Bleomycin induced apical-basal polarity loss in alveolar epithelial cell contributes to experimental pulmonary fibrosis
Bleomycin induced apical-basal polarity loss in alveolar epithelial cell contributes to experimental pulmonary fibrosis
复制标题
博莱霉素诱导肺泡上皮细胞顶端-基底极性丧失导致实验性肺纤维化
DOI：
10.1016/j.yexcr.2020.112295
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发表时间：
2020
影响因子：
3.7
通讯作者：
Wan-Li Ma
中科院分区：
文献类型：
--
作者：
Yu-Zhi Lu;Xin-Liang He;Fei Liu;Pei-Pei Cheng;Li-Mei Liang;Meng Wang;Shuai-Jun Chen;Yi Huang;Fan Yu;Jian-Bao Xin;Hong Ye;Lin-Jie Song;Wan-Li Ma
特发性肺纤维化（IPF）是一种致命的纤维化间质性肺病，治疗选择有限，诊断后的中位生存期为3年。上皮再生失调是引发和维持IPF的关键事件。II型肺泡上皮细胞（AECII）在上皮再生和肺泡稳定中起着至关重要的作用。细胞顶端-基底极性的丧失有助于纤维化。AECII具有顶部-基底极性，但对AECII顶部-基底极性丧失是否参与纤维化知之甚少。博莱霉素是肺纤维化的传统诱导剂。在这里，我们首先观察到博莱霉素诱导培养的AECIIs的顶端-基底极性丧失。接下来，研究了细胞极性蛋白致死（2）巨幼虫1（Lgl 1）、PAR-3A、aPKC和PAR-6 B。我们发现博莱霉素诱导的Lgl 1蛋白的增加和PAR-3A蛋白的减少，博莱霉素诱导的PAR-3A的抑制是由增加的Lgl 1介导的。然后将Lgl 1 siRNA转染AECIIs。Lgl 1 siRNA可防止博来霉素处理的AECII中的顶端-基底极性丧失。最后，将Lgl 1基因敲除小鼠应用于动物模型的建立。博莱霉素诱导肺纤维化，但这在Lgl 1条件性基因敲除小鼠中减弱。总之，这些数据表明博莱霉素介导的AECII顶端-基底极性丧失导致实验性肺纤维化。抑制Lgl 1应该是一种潜在的治疗策略。
Idiopathic pulmonary fibrosis (IPF) is a fatal fibrosing interstitial lung disease with limited therapeutic options and a median survival of 3 years after diagnosis. Dysregulated epithelial regeneration is key event involved in initiating and sustaining IPF. The type II alveolar epithelial cells (AECIIs) play a crucial role for epithelial regeneration and stabilisation of alveoli. Loss of cell apical-basal polarity contributes to fibrosis. AECII has apical-basal polarity, but it is poorly understood whether AECII apical-basal polarity loss is involved in fibrosis. Bleomycin is a traditional inducer of pulmonary fibrosis. Here firstly we observed that bleomycin induced apical-basal polarity loss in cultured AECIIs. Next, cell polarity proteins lethal (2) giant larvae 1 (Lgl1), PAR-3A, aPKC and PAR-6B were investigated. We found bleomycin induced increases of Lgl1 protein and decreases of PAR-3A protein, and bleomycin-induced PAR-3A depression was mediated by increased-Lgl1. Then Lgl1 siRNA was transfected into AECIIs. Lgl1 siRNA prevented apical-basal polarity loss in bleomycin-treated AECIIs. At last,Lgl1-conditional knockout mice were applied in making animal models. Bleomycin induced pulmonary fibrosis, but this was attenuated inLgl1-conditional knockout mice. Together, these data indicated that bleomycin mediated AECII apical-basal polarity loss which contributed to experimental pulmonary fibrosis. Inhibition of Lgl1 should be a potential therapeutic strategy for the disease.