Myronenko Oleh, Curcic Pero, Douschan Philipp, Zeder Katarina, John Teresa, Suessner Susanne, Hoetzenecker Konrad, Kovacs Gabor, Olschewski Andrea, Olschewski Horst, Foris Vasile
Division of Respiratory Medicine, Lung Research Cluster, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Austria.
European Research Network Lung Affiliated Pulmonary Hypertension National Expert Center, Graz, Austria.
Lung. 2025 Jul 14;203(1):79. doi: 10.1007/s00408-025-00833-3.
The pulmonary vascular involvement of COPD ranges from severe airway obstruction without pulmonary hypertension (PH) to mild airway obstruction with severe PH. Iron-dependent molecular regulators like hypoxia-inducible factor-2 (HIF-2) may contribute to these phenotypic variations. We explored the role of soluble transferrin receptor-1 (sTfR1) for diagnosis and prognosis of PH associated with COPD.
We analyzed COPD outpatients who underwent right heart catheterization and performed unsupervised clustering analysis based on sTfR1 levels and non-invasive clinical parameters to identify specific COPD phenotypes. Additionally, we examined explanted end-stage COPD lungs for TfR1 expression and iron deposition.
sTfR1 was associated with mean pulmonary artery pressure (mPAP) (r = 0.45, p < 0.001), pulmonary vascular resistance (PVR) (r = 0.395, p < 0.001) and poor survival. sTfR1 predicted severe PH (AUROC [95% CI], 0.72 [0.61-0.83]), and AUROC was further improved based on a combination of sTfR1 and low hemoglobin (0.82 [0.73-0.92]). sTfR1-based cluster analysis distinguished three COPD phenotypes with significantly different survival. One of the two clusters with poor survival was characterized by moderate airway obstruction and moderate PH but elevated sTfR1, anemia and inflammation. In explanted COPD lungs, TfR1-positive and iron-laden cells, most likely, consisted of macrophages, and iron-loaded cell density was negatively correlated with mPAP in patients with moderate/severe PH (r = - 0.681, p = 0.015).
Elevated sTfR1 predicts poor prognosis in patients with COPD and, particularly in combination with low hemoglobin, may serve as a biomarker for severe PH in COPD, identifying a distinct phenotype with systemic inflammation, anemia and iron deficiency.
慢性阻塞性肺疾病（COPD）的肺血管受累范围从无肺动脉高压（PH）的严重气道阻塞到伴有严重PH的轻度气道阻塞。像缺氧诱导因子-2（HIF-2）这样的铁依赖性分子调节因子可能导致这些表型差异。我们探讨了可溶性转铁蛋白受体-1（sTfR1）在与COPD相关的PH诊断和预后中的作用。
我们分析了接受右心导管检查的COPD门诊患者，并基于sTfR1水平和非侵入性临床参数进行无监督聚类分析，以确定特定的COPD表型。此外，我们检查了移植的终末期COPD肺组织中的转铁蛋白受体1（TfR1）表达和铁沉积情况。
sTfR1与平均肺动脉压（mPAP）（r = 0.45，p < 0.001）、肺血管阻力（PVR）（r = 0.395，p < 0.001）及不良生存率相关。sTfR1可预测严重PH（曲线下面积[95%置信区间]，0.72[0.61 - 0.83]），并且基于sTfR1和低血红蛋白的联合检测，曲线下面积进一步提高（0.82[0.73 - 0.92]）。基于sTfR1的聚类分析区分出三种生存率显著不同的COPD表型。生存率较差的两个聚类之一的特征是中度气道阻塞和中度PH，但sTfR1升高、贫血和炎症。在移植的COPD肺组织中，TfR1阳性且含铁的细胞很可能由巨噬细胞组成，并且在中度/重度PH患者中，含铁细胞密度与mPAP呈负相关（r = - 0.681，p = 0.015）。
sTfR1升高预示着COPD患者预后不良，特别是与低血红蛋白联合时，可作为COPD严重PH的生物标志物，识别出一种伴有全身炎症、贫血和缺铁的独特表型。
