Dach1 deficiency drives alveolar epithelium apoptosis in pulmonary fibrosis via modulating C-Jun/Bim activity
Dach1 deficiency drives alveolar epithelium apoptosis in pulmonary fibrosis via modulating C-Jun/Bim activity
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DOI：
10.1016/j.trsl.2023.01.006
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发表时间：
2023-05-13
影响因子：
7.8
通讯作者：
Xie, Jungang
中科院分区：
文献类型：
--
作者：
Lu, Yanjiao;Tang, Kum;Xie, Jungang
II型肺泡上皮细胞（AECII）的失调在肺纤维化（PF）的发生和发展中起着至关重要的作用。腊肠同源物1 (Dach1)，常在具有干细胞潜能的上皮细胞中表达，在组织发育和疾病过程中控制细胞增殖、凋亡和细胞周期。在本研究中，我们证明了从PF患者和BLM治疗小鼠的肺中收集的腊肠同源物1 （Dach1）的低表达，特别是在AECII中。肺泡上皮Dach1缺乏加重了blm处理小鼠的PF，肺功能降低和纤维化标志物表达增加就是证据。相反，肺特异性过表达Dach1的治疗减轻了blm治疗小鼠的组织病理学损伤、肺顺应性和纤维化。此外，Dach1过表达可抑制体外上皮细胞凋亡。相反，Dach1缺失的原发AECII在体内更容易发生细胞凋亡。机械上，Dach1与C-Jun原癌基因选择性结合b细胞淋巴瘤启动子2细胞死亡相互作用介质（Bim），从而抑制Bim表达，减轻上皮细胞凋亡。综上所述，我们的数据支持AECII中的Dach1有助于PF的进展，可能是预防和治疗PF的可行靶点。
Dysregulation of type II alveolar epithelial cells (AECII) plays a vital role in the initiation and development of pulmonary fibrosis (PF). Dachshund homolog 1 (Dach1), frequently expressed in epithelial cells with stem cell potential, controls cell proliferation, apoptosis, and cell cycle in tissue development and disease process. In this study, we demonstrated that the lungs collected from PF patients and mice of Bleomycin (BLM)-treated were characterized by low expression of Dachshund homolog 1 (Dach1), especially in AECII. Dach1 deficiency in the alveolar epithelium exacerbated PF in BLM-treated mice, as evidenced by reduced pulmonary function and increased expression of fibrosis markers. Rather, treatment with lung-specific overexpression of Dach1 alleviated histopathological damage, lung compliance, and fibrosis in BLM-treated mice. Moreover, overexpression of Dach1 could inhibit epithelial apoptosis in vitro. Conversely, primary AECII with Dach1 depletion were more susceptible to apoptosis in vivo. Mechanically, Dach1 combined with C-Jun protooncogene selectively bound to the promoter of B-cell lymphoma 2 interacting mediators of cell death (Bim), by which it repressed Bim expression and alleviated epithelial apoptosis. Taken together, our data support that Dach1 in AECII contributes to the progression of PF and may be a viable target for the prevention and treatment of PF.