TRIM72 promotes alveolar epithelial cell membrane repair and ameliorates lung fibrosis
TRIM72 promotes alveolar epithelial cell membrane repair and ameliorates lung fibrosis
复制标题
DOI：
10.1186/s12931-020-01384-2
复制
发表时间：
2020-05-29
影响因子：
5.8
通讯作者：
Zhao, Xiaoli
中科院分区：
文献类型：
--
作者：
Cong, Xiaofei;Nagre, Nagaraja;Zhao, Xiaoli
慢性组织损伤在纤维化疾病如特发性肺纤维化（IPF）中可诱导进行性瘢痕形成，同时一系列修复/再生和应激反应达到平衡，以确定器官水平损伤的结果。在肺中，I型肺泡上皮（ATI）细胞构成上皮屏障，而II型肺泡上皮（ATII）细胞在损伤的远端肺再生中起关键作用。研究表明真核细胞具有快速修复损伤细胞膜的功能，我们前期的研究发现TRIM 72在包括肺在内的少数组织中表达，具有修复损伤细胞膜的作用。然而，肺泡上皮细胞（AEC）修复在IPF发病机制中的作用尚未得到研究。方法本研究检测TRIM 72在ATII细胞修复和肺纤维化发生发展中的特异性作用。通过对分离的原代ATII细胞和大鼠ATII细胞系的皂苷测定来评估膜修复的作用。用博来霉素处理的转基因小鼠测试TRIM 72的抗纤维化潜力。结果我们发现TRIM 72在各种损伤后和人IPF肺中上调。然而，IPF肺的ATII细胞中的TRIM 72表达具有异常的亚细胞定位。体外研究表明，TRIM 72修复永生化和原发性ATII的膜损伤，导致抑制应激诱导的p53活化和减少细胞凋亡。体内研究表明，TRIM 72保护肺泡上皮层的完整性并减少肺纤维化。结论TRIM 72可能通过促进AEC损伤后的修复而对肺损伤具有保护作用。
Background Chronic tissue injury was shown to induce progressive scarring in fibrotic diseases such as idiopathic pulmonary fibrosis (IPF), while an array of repair/regeneration and stress responses come to equilibrium to determine the outcome of injury at the organ level. In the lung, type I alveolar epithelial (ATI) cells constitute the epithelial barrier, while type II alveolar epithelial (ATII) cells play a pivotal role in regenerating the injured distal lungs. It had been demonstrated that eukaryotic cells possess repair machinery that can quickly patch the damaged plasma membrane after injury, and our previous studies discovered the membrane-mending role of Tripartite motif containing 72 (TRIM72) that expresses in a limited number of tissues including the lung. Nevertheless, the role of alveolar epithelial cell (AEC) repair in the pathogenesis of IPF has not been examined yet. Method In this study, we tested the specific roles of TRIM72 in the repair of ATII cells and the development of lung fibrosis. The role of membrane repair was accessed by saponin assay on isolated primary ATII cells and rat ATII cell line. The anti-fibrotic potential of TRIM72 was tested with bleomycin-treated transgenic mice. Results We showed that TRIM72 was upregulated following various injuries and in human IPF lungs. However, TRIM72 expression in ATII cells of the IPF lungs had aberrant subcellular localization. In vitro studies showed that TRIM72 repairs membrane injury of immortalized and primary ATIIs, leading to inhibition of stress-induced p53 activation and reduction in cell apoptosis. In vivo studies demonstrated that TRIM72 protects the integrity of the alveolar epithelial layer and reduces lung fibrosis. Conclusion Our results suggest that TRIM72 protects injured lungs and ameliorates fibrosis through promoting post-injury repair of AECs.