Toronto Lung Transplant Program, University Health Network, University of Toronto, Toronto, ON, Canada.
Biostatistics Research Unit, University Health Network, University of Toronto, Toronto, ON, Canada.
Transpl Int. 2019 Sep;32(9):965-973. doi: 10.1111/tri.13444. Epub 2019 May 15.
Chronic lung allograft dysfunction (CLAD) remains the leading cause of late death after lung transplantation. Epithelial injury is thought to be a key event in the pathogenesis of CLAD. M30 and M65 are fragments of cytokeratin-18 released specifically during epithelial cell apoptosis and total cell death, respectively. We investigated whether M30 and M65 levels in bronchoalveolar lavage (BAL) correlate with CLAD subtypes: restrictive allograft syndrome (RAS) versus bronchiolitis obliterans syndrome (BOS). BALs were obtained from 26 patients with established CLAD (10 RAS, 16 BOS) and 19 long-term CLAD-free controls. Samples with concurrent infection or acute rejection were excluded. Protein levels were measured by ELISA. Variables were compared using Kruskal-Wallis, Mann-Whitney U test and Chi-squared tests. Association of M30 and M65 levels with post-CLAD survival was assessed using a Cox PH models. M65 levels were significantly higher in RAS compared to BOS and long-term CLAD-free controls and correlated with worse post-CLAD survival. Lung epithelial cell death is enhanced in patients with RAS. Detection of BAL M65 may be used to differentiate CLAD subtypes and as a prognostic marker in patients with established CLAD. Understanding the role of epithelial cell death in CLAD pathogenesis may help identify new therapeutic targets to improve outcome.
慢性肺移植功能障碍（CLAD）仍然是肺移植后晚期死亡的主要原因。上皮损伤被认为是 CLAD 发病机制中的关键事件。M30 和 M65 是细胞角蛋白-18 在特定的上皮细胞凋亡和总细胞死亡时释放的片段。我们研究了支气管肺泡灌洗液（BAL）中的 M30 和 M65 水平是否与 CLAD 亚型相关：限制性移植物综合征（RAS）与闭塞性细支气管炎综合征（BOS）。从 26 例已确诊的 CLAD 患者（10 例 RAS，16 例 BOS）和 19 例长期无 CLAD 对照组中获得 BAL。排除伴有合并感染或急性排斥反应的样本。通过 ELISA 测量蛋白水平。使用 Kruskal-Wallis、Mann-Whitney U 检验和卡方检验比较变量。使用 Cox PH 模型评估 M30 和 M65 水平与 CLAD 后生存的相关性。与 BOS 和长期无 CLAD 对照组相比，RAS 患者的 M65 水平显著升高，且与 CLAD 后生存预后较差相关。RAS 患者的肺上皮细胞死亡增加。检测 BAL 中的 M65 可用于区分 CLAD 亚型，并作为已确诊的 CLAD 患者的预后标志物。了解上皮细胞死亡在 CLAD 发病机制中的作用可能有助于确定新的治疗靶点以改善预后。
