University Hospital Erlangen, Department of Cardiac Surgery, Erlangen, Germany; Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Germany.
University Hospital Erlangen, Department of Cardiac Surgery, Erlangen, Germany.
Transpl Immunol. 2022 Aug;73:101608. doi: 10.1016/j.trim.2022.101608. Epub 2022 Apr 28.
The major obstacle for long-term survival after successful lung transplantation is the development of bronchiolitis obliterans (BO) which is one phenotype of chronic lung allograft dysfunction (CLAD). Nintedanib has beneficial effects treating neoplastic diseases and idiopathic pulmonary fibrosis by blocking tyrosine kinase receptors. These receptors play an important role in alloimmune-mediated proliferative diseases. The aim of this study was to determine the effect of nintedanib on proliferative airway changes after orthotopic trachea transplantation in mice.
C57BL/6 mice (H-2) donor tracheas were orthotopically transplanted into CBA/J mice (H-2). After transplantation, recipients were daily treated with nintedanib (60 mg/kg; p.o.). Histological and immunofluorescence analysis were performed after 30 days and intragraft gene expression measurements after 14 days of treatment, respectively.
Tracheal allografts from mice treated with nintedanib showed significantly less features of chronic rejection than untreated allografts reflected in a higher epithelium/lamina propria ratio (ELR) [ELR: 0.65 ± 0.13 nintedanib vs. 0.50 ± 0.07 untreated controls; p < 0.05] and a reduced submucosal smooth muscle actin (SMA) content [SMA: 1.26% ± 0.78% nintedanib vs. 2.18% ± 1.01% untreated controls; p < 0.01]. Furthermore, lower T cell, macrophage and dendritic cell infiltration was detected in the nintedanib treated grafts. The protein and intragraft mRNA expression of receptor subtypes was considerably decreased in grafts of nintedanib treated mice. The mRNA expression of relevant immune mediators was affected by nintedanib treatment.
Receptor blocking by nintedanib reduced alloimmune-induced inflammation and chronic airway changes in mouse trachea allografts and might be a promising approach to diminish the development of BO in lung transplants.
肺移植成功后长期存活的主要障碍是闭塞性细支气管炎（BO）的发展，BO 是慢性移植物肺功能障碍（CLAD）的一种表型。尼达尼布通过阻断酪氨酸激酶受体对治疗肿瘤疾病和特发性肺纤维化具有有益作用。这些受体在同种免疫介导的增殖性疾病中发挥重要作用。本研究旨在确定尼达尼布对小鼠原位气管移植后增殖性气道变化的影响。
C57BL/6 小鼠（H-2）供体气管原位移植到 CBA/J 小鼠（H-2）。移植后，受体每天用尼达尼布（60mg/kg；po）治疗。分别在 30 天后进行组织学和免疫荧光分析，在治疗 14 天后进行移植物内基因表达测量。
与未治疗的同种异体移植物相比，用尼达尼布治疗的气管同种异体移植物显示出明显较少的慢性排斥特征，表现为更高的上皮/固有层比（ELR）[ELR：0.65±0.13 尼达尼布 vs. 0.50±0.07 未治疗对照；p<0.05]和减少的黏膜下平滑肌肌动蛋白（SMA）含量[SMA：1.26%±0.78%尼达尼布 vs. 2.18%±1.01%未治疗对照；p<0.01]。此外，在尼达尼布治疗的移植物中检测到较低的 T 细胞、巨噬细胞和树突状细胞浸润。尼达尼布治疗小鼠移植物中受体亚型的蛋白和移植物内 mRNA 表达显著降低。尼达尼布治疗影响相关免疫介质的 mRNA 表达。
尼达尼布阻断受体减少了小鼠气管同种异体移植物中的同种免疫诱导炎症和慢性气道变化，可能是减少肺移植中 BO 发展的一种有前途的方法。
