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07-11-2023 | LUNG TRANSPLANTATION

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

Authors: Ye Cui, Zhe Lv, Zeran Yang, Jianfeng Lei

Published in: Lung | Issue 6/2023

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.

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Title: Inhibition of Prostaglandin-Degrading Enzyme 15-PGDH Mitigates Acute Murine Lung Allograft Rejection
Authors: Ye Cui
Zhe Lv
Zeran Yang
Jianfeng Lei
Publication date: 07-11-2023
Publisher: Springer US
Published in: Lung / Issue 6/2023
Print ISSN: 0341-2040
Electronic ISSN: 1432-1750
DOI: https://doi.org/10.1007/s00408-023-00651-5

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