Adenoviral Transduction of Dickkopf-1 Alleviates Silica-Induced Silicosis Development in Lungs of Mice
Adenoviral Transduction of Dickkopf-1 Alleviates Silica-Induced Silicosis Development in Lungs of Mice
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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部矽肺病的发展
DOI：
10.1089/hum.2021.008
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发表时间：
2021-09-28
影响因子：
4.2
通讯作者：
Liu，Xiaoming
中科院分区：
文献类型：
--
作者：
Cai，Qian;Ma，Jia;Liu，Xiaoming
矽肺是一种因吸入矽尘而引起的职业性疾病，其特征是进行性肺纤维化，预后不良。Wnt/β-连环蛋白信号传导与纤维化的发展有关，并且是纤维化疾病的治疗靶标。既往对尘肺（包括硅肺）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WNT 3A和DKK 1蛋白和炎性细胞的浓度增加。本研究探讨腺病毒介导的Wnt/β-catenin信号通路抑制剂Dickkopf-1（Dkk 1）对小鼠矽肺发病的影响。与先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，二氧化硅诱导的硅肺小鼠的异常Wnt/β-catenin信号传导活性与增加的Wnt 3a和Dkk 1蛋白和炎症一致。表达鼠Dkk 1的腺病毒（AdDkk 1）的气管内递送抑制小鼠肺中的Wnt/β-连环蛋白活性。腺病毒介导的Dkk 1基因转导表现出预防小鼠矽肺发展和改善二氧化硅诱导的肺纤维化的潜力，与“空”腺病毒载体治疗的小鼠相比，伴有上皮-间质转化标志物的表达减少和细胞外基质蛋白的沉积。机制上，AdDkk 1能够通过抑制二氧化硅诱导的TGF-β/Smad信号转导峰来减轻肺硅肺。此外，Dkk 1的强制表达抑制二氧化硅诱导的极化人支气管上皮细胞的上皮细胞增殖。本研究揭示了Wnt/β-catenin信号通路在矽肺发病中的潜在作用，并证明了通过Dkk 1基因转导靶向Wnt/β-catenin信号通路可能是预防和治疗矽肺肺病的另一种方法。
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 ofDickkopf-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-mediatedDkk1gene 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 byDkk1gene transduction may be an alternative approach in the prevention and treatment of silicosis lung disease.