Cai Qian, Ma Jia, Wang Jing, Wang Juying, Cui Jieda, Wu Shuang, Wang Zhaojun, Wang Na, Wang Jiaqi, Yang Dandan, Yang Jiali, Xue Jing, Li Feng, Chen Juan, Liu Xiaoming
Key Laboratory of Ministry of Education for Conservation and Utilization of Special Biological Resources of Western China, College of Life Science, Ningxia University, Yinchuan, China.
Department of Anatomy and Cell Biology, The University of Iowa, Iowa City, Iowa, USA.
Hum Gene Ther. 2022 Feb;33(3-4):155-174. doi: 10.1089/hum.2021.008. Epub 2021 Sep 28.
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 (), 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 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 gene transduction may be an alternative approach in the prevention and treatment of silicosis lung disease.
矽肺是一种因吸入二氧化硅粉尘所致的职业病，其特征为进行性肺纤维化且预后不良。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。先前针对包括矽肺在内的尘肺病患者的临床研究显示，与健康受试者相比，支气管肺泡灌洗中循环WNT3A和DKK1蛋白以及炎症细胞的浓度有所增加。本研究评估了腺病毒介导的Wnt/β-连环蛋白信号抑制剂DKK1转导对小鼠肺矽病发展的影响。与先前的人类临床研究一致，我们在小鼠身上进行的实验研究表明，与对照组相比，在二氧化硅诱导的矽肺小鼠的肺中，Wnt/β-连环蛋白信号活性异常，同时Wnt3a和Dkk1蛋白增加以及出现炎症。气管内递送表达小鼠Dkk1的腺病毒（AdDkk1）可抑制小鼠肺中的Wnt/β-连环蛋白活性。腺病毒介导的DKK1基因转导显示出预防矽病发展和改善小鼠二氧化硅诱导的肺纤维化的潜力，与用“空”腺病毒载体处理的小鼠相比，上皮-间质转化标志物的表达降低以及细胞外基质蛋白的沉积减少。从机制上讲，AdDkk1能够通过抑制二氧化硅诱导的TGF-β/Smad信号激增来减轻肺矽病。此外，DKK1的强制表达抑制了二氧化硅诱导的极化人支气管上皮细胞中的上皮细胞增殖。本研究深入了解了Wnt/β-连环蛋白信号传导在促进矽肺发病机制中的潜在作用，并证明通过DKK1基因转导靶向Wnt/β-连环蛋白信号传导可能是预防和治疗矽肺疾病的一种替代方法。
