Inhibition of Prostaglandin-Degrading Enzyme 15-PGDH Mitigates Acute Murine Lung Allograft Rejection.

IF 4.6 2区 医学 Q1 RESPIRATORY SYSTEM
Lung Pub Date : 2023-12-01 Epub Date: 2023-11-07 DOI:10.1007/s00408-023-00651-5
Ye Cui, Zhe Lv, Zeran Yang, Jianfeng Lei
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引用次数: 0

Abstract

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.

Abstract Image

前列腺素降解酶15-PGDH的抑制减轻小鼠急性肺移植排斥反应。
目的:急性排斥反应是肺移植受者的常见并发症,对治疗提出了重大挑战。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然难以捉摸。本研究旨在检测15-PGDH在排斥肺移植物中的表达,以及15-PGDH的抑制是否能改善急性肺移植物排斥反应。方法:在同一品系或异基因错配对的供体和受体小鼠之间进行原位小鼠肺移植。测定小鼠肺移植物中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)改善急性排斥反应的疗效。此外,使用从小鼠肺同种异体移植物中分离的CD8+T细胞来探索SW033291治疗效果的潜在机制。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的积累、CD8+T细胞反应和线粒体活性的调节,并改善同种异体移植物的功能和存活率。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提高移植物存活率的治疗潜力。PGE2的积累和CD8+T细胞反应的调节代表了该模型中15-PGDH抑制益处的潜在机制。我们的发现为进一步探索15-PGDH作为改善肺移植结果的靶点提供了动力。
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来源期刊
Lung
Lung 医学-呼吸系统
CiteScore
9.10
自引率
10.00%
发文量
95
审稿时长
6-12 weeks
期刊介绍: Lung publishes original articles, reviews and editorials on all aspects of the healthy and diseased lungs, of the airways, and of breathing. Epidemiological, clinical, pathophysiological, biochemical, and pharmacological studies fall within the scope of the journal. Case reports, short communications and technical notes can be accepted if they are of particular interest.
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