung transplantation. We previously demonstrated that sphingosine 1-phosphate (S1P), a phospholipid angiogenic factor and major barrier-enhancing agent, as well as S1P analogues serve to reduce vascular permeability and ischemia/reperfusion (I/R) lung injury in rodents via ligation of the S1P1 receptor, S1PR1. As primary lung graft dysfunction is induced by lung vascular endothelial cell barrier dysfunction, we hypothesized that SEW-2871, a S1PR1 agonist, may attenuate NPE when administered to the donor shortly after BD. Significant lung injury was observed 4h after BD in a rat BD model with ~60% increases in BAL total protein, BAL cell counts, and lung tissue W/D weight ratios. In contrast, rats receiving SEW-2871 (0.1 mg/kg) 15 minutes after the induction of BD and assessed 4h later exhibited significant lung protection (~50% reduction, p=0.01) reflected by reduced BAL total protein, BAL cytokines concentrations, BAL albumin, BAL total cell count and lung tissue wet/dry (W/D) weights ratio. Microarray analysis at 4hrs revealed a global impact of both BD and SEW on lung gene expression with differential expression of a subclass of genes enriched in immune/inflammation response pathways across the 4 experimental groups. Overall, SEW served to attenuate the BD-mediated ie gene expression upregulation. Two potentially useful biomarkers, Tnf and Ccrl2, exhibited gene dysregulation by microarray analysis, which was validated by qPCR. We conclude that SEW-2871 significantly attenuates BD-induced lung injury and may serve as a potential candidate to improve human lung donor availability and transplantation outcomes. Animals were divided into four groups: sham, BD (A Fogarty catheter 4 Fr. was inserted and secured into the extradural space and inflated to induce BD), SEW (injection of SEW-2871), and BD/SEW. Three replicates each.
2010-07-30 | E-GEOD-22531 | biostudies-arrayexpress
Project description:Lung transplantation remains the only viable therapy for patients with end-stage lung disease; however, full utilization of this treatment strategy is severely compromised by the lack of donor lung availability. For example, the vast majority of donor lungs available for transplantation are obtained from brain death (BD) individuals. Unfortunately, the autonomic storm which accompanies BD often results in neurogenic pulmonary edema (NPE), thereby either producing irreversible lung injury or leading to primary graft dysfunction following lung transplantation. We previously demonstrated that sphingosine 1-phosphate (S1P), a phospholipid angiogenic factor and major barrier-enhancing agent, as well as S1P analogues serve to reduce vascular permeability and ischemia/reperfusion (I/R) lung injury in rodents via ligation of the S1P1 receptor, S1PR1. As primary lung graft dysfunction is induced by lung vascular endothelial cell barrier dysfunction, we hypothesized that SEW-2871, a S1PR1 agonist, may attenuate NPE when administered to the donor shortly after BD. Significant lung injury was observed 4h after BD in a rat BD model with ~60% increases in BAL total protein, BAL cell counts, and lung tissue W/D weight ratios. In contrast, rats receiving SEW-2871 (0.1 mg/kg) 15 minutes after the induction of BD and assessed 4h later exhibited significant lung protection (~50% reduction, p=0.01) reflected by reduced BAL total protein, BAL cytokines concentrations, BAL albumin, BAL total cell count and lung tissue wet/dry (W/D) weights ratio. Microarray analysis at 4hrs revealed a global impact of both BD and SEW on lung gene expression with differential expression of a subclass of genes enriched in immune/inflammation response pathways across the 4 experimental groups. Overall, SEW served to attenuate the BD-mediated ie gene expression upregulation. Two potentially useful biomarkers, Tnf and Ccrl2, exhibited gene dysregulation by microarray analysis, which was validated by qPCR. We conclude that SEW-2871 significantly attenuates BD-induced lung injury and may serve as a potential candidate to improve human lung donor availability and transplantation outcomes.
2010-07-01 | GSE22531 | GEO
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