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 (z 50% reduction, P ¼ 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.Keywords: neurogenic pulmonary edema; lung injury; sphingosine 1-phosphate; sphingolipids; lung transplant donors Over the past decade, lung transplantation has become an increasingly important mode of therapy for patients with a variety of endstage lung diseases. The vast majority of lung donors are individuals with brain death (BD). However, the early autonomic storm accompanying brain BD triggers the development of systemic and pulmonary inflammatory responses, which lead to increased pulmonary endothelial permeability (1, 2) and to the sympathetic vasoconstriction of the systemic and pulmonary vasculature. These changes, in addition to possible ischemiareperfusion injury, disrupt the integrity of the alveolar capillary membrane, resulting in neurogenic pulmonary edema (NPE) (1-4). Increased pulmonary interstitial and alveolar fluid accumulation usually develops rapidly after acute injury to the central nervous system (1), and any preventive treatment should be given early after BD (3). This lung injury mimics a form of acute respiratory distress syndrome (ARDS), the most devastating form of acute lung injury (ALI), with excessive ...

MG132 protects against lung injury following brain death in rats

“…Thus, there is a need to study the mechanism of lung injury after BD and to develop effective therapeutics to decrease lung injury. In the present study, a decrease in the arterial oxygenation index and an increase in the left lung wet/dry weight ratio and the aggravation of lung pathological injury were observed after BD in rats, in accordance with published results describing the lung after BD (35,36).…”

RETRACTED ARTICLE: Serum sphingosine-1-phosphate levels and Sphingosine-1-Phosphate gene polymorphisms in acute respiratory distress syndrome: a multicenter prospective study

“…S1P can prevent neutrophil chemotaxis and the transmigration of neutrophils across an endothelial cell monolayer [27]. In ALI animal models, administration of S1PR agonists inhibited early pro-inflammatory cytokine production, inhibited innate immune cell recruitment and attenuated inflammatory lung injury [14,[28][29][30][31].…”

Sphingolipids as a Novel Therapeutic Target in Radiation-Induced Lung Injury

“…Accordingly, interest in S1P analogs, which similarly confer vascular protection but may have more favorable safety profiles, led to the study of these molecules in our RILI model. These include FTY720, which admittedly has safety concerns of its own, as well as SEW-2871, an S1PR1 agonist, and tyspinate, a phosphonate S1P analog, all three of which have demonstrated protective effects in pre-clinical ALI models [9,16,26,27].…”