循环鞘氨醇-1-磷酸增加可减轻离体肺灌注期间的肺损伤。
Increasing circulating sphingosine-1-phosphate attenuates lung injury during ex vivo lung perfusion.
机构信息
Department of Surgery, University of Virginia School of Medicine, Charlottesville, Va.
Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, Va.
出版信息
J Thorac Cardiovasc Surg. 2018 Aug;156(2):910-917. doi: 10.1016/j.jtcvs.2018.02.090. Epub 2018 Mar 11.
BACKGROUND
Sphingosine-1-phosphate regulates endothelial barrier integrity and promotes cell survival and proliferation. We hypothesized that upregulation of sphingosine-1-phosphate during ex vivo lung perfusion would attenuate acute lung injury and improve graft function.
METHODS
C57BL/6 mice (n = 4-8/group) were euthanized, followed by 1 hour of warm ischemia and 1 hour of cold preservation in a model of donation after cardiac death. Subsequently, mice underwent 1 hour of ex vivo lung perfusion with 1 of 4 different perfusion solutions: Steen solution (Steen, control arm), Steen with added sphingosine-1-phosphate (Steen + sphingosine-1-phosphate), Steen plus a selective sphingosine kinase 2 inhibitor (Steen + sphingosine kinase inhibitor), or Steen plus both additives (Steen + sphingosine-1-phosphate + sphingosine kinase inhibitor). During ex vivo lung perfusion, lung compliance and pulmonary artery pressure were continuously measured. Pulmonary vascular permeability was assessed with injection of Evans Blue dye.
RESULTS
The combination of 1 hour of warm ischemia, followed by 1 hour of cold ischemia created significant lung injury compared with lungs that were immediately harvested after circulatory death and put on ex vivo lung perfusion. Addition of sphingosine-1-phosphate or sphingosine kinase inhibitor alone did not significantly improve lung function during ex vivo lung perfusion compared with Steen without additives. However, group Steen + sphingosine-1-phosphate + sphingosine kinase inhibitor resulted in significantly increased compliance (110% ± 13.9% vs 57.7% ± 6.6%, P < .0001) and decreased pulmonary vascular permeability (33.1 ± 11.9 μg/g vs 75.8 ± 11.4 μg/g tissue, P = .04) compared with Steen alone.
CONCLUSIONS
Targeted drug therapy with a combination of sphingosine-1-phosphate + sphingosine kinase inhibitor during ex vivo lung perfusion improves lung function in a murine donation after cardiac death model. Elevation of circulating sphingosine-1-phosphate via specific pharmacologic modalities during ex vivo lung perfusion may provide endothelial protection in marginal donor lungs leading to successful lung rehabilitation for transplantation.
背景
鞘氨醇-1-磷酸可调节内皮细胞屏障完整性，并促进细胞存活和增殖。我们假设，在体外肺灌注过程中鞘氨醇-1-磷酸的上调可减轻急性肺损伤并改善移植物功能。
方法
C57BL/6 小鼠（每组 4-8 只）被安乐死，随后进行 1 小时热缺血和 1 小时冷保存，模型为心脏死亡后的供体。随后，将小鼠进行 1 小时的体外肺灌注，使用 4 种不同的灌注液中的 1 种：Steen 溶液（Steen，对照臂）、添加鞘氨醇-1-磷酸的 Steen 溶液（Steen+鞘氨醇-1-磷酸）、添加选择性鞘氨醇激酶 2 抑制剂的 Steen 溶液（Steen+鞘氨醇激酶抑制剂）或添加两者的 Steen 溶液（Steen+鞘氨醇-1-磷酸+鞘氨醇激酶抑制剂）。在体外肺灌注过程中，连续测量肺顺应性和肺动脉压。通过注射 Evans Blue 染料评估肺血管通透性。
结果
与立即收获循环死亡并进行体外肺灌注的肺相比，1 小时热缺血后再进行 1 小时冷缺血会导致明显的肺损伤。与没有添加剂的 Steen 相比，单独添加鞘氨醇-1-磷酸或鞘氨醇激酶抑制剂在体外肺灌注过程中并未显著改善肺功能。然而，Steen+鞘氨醇-1-磷酸+鞘氨醇激酶抑制剂组的顺应性明显增加（110%±13.9%比 57.7%±6.6%，P<0.0001），肺血管通透性降低（33.1±11.9μg/g 比 75.8±11.4μg/g 组织，P=0.04）。
结论
在心脏死亡后的供体鼠模型中，通过体外肺灌注靶向药物治疗，使用鞘氨醇-1-磷酸+鞘氨醇激酶抑制剂的组合可改善肺功能。通过特定的药理学方法在体外肺灌注过程中升高循环鞘氨醇-1-磷酸水平，可能会为边缘供体肺提供内皮保护，从而实现肺康复并成功移植。
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