Silicosis is an occupational disease caused by inhalation of silica dust, which is hallmarked by progressive pulmonary fibrosis associated with poor prognosis. Wnt/β-catenin signaling is implicated in the development of fibrosis and is a therapeutic target for fibrotic diseases. Previous clinical studies of patients with pneumoconiosis, including silicosis, revealed an increased concentration of circulating WNT3A and DKK1 proteins and inflammatory cells in bronchoalveolar lavage compared with healthy subjects. The present study evaluated the effects of adenovirus-mediated transduction of Dickkopf-1 (Dkk1), a Wnt/β-catenin signaling inhibitor, on the development of pulmonary silicosis in mice. Consistent with previous human clinical studies, our experimental studies in mice demonstrated an aberrant Wnt/β-catenin signaling activity coinciding with increased Wnt3a and Dkk1 proteins and inflammation in lungs of silica-induced silicosis mice compared with controls. Intratracheal delivery of adenovirus expressing murine Dkk1 (AdDkk1) inhibited Wnt/β-catenin activity in mouse lungs. The adenovirus-mediated Dkk1 gene transduction demonstrated the potential to prevent silicosis development and ameliorate silica-induced lung fibrogenesis in mice, accompanied by the reduced expression of epithelia–-mesenchymal transition markers and deposition of extracellular matrix proteins compared with mice treated with “null” adenoviral vector. Mechanistically, AdDkk1 is able to attenuate the lung silicosis by inhibiting a silica-induced spike in TGF-β/Smad signaling. In addition, the forced expression of Dkk1 suppressed silica-induced epithelial cell proliferation in polarized human bronchial epithelial cells. This study provides insight into the underlying role of Wnt/β-catenin signaling in promoting the pathogenesis of silicosis and is proof-of-concept that targeting Wnt/β-catenin signaling by Dkk1 gene transduction may be an alternative approach in the prevention and treatment of silicosis lung disease.

中文翻译：

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Dickkopf-1 的腺病毒转导可减轻二氧化硅诱导的小鼠肺矽肺发展

矽肺是一种由吸入矽尘引起的职业病，其特征是与预后不良相关的进行性肺纤维化。Wnt/β-连环蛋白信号传导与纤维化的发展有关，是纤维化疾病的治疗靶点。先前对包括矽肺在内的尘肺患者的临床研究显示，与健康受试者相比，支气管肺泡灌洗液中循环 WNT3A 和 DKK1 蛋白和炎症细胞的浓度增加。本研究评估了腺病毒介导的Dickkopf-1 ( Dkk1)，一种 Wnt/β-连环蛋白信号抑制剂，对小鼠肺矽肺的发展有影响。与之前的人类临床研究一致，我们在小鼠中的实验研究表明，与对照组相比，二氧化硅诱导的矽肺小鼠肺部出现异常的 Wnt/β-catenin 信号传导活性，与 Wnt3a 和 Dkk1 蛋白增加和炎症一致。表达鼠 Dkk1 (AdDkk1) 的腺病毒的气管内递送抑制了小鼠肺中的 Wnt/β-连环蛋白活性。腺病毒介导的Dkk1与用“无效”腺病毒载体处理的小鼠相比，基因转导证明了在小鼠中预防矽肺发展和改善二氧化硅诱导的肺纤维化的潜力，伴随着上皮-间质转化标志物的表达减少和细胞外基质蛋白的沉积。从机制上讲，AdDkk1 能够通过抑制二氧化硅诱导的 TGF-β/Smad 信号尖峰来减轻肺矽肺。此外，Dkk1 的强制表达抑制了极化的人支气管上皮细胞中二氧化硅诱导的上皮细胞增殖。本研究提供了对 Wnt/β-catenin 信号传导在促进矽肺发病机制中的潜在作用的深入了解，并且是Dkk1靶向 Wnt/β-catenin 信号传导的概念验证基因转导可能是预防和治疗矽肺病的一种替代方法。