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

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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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Acknowledgements

The illustration was partly generated using Figdraw (https://www.figdraw.com/static/index.html#/) and Servier Medical Art (provided by Servier, licensed under a Creative Commons Attribution 3.0 unported license).

Funding

This work was supported by National Natural Science Foundation of China [Grant Number 81974050]; Scientific Research Common Program of Beijing Municipal Commission of Education [Grant Number KM202010025003]; and Clinical Research Fund from Wu Jieping Medical Foundation [Grant Number 320.6750.2021-12-4].

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Authors and Affiliations

  1. Department of Immunology, School of Basic Medical Sciences, Capital Medical University, #10 Xi Tou Tiao, You An Men Wai, Fengtai, Beijing, 100069, People’s Republic of China

    Ye Cui & Zhe Lv

  2. Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, People’s Republic of China

    Zeran Yang

  3. Research Core Facilities, Capital Medical University, Beijing, 100069, People’s Republic of China

    Jianfeng Lei

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YC contributed to conceptualization, data curation, formal analysis, funding acquisition, investigation, methodology, writing—original draft, and writing—review & editing. ZL contributed to conceptualization, data curation, formal analysis, investigation; methodology, and writing—review & editing. ZY contributed to data curation, formal analysis, funding acquisition, investigation, methodology, and writing—review & editing. JL contributed to data curation, formal analysis, investigation, methodology, and writing—review & editing.

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Cui, Y., Lv, Z., Yang, Z. et al. Inhibition of Prostaglandin-Degrading Enzyme 15-PGDH Mitigates Acute Murine Lung Allograft Rejection. Lung 201, 591–601 (2023). https://doi.org/10.1007/s00408-023-00651-5

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