白细胞介素-18：同种异体肺移植后闭塞性细支气管炎发生、发展及药物治疗的新靶点

Interleukin-18: A Novel Participant in the Occurrence, Development, and Drug Therapy of Obliterative Bronchiolitis Postlung Transplantation.

机构信息

Department of Pharmacy, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China.

Department of Pharmacy, The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China.

出版信息

Dis Markers. 2021 Jul 27;2021:5586312. doi: 10.1155/2021/5586312. eCollection 2021.

DOI:10.1155/2021/5586312

PMID:34367377

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8337162/

Abstract

BACKGROUND

Obliterative bronchiolitis (OB) was a main cause of deterioration of long-term prognosis in lung transplant recipients after the first posttransplant year. Proinflammatory cytokine interleukin-18 (IL-18) strengthened both the natural immunity and acquired immunity and played an important role in organ transplantation. The roles of IL-18 in the occurrence, development, and drug treatment of OB remained unclear.

METHODS

Small interfering RNA (siRNA) against mouse IL-18 (siRNA-IL-18) was used to silence IL-18 expression. Mouse heterotopic tracheal transplantation model was used to simulate OB. Recipient mice were divided into 5 groups ( = 12) according to donor mouse strains and drug treatment: isograft group, allograft group, allograft+tacrolimus group, allograft+azithromycin group, and allograft+tacrolimus+azithromycin group. The luminal obliteration rates were pathological evaluation. Expressions of cytokines and MMPs were detected by real-time PCR, western blot, and enzyme chain immunosorbent assay (ELISA).

RESULTS

The luminal obliteration rates of IL-18 of the siRNA-IL-18 group were significantly lower than those of the negative control group ( < 0.0001) and the blank control group ( = 0.0002). mRNA expressions of IFN-, EMMPRIN, MMP-8, and MMP-9 of the siRNA-IL-18 group were significantly lower than those of the negative and blank control groups. No tracheal occlusion occurred in grafts of the isograft group. The rates of tracheal occlusion of the allograft group, allograft+tacrolimus group, allograft+azithromycin group, and allograft+tacrolimus+azithromycin group were 72.17 ± 4.66%, 40.33 ± 3.00%, 38.50 ± 2.08%, and 23.33 ± 3.24%, respectively. There were significant differences between the 4 groups ( < 0.001). Serum protein expressions of IL-17 ( = 0.0017), IL-18 ( = 0.0036), IFN- ( = 0.0102), and MMP-9 ( = 0.0194) were significantly decreased in the allograft+tacrolimus+azithromycin group compared to the allograft group.

CONCLUSIONS

IL-18 could be a novel molecular involved in the occurrence, development, and drug treatment of OB.

摘要

背景

闭塞性细支气管炎（OB）是肺移植受者移植后第一年以后长期预后恶化的主要原因。前炎症细胞因子白细胞介素-18（IL-18）增强了天然免疫和获得性免疫，在器官移植中发挥重要作用。IL-18在 OB 的发生、发展和药物治疗中的作用尚不清楚。

方法

使用针对小鼠 IL-18 的小干扰 RNA（siRNA）（siRNA-IL-18）沉默 IL-18 表达。使用小鼠异位气管移植模型模拟 OB。根据供体小鼠株和药物治疗将受体小鼠分为 5 组（每组 12 只）：同系移植组、同种异体移植组、同种异体移植+他克莫司组、同种异体移植+阿奇霉素组和同种异体移植+他克莫司+阿奇霉素组。通过病理评估管腔闭塞率。通过实时 PCR、western blot 和酶联免疫吸附试验（ELISA）检测细胞因子和 MMPs 的表达。

结果

siRNA-IL-18 组的 IL-18 管腔闭塞率明显低于阴性对照组（<0.0001）和空白对照组（=0.0002）。siRNA-IL-18 组 IFN-、EMMPRIN、MMP-8 和 MMP-9 的 mRNA 表达明显低于阴性和空白对照组。同系移植组移植物无气管闭塞。同种异体移植组、同种异体移植+他克莫司组、同种异体移植+阿奇霉素组和同种异体移植+他克莫司+阿奇霉素组的气管闭塞率分别为 72.17±4.66%、40.33±3.00%、38.50±2.08%和 23.33±3.24%。四组间差异有统计学意义（<0.001）。与同种异体移植组相比，同种异体移植+他克莫司+阿奇霉素组血清中白细胞介素-17（=0.0017）、白细胞介素-18（=0.0036）、IFN-（=0.0102）和 MMP-9（=0.0194）的蛋白表达明显降低。