State Key Laboratory Cell Differentiation and Regulation, Henan International Joint Laboratory of Pulmonary Fibrosis, Henan Center for Outstanding Overseas Scientists of Organ Fibrosis, College of Life Science, Henan Normal University, 46 Jianshe Road, Xinxiang, 453007, Henan, China.
The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, China.
Respir Res. 2023 Dec 17;24(1):318. doi: 10.1186/s12931-023-02633-w.
Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease (ILD) with unknown etiology, characterized by sustained damage repair of epithelial cells and abnormal activation of fibroblasts, the underlying mechanism of the disease remains elusive.
To evaluate the role of Tuftelin1 (TUFT1) in IPF and elucidate its molecular mechanism. We investigated the level of TUFT1 in the IPF and bleomycin-induced mouse models and explored the influence of TUFT1 deficiency on pulmonary fibrosis. Additionally, we explored the effect of TUFT1 on the cytoskeleton and illustrated the relationship between stress fiber and pulmonary fibrosis.
Our results demonstrated a significant upregulation of TUFT1 in IPF and the bleomycin (BLM)-induced fibrosis model. Disruption of TUFT1 exerted inhibitory effects on pulmonary fibrosis in both in vivo and in vitro. TUFT1 facilitated the assembly of microfilaments in A549 and MRC-5 cells, with a pronounced association between TUFT1 and Neuronal Wiskott-Aldrich syndrome protein (N-WASP) observed during microfilament formation. TUFT1 can promote the phosphorylation of tyrosine residue 256 (Y256) of the N-WASP (pN-WASP). Furthermore, TUFT1 promoted transforming growth factor-β1 (TGF-β1) induced fibroblast activation by increasing nuclear translocation of pN-WASP in fibroblasts, while wiskostatin (Wis), an N-WASP inhibitor, suppressed these processes.
Our findings suggested that TUFT1 plays a critical role in pulmonary fibrosis via its influence on stress fiber, and blockade of TUFT1 effectively reduces pro-fibrotic phenotypes. Pharmacological targeting of the TUFT1-N-WASP axis may represent a promising therapeutic approach for pulmonary fibrosis.
特发性肺纤维化（IPF）是一种病因不明的进行性间质性肺疾病，其特征为上皮细胞的持续损伤修复和成纤维细胞的异常激活，疾病的潜在机制仍难以捉摸。
评估 Tuftelin1（TUFT1）在特发性肺纤维化中的作用，并阐明其分子机制。我们研究了 TUFT1 在特发性肺纤维化和博来霉素诱导的小鼠模型中的水平，并探讨了 TUFT1 缺乏对肺纤维化的影响。此外，我们还探讨了 TUFT1 对细胞骨架的影响，并说明了应激纤维与肺纤维化之间的关系。
我们的结果表明，TUFT1 在特发性肺纤维化和博来霉素（BLM）诱导的纤维化模型中显著上调。TUFT1 的破坏对体内和体外的肺纤维化均具有抑制作用。TUFT1 促进 A549 和 MRC-5 细胞中微丝的组装，在微丝形成过程中观察到 TUFT1 与神经元 Wiskott-Aldrich 综合征蛋白（N-WASP）之间的显著关联。TUFT1 可以促进 N-WASP 酪氨酸残基 256（Y256）的磷酸化（pN-WASP）。此外，TUFT1 通过增加成纤维细胞中 pN-WASP 的核易位，促进转化生长因子-β1（TGF-β1）诱导的成纤维细胞活化，而 N-WASP 抑制剂 wiskostatin（Wis）则抑制了这些过程。
我们的研究结果表明，TUFT1 通过影响应激纤维在肺纤维化中发挥关键作用，而 TUFT1 的阻断可有效减少促纤维化表型。靶向 TUFT1-N-WASP 轴的药理学方法可能代表治疗肺纤维化的一种有前途的治疗方法。
