Tahmasbpour Eisa, Philp Ashleigh, Sivasubramaniam Vanathi, Thomson Claire, Plit Marshall, Ravipati Anjaneyaswamy, Raftery Mark, Darley David
Department of Thoracic Medicine and Lung Transplantation, St Vincent's Hospital Sydney, University of New South Wales, Sydney, NSW, Australia.
School of Clinical Medicine, UNSW Medicine and Health, St Vincent's Healthcare Clinical Campus, University of New South Wales, Sydney, Australia.
Transplant Direct. 2025 May 12;11(6):e1800. doi: 10.1097/TXD.0000000000001800. eCollection 2025 Jun.
Chronic lung allograft dysfunction (CLAD) is a major contributor to poor long-term survival after lung transplantation (LTx). There is a paucity of validated tissue biomarkers which limits the early detection of CLAD. The aim of this study was to discover novel tissue proteins in CLAD.
A longitudinal cohort study analyzed 15 tissue specimens from 2 groups of bilateral LTx recipients; those with CLAD (n = 3) and those without CLAD (n = 3). In both groups, transbronchial biopsies (TBBx) were retrieved from 2 timepoints; stable surveillance at 90 d after transplant, and during episodes of acute lung allograft dysfunction. In the CLAD cohort, additional tissue from explant CLAD lungs collected at retransplantation was analyzed. Proteomics analysis and immunohistochemistry were used to identify and validate differentially expressed proteins.
Tissue upregulation of a number of proteins including SerpinB1, SerpinH1, Cofilin 1, MUC1, COL15A1, COL4A4, and Coronin1B was found in recipients with CLAD. This finding was present when comparing CLAD onset and explant pathology to stable surveillance among recipients with CLAD and evident when compared with recipients without CLAD. Most of the upregulated tissue proteins in patients with CLAD had collectively critical roles in leukocytes migration and activation, inflammation, free radicals production and oxidative stress, epithelial-mesenchymal transition, myofibroblasts activation, and excessive deposition of extracellular matrix, which in turn enhance the risk of lung fibrosis and graft rejection. We also found exclusive expression of HLA-DQB1, JCHAIN, SAP18, FUCA1, MZB1, G3BP2, and BTF3 in CLAD cases, indicating they could be specific biomarkers of CLAD.
This study identifies distinct proteomes that are linked to CLAD development and consequently may be a useful indicator for identifying LTx patients at higher risk of CLAD.
慢性肺移植功能障碍（CLAD）是肺移植（LTx）后长期生存率低下的主要原因。目前缺乏经过验证的组织生物标志物，这限制了CLAD的早期检测。本研究的目的是发现CLAD中新型的组织蛋白。
一项纵向队列研究分析了两组双侧LTx受者的15份组织标本；患有CLAD的受者（n = 3）和未患有CLAD的受者（n = 3）。在两组中，从两个时间点获取经支气管活检（TBBx）标本；移植后90天的稳定监测期，以及急性肺移植功能障碍发作期间。在CLAD队列中，分析了再次移植时从CLAD肺移植切除标本中获取的额外组织。采用蛋白质组学分析和免疫组织化学来鉴定和验证差异表达的蛋白质。
在患有CLAD的受者中发现了多种蛋白质的组织上调，包括丝氨酸蛋白酶抑制剂B1（SerpinB1）、丝氨酸蛋白酶抑制剂H1（SerpinH1）、丝切蛋白1（Cofilin 1）、粘蛋白1（MUC1）、胶原蛋白15A1（COL15A1）、胶原蛋白4A4（COL4A4）和冠蛋白1B（Coronin1B）。将CLAD发作期和移植切除标本的病理与CLAD受者的稳定监测期进行比较时发现了这一结果，与未患CLAD的受者相比时也很明显。CLAD患者中大多数上调的组织蛋白在白细胞迁移和激活、炎症、自由基产生和氧化应激、上皮-间质转化、肌成纤维细胞激活以及细胞外基质过度沉积中共同发挥关键作用，进而增加了肺纤维化和移植排斥的风险。我们还发现在CLAD病例中HLA-DQB1、连接链蛋白（JCHAIN）、SAP18、岩藻糖苷酶1（FUCA1）、MZB1、G3BP2和BTF3有特异性表达，表明它们可能是CLAD的特异性生物标志物。
本研究确定了与CLAD发展相关的独特蛋白质组，因此可能是识别CLAD风险较高的LTx患者的有用指标。
