Liang Chun-Lian, Li Xiu-Li, Quan Xiao-Juan, Zhang Lin
Department of Geriatrics, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China.
Exp Ther Med. 2023 Mar 10;25(4):183. doi: 10.3892/etm.2023.11882. eCollection 2023 Apr.
Idiopathic pulmonary fibrosis (IPF) is a heterogeneous lung disease associated with high mortality. Disabled-2 (DAB2), an adapter protein, regulates cell-fibrinogen adhesion and fibrinogen uptake. DAB2 is differentially expressed in mouse fibrotic lungs induced by bleomycin according to a genome microarray analysis based on Gene Expression Omnibus database. However, the role of DAB2 in IPF has not been revealed. A bleomycin-induced mouse model of pulmonary fibrosis was constructed in the present study. It found that the expression of DAB2 was upregulated in bleomycin-induced fibrotic lung tissue with collagen fiber deposition and pulmonary interstitium thickening. Colocalization of DAB2 with α-smooth muscle actin (SMA) was observed in lung tissue sections. , human lung fibroblast MRC-5 cells were treated with TGF-β1 and the expression of DAB2 was increased. Knockdown of DAB2 suppressed cell proliferation and the expression of α-SMA, collagen I, collagen IV and fibronectin in TGF-β1-treated MRC-5 cells. The phosphorylation levels of PI3K and AKT were suppressed in DAB2-knockdown cells. IGF-1/IGF-1R has been reported to promote pulmonary fibrosis and activate the PI3K/Akt signaling. In the present study, the activation of IGF-1/IGF-1R signaling pathways in bleomycin-induced fibrotic lung tissues were positively associated with DAB2 expression. The phosphorylation level of IGF-1R was increased in MRC-5 cells with TGF-β1 treatment, and DAB2 expression was decreased by silencing of IGF-1R. This suggested that DAB2 might be a downstream target of the IGF-1R pathway and thus induced PI3K/AKT signaling activation and fibrogenesis. The current study demonstrated the importance of DAB2 in pulmonary fibrosis and suggested the potential of IGF-1R/DAB2/PI3K in the pathogenesis of IPF.
特发性肺纤维化（IPF）是一种异质性肺部疾病，死亡率很高。衔接蛋白Disabled-2（DAB2）可调节细胞与纤维蛋白原的黏附以及纤维蛋白原的摄取。根据基于基因表达综合数据库的基因组微阵列分析，DAB2在博来霉素诱导的小鼠纤维化肺中表达存在差异。然而，DAB2在IPF中的作用尚未明确。本研究构建了博来霉素诱导的小鼠肺纤维化模型。研究发现，在博来霉素诱导的、伴有胶原纤维沉积和肺间质增厚的纤维化肺组织中，DAB2的表达上调。在肺组织切片中观察到DAB2与α平滑肌肌动蛋白（SMA）共定位。此外，用转化生长因子-β1（TGF-β1）处理人肺成纤维细胞MRC-5，DAB2的表达增加。敲低DAB2可抑制TGF-β1处理的MRC-5细胞的增殖以及α-SMA、I型胶原、IV型胶原和纤连蛋白的表达。在敲低DAB2的细胞中，PI3K和AKT的磷酸化水平受到抑制。据报道，胰岛素样生长因子-1（IGF-1）/胰岛素样生长因子-1受体（IGF-1R）可促进肺纤维化并激活PI3K/Akt信号通路。在本研究中，博来霉素诱导的纤维化肺组织中IGF-1/IGF-1R信号通路的激活与DAB2表达呈正相关。用TGF-β1处理MRC-5细胞后，IGF-1R的磷酸化水平升高，而沉默IGF-1R可使DAB2表达降低。这表明DAB2可能是IGF-1R途径的下游靶点，从而诱导PI3K/AKT信号激活和纤维化形成。当前研究证明了DAB2在肺纤维化中的重要性，并提示了IGF-1R/DAB2/PI3K在IPF发病机制中的潜在作用。
