The dual mTORC1/2 inhibitor AZD2014 inhibits acute graft rejection in a rat liver transplantation model.
10.12122/j.issn.1673-4254.2022.04.17
- Author:
Hui LIAO
1
;
Yi WANG
1
;
Xiao Ping XU
1
;
Chen Jie ZHOU
1
;
Jian Min ZHANG
1
;
Ke Bo ZHONG
1
;
Ding Hua YANG
2
Author Information
1. Second Department of Hepatobiliary Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China.
2. Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
- Publication Type:Randomized Controlled Trial, Veterinary
- Keywords:
AZD2014;
graft rejection;
liver transplantation;
mTOR inhibitor
- MeSH:
Animals;
Benzamides;
Graft Rejection/prevention & control*;
Graft Survival;
Liver/pathology*;
Liver Transplantation;
Mechanistic Target of Rapamycin Complex 1;
Morpholines;
Pyrimidines;
Rats;
Rats, Inbred Lew
- From:
Journal of Southern Medical University
2022;42(4):598-603
- CountryChina
- Language:Chinese
-
Abstract:
OBJECTIVE:To investigate the inhibitory effect of AZD2014, a dual mTORC1/2 inhibitor, against acute graft rejection in a rat model of allogeneic liver transplantation.
METHODS:Liver transplantation from Lewis rat to recipient BN rat (a donor-recipient combination that was prone to induce acute graft rejection) was performed using Kamada's two-cuff technique. The recipient BN rats were randomized into 2 groups for treatment with daily intraperitoneal injection of AZD2014 (5 mg/kg, n=4) or vehicle (2.5 mL/kg, n=4) for 14 consecutive days, starting from the first day after the transplantation. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total bilirubin (TBIL) levels of the rats were measured 3 days before and at 1, 3, 5, 7, 10, and 14 days after the transplantation, and the survival time of the rats within 14 days were recorded. Immunohistochemical staining was used to examine the expressions of CD3 and Foxp3 in the liver graft, and acute graft rejection was assessed using HE staining based on the Banff schema.
RESULTS:Three rats in the control group died within 14 days after the surgery, while no death occurred in the AZD2014 group, demonstrating a significantly longer survival time of the rats in AZD2014 group (χ2=4.213, P=0.04). Serum ALT, AST and TBIL levels in the control group increased progressively after the surgery and were all significantly higher than those in AZD2014 group at the same time point (P < 0.05). Pathological examination revealed significantly worse liver graft rejection in the control group than in AZD2014 group based on assessment of the rejection index (P < 0.01); the rats in the control group showed more serious T lymphocyte infiltration and significantly fewer Treg cells in the liver graft than those in AZD2014 group (P < 0.01).
CONCLUSIONS:AZD2014 can effectively inhibit acute graft rejection in rats with allogeneic liver transplantation.
