van der Ploeg Eline A, Faiz Alen, Teitsma Greta J, Brotons Alejandro Sánchez, Govorukhina Natalia, Sand Jannie M B, Leeming Diana J, Melgert Barbro N, Horvatovich Peter, Burgess Janette K, Gan C Tji
Department of Pulmonary Medicine, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
Respiratory Bioinformatics and Molecular Biology (RBMB), School of Life Sciences, University of Technology Sydney, Sydney, Australia.
JHLT Open. 2025 May 29;9:100303. doi: 10.1016/j.jhlto.2025.100303. eCollection 2025 Aug.
The obstructive phenotype of chronic lung allograft dysfunction, bronchiolitis obliterans syndrome (BOS), is diagnosed after lung transplantation (LTx) when irreversible airway obstruction is already present. This study aimed to investigate biomarkers indicative of aberrant repair resulting in a fibrotic response and inflammation signals in the serum of patients with BOS.
LTx patients transplanted at the University Medical Center Groningen between 2004 and 2017 were screened. Nineteen patients with BOS were selected and matched with 19 patients with non-BOS. Only patients for whom lung function and longitudinal serum samples post-LTx were available were included. Enzyme-linked immunosorbent assays were performed for neoepitopes of collagen types I, III, and VI and osteoprotegerin (OPG) in serum. Additionally, serum samples were analyzed by label-free liquid chromatography with tandem mass spectrometry proteomics analysis.
Collagen neoepitopes did not differ significantly between patients with BOS and non-BOS at any timepoint. OPG was significantly higher in non-BOS compared to BOS 6 months before BOS onset ( < 0.04). In proteomics analysis, proteins indicating cell repair and proliferation, namely human type II keratin-6 and centromere protein F (both FDR < 0.1), were significantly lower 3 months before BOS onset in patients with BOS compared to patients with non-BOS. C-reactive protein (FDR < 0.05) and SERPINA3 (FDR < 0.05), among others, were higher in end-stage patients with BOS compared to patients with non-BOS.
Differences in the expression of proteins that reflect the complex interplay between aberrant repair and inflammation in BOS were identified. These proteins should be investigated and validated in larger cohorts and may aid in expanding knowledge about the development of BOS.
慢性肺移植功能障碍的阻塞性表型，即闭塞性细支气管炎综合征（BOS），在肺移植（LTx）后出现不可逆气道阻塞时被诊断出来。本研究旨在调查可指示异常修复导致纤维化反应和BOS患者血清中炎症信号的生物标志物。
对2004年至2017年在格罗宁根大学医学中心接受移植的LTx患者进行筛查。选择19例BOS患者并与19例非BOS患者进行匹配。仅纳入肺功能和LTx后纵向血清样本可用的患者。对血清中I型、III型和VI型胶原蛋白的新表位以及骨保护素（OPG）进行酶联免疫吸附测定。此外，通过无标记液相色谱串联质谱蛋白质组学分析对血清样本进行分析。
在任何时间点，BOS患者和非BOS患者之间的胶原蛋白新表位均无显著差异。在BOS发作前6个月，非BOS患者的OPG显著高于BOS患者（<0.04）。在蛋白质组学分析中，与非BOS患者相比，BOS患者在BOS发作前3个月时，指示细胞修复和增殖的蛋白质，即人II型角蛋白-6和着丝粒蛋白F（两者FDR<0.1）显著降低。与非BOS患者相比，终末期BOS患者的C反应蛋白（FDR<0.05）和丝氨酸蛋白酶抑制剂A3（FDR<0.05）等更高。
确定了反映BOS中异常修复与炎症之间复杂相互作用的蛋白质表达差异。这些蛋白质应在更大的队列中进行研究和验证，可能有助于扩展对BOS发病机制的认识。
