Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Augustenburger Platz 1, 13353 Berlin, Germany.
Translational Lung Research Center (TLRC), Member of the German Center for Lung Research (DZL), Department of Translational Pulmonology, University of Heidelberg, Im Neuenheimer Feld 156, 69120 Heidelberg, Germany.
Int J Mol Sci. 2021 Jun 7;22(11):6146. doi: 10.3390/ijms22116146.
Recent studies found that expression of NEDD4-2 is reduced in lung tissue from patients with idiopathic pulmonary fibrosis (IPF) and that the conditional deletion of in lung epithelial cells causes IPF-like disease in adult mice via multiple defects, including dysregulation of the epithelial Na channel (ENaC), TGFβ signaling and the biosynthesis of surfactant protein-C proprotein (proSP-C). However, knowledge of the impact of congenital deletion of on the lung phenotype remains limited. In this study, we therefore determined the effects of congenital deletion of in the lung epithelial cells of neonatal doxycycline-induced triple transgenic mice, with a focus on clinical phenotype, survival, lung morphology, inflammation markers in BAL, mucin expression, ENaC function and proSP-C trafficking. We found that the congenital deletion of caused a rapidly progressive lung disease in neonatal mice that shares key features with interstitial lung diseases in children (chILD), including hypoxemia, growth failure, sterile pneumonitis, fibrotic lung remodeling and high mortality. The congenital deletion of in lung epithelial cells caused increased expression of and mucus plugging of distal airways, increased ENaC activity and proSP-C mistrafficking. This model of congenital deletion of may support studies of the pathogenesis and preclinical development of therapies for chILD.
最近的研究发现，特发性肺纤维化（IPF）患者的肺组织中 NEDD4-2 的表达减少，而条件性敲除肺上皮细胞中的 会导致成年小鼠出现类似 IPF 的疾病，其机制涉及多个缺陷，包括上皮钠通道（ENaC）的失调、TGFβ 信号通路和表面活性蛋白-C 前体蛋白（proSP-C）的生物合成。然而，关于先天性敲除 对肺表型的影响的知识仍然有限。在这项研究中，我们因此确定了在新生的多西环素诱导的三重转基因 小鼠的肺上皮细胞中先天性敲除 的影响，重点关注临床表型、生存、肺形态、BAL 中的炎症标志物、粘蛋白表达、ENaC 功能和 proSP-C 易位。我们发现，先天性敲除 会导致新生小鼠发生快速进展性肺疾病，其具有与儿童间质性肺疾病（chILD）的关键特征，包括低氧血症、生长发育迟缓、无菌性肺炎、纤维性肺重塑和高死亡率。肺上皮细胞中 的先天性敲除会导致 表达增加和远端气道粘液栓形成，ENaC 活性增加和 proSP-C 易位。这种先天性敲除 的模型可能有助于研究 chILD 的发病机制和临床前治疗方法的开发。
