Complement inhibition alleviates donor brain death-induced liver injury and posttransplant cascade injury by regulating phosphoinositide 3-kinase signaling

Chengjie Lin; Biao Lei; Chunqiang Dong; Junze Chen; Shilian Chen; Keqing Jiang; Yonglian Zeng; Huizhao Su; Hu Jin; Xiaoqiang Qiu; Zeyuan Li; Zhigao Hu; Shuiping Yu; Cheng Zhang; Shiliu Lu; Carl Atkinson; Stephen Tomlinson; Fudi Zhong; Guandou Yuan; Songqing He

doi:10.1016/j.ajt.2023.01.019

Complement inhibition alleviates donor brain death-induced liver injury and posttransplant cascade injury by regulating phosphoinositide 3-kinase signaling

Chengjie Lin, Biao Lei, Chunqiang Dong, Junze Chen, Shilian Chen, Keqing Jiang, Yonglian Zeng, Huizhao Su, Hu Jin, Xiaoqiang Qiu, Zeyuan Li, Zhigao Hu, Shuiping Yu, Cheng Zhang, Shiliu Lu, Carl Atkinson, Stephen Tomlinson, Fudi Zhong^*, Guandou Yuan^*, Songqing He^*

^*Corresponding author for this work

Surgery

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

Abstract

Brain death (BD) donors are the primary source of donor organs for liver transplantation. However, the effects of BD on donor livers and outcomes after liver transplantation remain unclear. Here, we explored the role of complement and the therapeutic effect of complement inhibition in BD-induced liver injury and posttransplantation injury in a mouse BD and liver transplantation model. For complement inhibition, we used complement receptor 2 (CR2)-Crry, a murine inhibitor of C3 activation that specifically targets sites of complement activation. In the mouse model, BD resulted in complement activation and liver injury in donor livers and a cascade liver injury posttransplantation, mediated in part through the C3a-C3aR (C3a receptor) signaling pathway, which was ameliorated by treatment with CR2-Crry. Treatment of BD donors with CR2-Crry improved graft survival, which was further improved when recipients received an additional dose of CR2-Crry posttransplantation. Mechanistically, we determined that complement inhibition alleviated BD-induced donor liver injury and posttransplant cascade injury by regulating phosphoinositide 3-kinase (PI3K) signaling pathways. Together, BD induced donor liver injury and cascade injury post-transplantation, which was mediated by complement activation products acting on PI3K signaling pathways. Our study provides an experimental basis for developing strategies to improve the survival of BD donor grafts in liver transplantation.

Original language	English (US)
Pages (from-to)	484-497
Number of pages	14
Journal	American Journal of Transplantation
Volume	23
Issue number	4
DOIs	https://doi.org/10.1016/j.ajt.2023.01.019
State	Published - Apr 2023

Funding

This study was supported in part by the National Natural Science Foundation of China (No. 31370917 to S.H., No. 82160500 to G.Y.), the National Key Research and Development Program (No. 2022YFE0131600 to S.H.), the 111 Project ( D17011 , to S.H.), U.S. Department of Defense ( W81XWH2010939 , to S.T.) Guangxi science and technology base and talent project ( GuikeAA21220002 , to S.H.), Guangxi Key Research and Development Plan ( 2018AD03001 , to S.H.), the Natural Science Foundation of Guangxi Province ( 2020GXNSFAA159050 , to Z.F.), Special project of central government guiding local science and technology development ( ZY20198011 , to S.H.).

Keywords

brain death
cascade injury
complement inhibition
liver transplantation
PI3K signaling

ASJC Scopus subject areas

Immunology and Allergy
Transplantation
Pharmacology (medical)

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10.1016/j.ajt.2023.01.019

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Lin, C., Lei, B., Dong, C., Chen, J., Chen, S., Jiang, K., Zeng, Y., Su, H., Jin, H., Qiu, X., Li, Z., Hu, Z., Yu, S., Zhang, C., Lu, S., Atkinson, C., Tomlinson, S., Zhong, F., Yuan, G., & He, S. (2023). Complement inhibition alleviates donor brain death-induced liver injury and posttransplant cascade injury by regulating phosphoinositide 3-kinase signaling. American Journal of Transplantation, 23(4), 484-497. https://doi.org/10.1016/j.ajt.2023.01.019

@article{7b861a4747db4fce82d06fe6b129afb5,

title = "Complement inhibition alleviates donor brain death-induced liver injury and posttransplant cascade injury by regulating phosphoinositide 3-kinase signaling",

abstract = "Brain death (BD) donors are the primary source of donor organs for liver transplantation. However, the effects of BD on donor livers and outcomes after liver transplantation remain unclear. Here, we explored the role of complement and the therapeutic effect of complement inhibition in BD-induced liver injury and posttransplantation injury in a mouse BD and liver transplantation model. For complement inhibition, we used complement receptor 2 (CR2)-Crry, a murine inhibitor of C3 activation that specifically targets sites of complement activation. In the mouse model, BD resulted in complement activation and liver injury in donor livers and a cascade liver injury posttransplantation, mediated in part through the C3a-C3aR (C3a receptor) signaling pathway, which was ameliorated by treatment with CR2-Crry. Treatment of BD donors with CR2-Crry improved graft survival, which was further improved when recipients received an additional dose of CR2-Crry posttransplantation. Mechanistically, we determined that complement inhibition alleviated BD-induced donor liver injury and posttransplant cascade injury by regulating phosphoinositide 3-kinase (PI3K) signaling pathways. Together, BD induced donor liver injury and cascade injury post-transplantation, which was mediated by complement activation products acting on PI3K signaling pathways. Our study provides an experimental basis for developing strategies to improve the survival of BD donor grafts in liver transplantation.",

keywords = "brain death, cascade injury, complement inhibition, liver transplantation, PI3K signaling",

author = "Chengjie Lin and Biao Lei and Chunqiang Dong and Junze Chen and Shilian Chen and Keqing Jiang and Yonglian Zeng and Huizhao Su and Hu Jin and Xiaoqiang Qiu and Zeyuan Li and Zhigao Hu and Shuiping Yu and Cheng Zhang and Shiliu Lu and Carl Atkinson and Stephen Tomlinson and Fudi Zhong and Guandou Yuan and Songqing He",

note = "Publisher Copyright: {\textcopyright} 2023 American Society of Transplantation & American Society of Transplant Surgeons",

year = "2023",

month = apr,

doi = "10.1016/j.ajt.2023.01.019",

language = "English (US)",

volume = "23",

pages = "484--497",

journal = "American Journal of Transplantation",

issn = "1600-6135",

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Lin, C, Lei, B, Dong, C, Chen, J, Chen, S, Jiang, K, Zeng, Y, Su, H, Jin, H, Qiu, X, Li, Z, Hu, Z, Yu, S, Zhang, C, Lu, S, Atkinson, C, Tomlinson, S, Zhong, F, Yuan, G & He, S 2023, 'Complement inhibition alleviates donor brain death-induced liver injury and posttransplant cascade injury by regulating phosphoinositide 3-kinase signaling', American Journal of Transplantation, vol. 23, no. 4, pp. 484-497. https://doi.org/10.1016/j.ajt.2023.01.019

TY - JOUR

T1 - Complement inhibition alleviates donor brain death-induced liver injury and posttransplant cascade injury by regulating phosphoinositide 3-kinase signaling

AU - Lin, Chengjie

AU - Lei, Biao

AU - Dong, Chunqiang

AU - Chen, Junze

AU - Chen, Shilian

AU - Jiang, Keqing

AU - Zeng, Yonglian

AU - Su, Huizhao

AU - Jin, Hu

AU - Qiu, Xiaoqiang

AU - Li, Zeyuan

AU - Hu, Zhigao

AU - Yu, Shuiping

AU - Zhang, Cheng

AU - Lu, Shiliu

AU - Atkinson, Carl

AU - Tomlinson, Stephen

AU - Zhong, Fudi

AU - Yuan, Guandou

AU - He, Songqing

PY - 2023/4

Y1 - 2023/4

N2 - Brain death (BD) donors are the primary source of donor organs for liver transplantation. However, the effects of BD on donor livers and outcomes after liver transplantation remain unclear. Here, we explored the role of complement and the therapeutic effect of complement inhibition in BD-induced liver injury and posttransplantation injury in a mouse BD and liver transplantation model. For complement inhibition, we used complement receptor 2 (CR2)-Crry, a murine inhibitor of C3 activation that specifically targets sites of complement activation. In the mouse model, BD resulted in complement activation and liver injury in donor livers and a cascade liver injury posttransplantation, mediated in part through the C3a-C3aR (C3a receptor) signaling pathway, which was ameliorated by treatment with CR2-Crry. Treatment of BD donors with CR2-Crry improved graft survival, which was further improved when recipients received an additional dose of CR2-Crry posttransplantation. Mechanistically, we determined that complement inhibition alleviated BD-induced donor liver injury and posttransplant cascade injury by regulating phosphoinositide 3-kinase (PI3K) signaling pathways. Together, BD induced donor liver injury and cascade injury post-transplantation, which was mediated by complement activation products acting on PI3K signaling pathways. Our study provides an experimental basis for developing strategies to improve the survival of BD donor grafts in liver transplantation.

AB - Brain death (BD) donors are the primary source of donor organs for liver transplantation. However, the effects of BD on donor livers and outcomes after liver transplantation remain unclear. Here, we explored the role of complement and the therapeutic effect of complement inhibition in BD-induced liver injury and posttransplantation injury in a mouse BD and liver transplantation model. For complement inhibition, we used complement receptor 2 (CR2)-Crry, a murine inhibitor of C3 activation that specifically targets sites of complement activation. In the mouse model, BD resulted in complement activation and liver injury in donor livers and a cascade liver injury posttransplantation, mediated in part through the C3a-C3aR (C3a receptor) signaling pathway, which was ameliorated by treatment with CR2-Crry. Treatment of BD donors with CR2-Crry improved graft survival, which was further improved when recipients received an additional dose of CR2-Crry posttransplantation. Mechanistically, we determined that complement inhibition alleviated BD-induced donor liver injury and posttransplant cascade injury by regulating phosphoinositide 3-kinase (PI3K) signaling pathways. Together, BD induced donor liver injury and cascade injury post-transplantation, which was mediated by complement activation products acting on PI3K signaling pathways. Our study provides an experimental basis for developing strategies to improve the survival of BD donor grafts in liver transplantation.

KW - brain death

KW - cascade injury

KW - complement inhibition

KW - liver transplantation

KW - PI3K signaling

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U2 - 10.1016/j.ajt.2023.01.019

DO - 10.1016/j.ajt.2023.01.019

M3 - Article

C2 - 36746335

AN - SCOPUS:85151456691

SN - 1600-6135

VL - 23

SP - 484

EP - 497

JO - American Journal of Transplantation

JF - American Journal of Transplantation

IS - 4

ER -

Complement inhibition alleviates donor brain death-induced liver injury and posttransplant cascade injury by regulating phosphoinositide 3-kinase signaling

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