Sand Jannie M B, Frederiksen Peder, John Alison E, Simões Filipa B, Hoyer Nils, Prior Thomas S, Avdic-Belltheus Adnan, Molyneaux Philip L, Stewart Iain D, Fainberg Hernan P, Johnson Simon R, Karsdal Morten A, Leeming Diana J, Bendstrup Elisabeth, Shaker Saher B, Maher Toby M, Jenkins Gisli
Nordic Bioscience, Herlev, Denmark
Nordic Bioscience, Herlev, Denmark.
Thorax. 2025 Jun 19. doi: 10.1136/thorax-2024-221868.
Idiopathic pulmonary fibrosis (IPF) is characterised by damage to the epithelial layer, closely associated with the alveolar basement membrane (BM). We aimed to investigate how type IV collagen (COL4) in the BM changes with the progression of IPF.
COL4 synthesis (PRO-C4) was detected in blood by the nordicPRO-C4 biomarker in patients with IPF from the two prospective, multicentre, observational, longitudinal cohorts, pulmonary fibrosis biomarker (PFBIO) and prospective observation of fibrosis in the lung clinical endpoints (PROFILE). PRO-C4 trajectories over 12 months were compared between progressors and non-progressors by linear mixed effects regression models. Rate of change in PRO-C4 and lung function were compared by Bayesian bivariate longitudinal models. Cox proportional hazards models analysed baseline PRO-C4 and 3 years mortality. COL4 staining in IPF and non-IPF lungs was evaluated by immunohistochemistry.
In PFBIO and PROFILE, 51/220 (23.2%) and 221/459 (48.1%) patients, respectively, had progressive disease at 12 months. Longitudinal PRO-C4 levels were higher in progressors versus non-progressors (average differences: PFBIO 21.5% (95% CI 3.4% to 42.9%, p=0.0184); PROFILE 10.9% (95% CI 0.8% to 22.1%; p=0.0340). Monthly rate of change in PRO-C4 was steeper in non-survivors versus survivors (mean difference up to 3.12% (95% CI 0.35% to 5.91%)) and was inversely correlated with the change in lung function. High baseline PRO-C4 was associated with increased mortality risk in PFBIO (HR 2.55 (95% CI 1.27 to 5.12), p=0.0083). COL4 staining was higher in IPF versus non-IPF lung but was less obvious in end-stage tissue.
High and increasing serological PRO-C4 levels were prognostic for progression in two independent IPF cohorts. This study suggests that COL4 synthesis assessed by PRO-C4 is a pathologically relevant biomarker of alveolar BM repair in IPF.
特发性肺纤维化（IPF）的特征是上皮层受损，与肺泡基底膜（BM）密切相关。我们旨在研究BM中的IV型胶原（COL4）如何随IPF的进展而变化。
在两项前瞻性、多中心、观察性纵向队列研究，即肺纤维化生物标志物（PFBIO）研究和肺临床终点纤维化前瞻性观察（PROFILE）研究中，通过北欧PRO-C4生物标志物检测IPF患者血液中的COL4合成（PRO-C4）。通过线性混合效应回归模型比较进展者和非进展者在12个月内的PRO-C4轨迹。通过贝叶斯双变量纵向模型比较PRO-C4的变化率和肺功能。Cox比例风险模型分析基线PRO-C4和3年死亡率。通过免疫组织化学评估IPF和非IPF肺组织中的COL4染色。
在PFBIO和PROFILE研究中，分别有51/220（23.2%）和221/459（48.1%）的患者在12个月时病情进展。进展者的纵向PRO-C4水平高于非进展者（平均差异：PFBIO为21.5%（95%CI 3.4%至42.9%，p=0.0184）；PROFILE为10.9%（95%CI 0.8%至22.1%；p=0.0340）。非幸存者的PRO-C4每月变化率比幸存者更陡峭（平均差异高达3.12%（95%CI 0.35%至5.91%）），且与肺功能变化呈负相关。在PFBIO研究中，高基线PRO-C4与死亡风险增加相关（HR 2.55（95%CI 1.27至5.12），p=0.0083）。IPF肺组织中的COL4染色高于非IPF肺组织，但在终末期组织中不太明显。
在两个独立的IPF队列中，血清PRO-C4水平升高且持续升高对疾病进展具有预后意义。本研究表明，通过PRO-C4评估的COL4合成是IPF中肺泡BM修复的病理相关生物标志物。
