Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.
Department of Emergency and Critical Care Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
Respir Res. 2024 May 4;25(1):195. doi: 10.1186/s12931-024-02825-y.
Lipocalin-2 (LCN2) is a secretory glycoprotein upregulated by oxidative stress; moreover, patients with idiopathic pulmonary fibrosis (IPF) have shown increased LCN2 levels in bronchoalveolar lavage fluid (BALF). This study aimed to determine whether circulatory LCN2 could be a systemic biomarker in patients with IPF and to investigate the role of LCN2 in a bleomycin-induced lung injury mouse model.
We measured serum LCN2 levels in 99 patients with stable IPF, 27 patients with acute exacerbation (AE) of IPF, 51 patients with chronic hypersensitivity pneumonitis, and 67 healthy controls. Further, LCN2 expression in lung tissue was evaluated in a bleomycin-induced lung injury mouse model, and the role of LCN2 was investigated using LCN2-knockout (LCN2 -/-) mice.
Serum levels of LCN2 were significantly higher in patients with AE-IPF than in the other groups. The multivariate Cox proportional hazards model showed that elevated serum LCN2 level was an independent predictor of poor survival in patients with AE-IPF. In the bleomycin-induced lung injury mouse model, a higher dose of bleomycin resulted in higher LCN2 levels and shorter survival. Bleomycin-treated LCN2 -/- mice exhibited increased BALF cell and protein levels as well as hydroxyproline content. Moreover, compared with wild-type mice, LCN2-/- mice showed higher levels of circulatory 8-isoprostane as well as lower Nrf-2, GCLC, and NQO1 expression levels in lung tissue following bleomycin administration.
Our findings demonstrate that serum LCN2 might be a potential prognostic marker of AE-IPF. Moreover, LCN2 expression levels may reflect the severity of lung injury, and LCN2 may be a protective factor against bleomycin-induced acute lung injury and oxidative stress.
脂联素-2（LCN2）是一种受氧化应激上调的分泌性糖蛋白；此外，特发性肺纤维化（IPF）患者的支气管肺泡灌洗液（BALF）中显示 LCN2 水平升高。本研究旨在确定循环 LCN2 是否可以作为 IPF 患者的系统性生物标志物，并研究 LCN2 在博来霉素诱导的肺损伤小鼠模型中的作用。
我们测量了 99 例稳定型 IPF 患者、27 例急性加重型 IPF（AE-IPF）患者、51 例慢性过敏反应性肺炎患者和 67 例健康对照者的血清 LCN2 水平。此外，我们在博来霉素诱导的肺损伤小鼠模型中评估了肺组织中 LCN2 的表达，并使用 LCN2 敲除（LCN2 -/-）小鼠研究了 LCN2 的作用。
AE-IPF 患者的血清 LCN2 水平明显高于其他组。多变量 Cox 比例风险模型显示，升高的血清 LCN2 水平是 AE-IPF 患者不良预后的独立预测因子。在博来霉素诱导的肺损伤小鼠模型中，较高剂量的博来霉素导致 LCN2 水平升高和生存时间缩短。博来霉素处理的 LCN2 -/-小鼠的 BALF 细胞和蛋白水平以及羟脯氨酸含量增加。此外，与野生型小鼠相比，LCN2 -/-小鼠在给予博来霉素后肺组织中的循环 8-异前列腺素水平升高，Nrf-2、GCLC 和 NQO1 表达水平降低。
我们的研究结果表明，血清 LCN2 可能是 AE-IPF 的潜在预后标志物。此外，LCN2 表达水平可能反映肺损伤的严重程度，LCN2 可能是博来霉素诱导的急性肺损伤和氧化应激的保护因素。
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