Conditional knockout of ITGB4 in bronchial epithelial cells directs bronchopulmonary dysplasia.
Conditional knockout of ITGB4 in bronchial epithelial cells directs bronchopulmonary dysplasia.
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DOI：
10.1111/jcmm.17948
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发表时间：
2023-12
影响因子：
5.3
通讯作者：
中科院分区：
文献类型：
--
作者：
新生儿呼吸系统疾病与胚胎肺发育密切相关。我们的研究小组发现，整合素β4（ITGB 4）在哮喘患者的气道上皮中下调。哮喘是儿童时期最常见的慢性呼吸道疾病。因此，我们怀疑ITGB 4的缺失是否会影响胎肺发育。在这项研究中，我们的特点ITGB 4缺乏在支气管肺发育不良（BPD）的作用。在CCSP-rtTA、泰特-O-Cre和ITGB 4f/f三重转基因小鼠中有条件地敲除ITGB 4。收集不同发育阶段的肺组织进行实验检测和转录组测序。采用胎鼠肺组织块培养法观察ITGB 4缺陷对肺分支形态发生的影响。从气道上皮细胞中删除ITGB 4导致肺泡气腔扩大、分支抑制、上皮细胞结构异常和肺发育期间纤毛生长受损。扫描电镜显示β4ccsp.cre组气道上皮纤毛稀疏、缩短、倒伏。肺发育相关因子如SftpC和SOX 2显著降低mRNA和蛋白水平。KEGG通路分析表明，多种个体发育调节相关通路会聚于FAK。因此，ITGB 4缺失降低了磷酸化FAK、磷酸化GSK 3 β和SOX 2水平，并且在用GSK 3 β激动剂（渥曼青霉素）处理后检测到相应的相反结果。经渥曼青霉素处理后，β4ccsp.cre小鼠肺外植体的气道分支缺陷也部分恢复。气道上皮特异性ITGB 4缺失导致肺发育缺陷，这可能通过FAK/GSK 3 β/SOX 2信号通路实现。
Neonatal respiratory system disease is closely associated with embryonic lung development. Our group found that integrin β4 (ITGB4) is downregulated in the airway epithelium of asthma patients. Asthma is the most common chronic respiratory illness in childhood. Therefore, we suspect whether the deletion of ITGB4 would affect fetal lung development. In this study, we characterized the role of ITGB4 deficiency in bronchopulmonary dysplasia (BPD). ITGB4 was conditionally knocked out in CCSP‐rtTA, Tet‐O‐Cre and ITGB4f/f triple transgenic mice. Lung tissues at different developmental stages were collected for experimental detection and transcriptome sequencing. The effects of ITGB4 deficiency on lung branching morphogenesis were observed by fetal mouse lung explant culture. Deleting ITGB4 from the airway epithelial cells results in enlargement of alveolar airspaces, inhibition of branching, the abnormal structure of epithelium cells and the impairment of cilia growth during lung development. Scanning electron microscopy showed that the airway epithelial cilia of the β4ccsp.cre group appear to be sparse, shortened and lodging. Lung‐development‐relevant factors such as SftpC and SOX2 significantly decreased both mRNA and protein levels. KEGG pathway analysis indicated that multiple ontogenesis‐regulating‐relevant pathways converge to FAK. Accordingly, ITGB4 deletion decreased phospho‐FAK, phospho‐GSK3β and SOX2 levels, and the correspondingly contrary consequence was detected after treatment with GSK3β agonist (wortmannin). Airway branching defect of β4ccsp.cre mice lung explants was also partly recovered after wortmannin treatment. Airway epithelial‐specific deletion of ITGB4 contributes to lung developmental defect, which could be achieved through the FAK/GSK3β/SOX2 signal pathway.
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