Department of Physiological Sciences, Eastern Virginia Medical School, Norfolk, Virginia, USA.
Department of Medicine, University of Minnesota, Minneapolis, MN, USA.
Respir Res. 2020 May 29;21(1):132. doi: 10.1186/s12931-020-01384-2.
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.
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.
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.
Our results suggest that TRIM72 protects injured lungs and ameliorates fibrosis through promoting post-injury repair of AECs.
慢性组织损伤可诱导纤维化疾病（如特发性肺纤维化 (IPF)）中进行性瘢痕形成，而一系列修复/再生和应激反应达到平衡，从而决定器官水平损伤的结局。在肺部，I 型肺泡上皮 (ATI) 细胞构成上皮屏障，而 II 型肺泡上皮 (ATII) 细胞在修复受损的远端肺部方面发挥关键作用。已经证明真核细胞具有可在损伤后迅速修复受损质膜的修复机制，我们之前的研究发现三结构域蛋白 72 (TRIM72) 在包括肺在内的少数组织中表达，具有膜修复作用。然而，肺泡上皮细胞 (AEC) 修复在 IPF 发病机制中的作用尚未被研究过。
在这项研究中，我们测试了 TRIM72 在 ATII 细胞修复和肺纤维化发展中的特定作用。通过皂苷测定法在分离的原代 ATII 细胞和大鼠 ATII 细胞系上评估膜修复作用。使用博来霉素处理的转基因小鼠测试 TRIM72 的抗纤维化潜力。
我们表明，TRIM72 在各种损伤后和人 IPF 肺中上调。然而，IPF 肺中 ATII 细胞的 TRIM72 表达存在异常的亚细胞定位。体外研究表明，TRIM72 修复永生化和原代 ATII 的膜损伤，导致应激诱导的 p53 激活减少和细胞凋亡减少。体内研究表明，TRIM72 可保护肺泡上皮层的完整性并减少肺纤维化。
我们的结果表明，TRIM72 通过促进 AEC 损伤后的修复来保护受损的肺部并改善纤维化。
