Congenital Deletion of Nedd4-2 in Lung Epithelial Cells Causes Progressive Alveolitis and Pulmonary Fibrosis in Neonatal Mice.
Congenital Deletion of Nedd4-2 in Lung Epithelial Cells Causes Progressive Alveolitis and Pulmonary Fibrosis in Neonatal Mice.
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DOI：
10.3390/ijms22116146
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发表时间：
2021-06-07
影响因子：
5.6
通讯作者：
Mall MA
中科院分区：
文献类型：
--
作者：
Leitz DHW;Duerr J;Mulugeta S;Seyhan Agircan A;Zimmermann S;Kawabe H;Dalpke AH;Beers MF;Mall MA
最近的研究发现，特发性肺纤维化 (IPF) 患者肺组织中 NEDD4-2 的表达降低，肺上皮细胞中 Nedd4-2 的条件性缺失会通过多种缺陷导致成年小鼠出现 IPF 样疾病，包括上皮 Na+ 通道 (ENaC) 失调、TGFβ 信号传导和表面活性蛋白 C 前蛋白 (proSP-C) 的生物合成。然而，关于 Nedd4-2 先天性缺失对肺表型影响的了解仍然有限。因此，在本研究中，我们确定了先天性缺失 Nedd4-2 对新生强力霉素诱导的三重转基因 Nedd4-2fl/fl/CCSP-rtTA2S-M2/LC1 小鼠肺上皮细胞的影响，重点是临床表型、存活、肺形态、BAL 中的炎症标志物、粘蛋白表达、ENaC 功能和 proSP-C 运输。我们发现 Nedd4-2 先天性缺失会导致新生小鼠出现快速进展的肺部疾病，其与儿童间质性肺疾病 (chILD) 具有共同的关键特征，包括低氧血症、生长障碍、无菌性肺炎、纤维化肺重塑和高死亡率。肺上皮细胞中 Nedd4-2 的先天性缺失导致 Muc5b 表达增加和远端气道粘液堵塞、ENaC 活性增加和 proSP-C 错误运输。这种 Nedd4-2 先天性缺失模型可能支持儿童发病机制的研究和儿童疗法的临床前开发。
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 Nedd4-2 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 Nedd4-2 on the lung phenotype remains limited. In this study, we therefore determined the effects of congenital deletion of Nedd4-2 in the lung epithelial cells of neonatal doxycycline-induced triple transgenic Nedd4-2fl/fl/CCSP-rtTA2S-M2/LC1 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 Nedd4-2 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 Nedd4-2 in lung epithelial cells caused increased expression of Muc5b and mucus plugging of distal airways, increased ENaC activity and proSP-C mistrafficking. This model of congenital deletion of Nedd4-2 may support studies of the pathogenesis and preclinical development of therapies for chILD.
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DOI：
10.1126/science.1223012
发表时间：
2012-08-24
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Button B;Cai LH;Ehre C;Kesimer M;Hill DB;Sheehan JK;Boucher RC;Rubinstein M
通讯作者：
Rubinstein M
影响因子：
16.6
作者：
Boase, Natasha A.;Rychkov, Grigori Y.;Townley, Scott L.;Dinudom, Anuwat;Candi, Eleanora;Voss, Anne K.;Tsoutsman, Tatiana;Semsarian, Chris;Melino, Gerry;Koentgen, Frank;Cook, David I.;Kumar, Sharad
通讯作者：
Kumar, Sharad
影响因子：
3.5
作者：
Goel P;Manning JA;Kumar S
通讯作者：
Kumar S
影响因子：
14.8
作者：
Cobos-Correa, Amanda;Trojanek, Johanna B.;Schultz, Carsten
通讯作者：
Schultz, Carsten
影响因子：
11.1
作者：
Boucher, R. C.
通讯作者：
Boucher, R. C.