Department of Respiratory and Critical Care Medicine, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu 611731, P.R. China.
Int J Biol Sci. 2021 Jul 25;17(13):3320-3330. doi: 10.7150/ijbs.57247. eCollection 2021.
Interstitial pulmonary fibrosis (IPF) is a severe progressive lung disease with limited therapeutic options and poor prognosis. Initially, we found the downregulated level of neural precursor cell expressed developmentally down-regulated 4-like protein (NEDD4L) in IPF-related expression microarray dataset, and this study was thus performed to explore the molecular mechanism of NEDD4L in IPF. The expression of NEDD4L was subsequently validated in lung tissues of IPF patients and mouse models. Then, mouse primary lung fibroblasts (LFs) were collected for functional experiments, with CCK-8, Transwell, and immunofluorescence assays used to examine the viability, migration, and differentiation of LFs. The findings were further assessed using mouse models. The expression of NEDD4L was down-regulated in lung tissues of IPF patients and mouse models. Overexpression of NEDD4L restricted the formation and progression of IPF in mice and attenuated the proliferative, invasive and differentiative abilities of LFs. Further, NEDD4L halted LFs activity by enhancing β-catenin ubiquitination and down-regulating the CTHRC1/HIF-1α axis. Also, experiments then validated that NEDD4L silencing repressed β-catenin ubiquitination and activated the CTHRC1/HIF-1α axis, thereby aggravating IPF in mice. NEDD4L may suppress the formation and progression of IPF through augmenting β-catenin ubiquitination and inhibiting the CTHRC1/HIF-1α axis.
特发性肺纤维化（IPF）是一种严重的进行性肺部疾病，治疗选择有限，预后不良。最初，我们在与 IPF 相关的表达微阵列数据集发现下调的神经前体细胞表达发育下调 4 样蛋白（NEDD4L）水平，因此进行了这项研究以探索 NEDD4L 在 IPF 中的分子机制。随后在 IPF 患者和小鼠模型的肺组织中验证了 NEDD4L 的表达。然后，收集小鼠原代肺成纤维细胞（LFs）进行功能实验，使用 CCK-8、Transwell 和免疫荧光测定法来检测 LFs 的活力、迁移和分化。使用小鼠模型进一步评估了这些发现。在 IPF 患者和小鼠模型的肺组织中，NEDD4L 的表达下调。NEDD4L 的过表达限制了小鼠中 IPF 的形成和进展，并减弱了 LFs 的增殖、侵袭和分化能力。此外，NEDD4L 通过增强β-连环蛋白泛素化并下调 CTHRC1/HIF-1α 轴来阻止 LFs 的活性。此外，实验随后验证了 NEDD4L 沉默抑制β-连环蛋白泛素化并激活 CTHRC1/HIF-1α 轴，从而加重了小鼠中的 IPF。NEDD4L 可能通过增强β-连环蛋白泛素化并抑制 CTHRC1/HIF-1α 轴来抑制 IPF 的形成和进展。
