Purpose

Acute rejection is a frequent complication among lung transplant recipients and poses substantial therapeutic challenges. 15-hydroxyprostaglandin dehydrogenase (15-PGDH), an enzyme responsible for the inactivation of prostaglandin E2 (PGE2), has recently been implicated in inflammatory lung diseases. However, the role of 15-PGDH in lung transplantation rejection remains elusive. The present study was undertaken to examine the expression of 15-PGDH in rejected lung allografts and whether inhibition of 15-PGDH ameliorates acute lung allograft rejection.

Methods

Orthotopic mouse lung transplantations were performed between donor and recipient mice of the same strain or allogeneic mismatched pairs. The expression of 15-PGDH in mouse lung grafts was measured. The efficacy of a selective 15-PGDH inhibitor (SW033291) in ameliorating acute rejection was assessed through histopathological examination, micro-CT imaging, and pulmonary function tests. Additionally, the mechanism underlying the effects of SW033291 treatment was explored using CD8⁺ T cells isolated from mouse lung allografts.

Results

Increased 15-PGDH expression was observed in rejected allografts and allogeneic CD8⁺ T cells. Treatment with SW033291 led to an accumulation of PGE2, modulation of CD8⁺ T-cell responses and mitochondrial activity, and improved allograft function and survival.

Conclusion

Our study provides new insights into the role of 15-PGDH in acute lung rejection and highlights the therapeutic potential of inhibiting 15-PGDH for enhancing graft survival. The accumulation of PGE2 and modulation of CD8⁺ T-cell responses represent potential mechanisms underlying the benefits of 15-PGDH inhibition in this model. Our findings provide impetus for further exploring 15-PGDH as a target for improving lung transplantation outcomes.

中文翻译：

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抑制前列腺素降解酶 15-PGDH 可减轻急性小鼠肺同种异体移植排斥反应

目的

急性排斥反应是肺移植受者中常见的并发症，给治疗带来了巨大的挑战。15-羟基前列腺素脱氢酶 (15-PGDH) 是一种负责前列腺素 E2 (PGE2) 失活的酶，最近被认为与炎症性肺部疾病有关。然而，15-PGDH 在肺移植排斥反应中的作用仍不清楚。本研究旨在检查15-PGDH在排斥的肺同种异体移植物中的表达以及抑制15-PGDH是否改善急性肺同种异体移植排斥。

方法

在同一品系或同种异体错配对的供体和受体小鼠之间进行原位小鼠肺移植。测量小鼠肺移植物中15-PGDH的表达。通过组织病理学检查、显微 CT 成像和肺功能测试评估选择性 15-PGDH 抑制剂 (SW033291) 在改善急性排斥反应中的功效。此外，使用从小鼠同种异体肺移植物中分离的CD8 ⁺ T 细胞探索了 SW033291 治疗作用的潜在机制。

结果

^{在排斥的同种异体移植物和同种异体 CD8 +} T 细胞中观察到 15-PGDH 表达增加。SW033291 治疗导致 PGE2 积累，调节 CD8 ⁺ T 细胞反应和线粒体活性，并改善同种异体移植物功能和存活率。

结论

我们的研究为 15-PGDH 在急性肺排斥反应中的作用提供了新的见解，并强调了抑制 15-PGDH 在提高移植物存活方面的治疗潜力。PGE2 的积累和 CD8 ⁺ T 细胞反应的调节代表了该模型中 15-PGDH 抑制的潜在机制。我们的研究结果为进一步探索 15-PGDH 作为改善肺移植结果的目标提供了动力。