ACP5在特发性肺纤维化发病机制中作用的研究

Current studies have shown that epithelial-mesenchymal transition (EMT) promotes the development of idiopathic pulmonary fibrosis (IPF). The transcription factor FoxM1 can be involved in pulmonary fibrosis by regulating EMT, while tartrate-resistant phosphatase 5 (ACP5) has not been studied as a transcription target of FoxM1 in EMT or pulmonary fibrosis. In our pre-experiment, the expression and localization of ACP5 in lung tissue of IPF patients and the mouse with pulmonary fibrosis were detected, then we found that the effect of ACP5 on pulmonary fibrosis mainly occurred in alveolar epithelial cells. The results of cell experiments showed that knockdown of ACP5 could inhibit the EMT induced by TGF-β1. Based on the above research, this study will investigate the relationship between ACP5 and EMT in lung tissue of IPF patients, and analysis the correlation between ACP5 level in IPF patients` serum and their clinical symptoms, so that to explore the role of ACP5 in idiopathic pulmonary fibrosis. The ACP5 knockout mice will be used as the main tool in elucidating the effect of ACP5 on alveolar epithelial cells in pulmonary fibrosis and its specific molecular mechanism in animal modles and vitro experiments. The implementation of this study will further expand our understanding of the pathogenesis of IPF, and may find new biomarkers and therapeutic targets.

研究表明，上皮细胞间充质转化（EMT）促进特发性肺纤维化（IPF）的发生发展。转录因子FoxM1可通过调控EMT参与肺纤维化过程，而耐酒石酸性磷酸酶5（ACP5）作为FoxM1的一个转录靶点在EMT或肺纤维化中尚无研究。预实验中，通过检测IPF患者、小鼠肺纤维化模型肺组织ACP5的表达与定位，发现ACP5对肺纤维化的影响主要发生在肺泡上皮细胞，细胞实验结果表明敲减ACP5可抑制TGF-β1诱导的EMT。本项目拟通过观察IPF患者肺组织中ACP5的表达与EMT及血清中ACP5水平与临床症状的关系，分析探讨ACP5对IPF的影响；并进一步以ACP5敲除小鼠为主要工具，通过动物模型与细胞体外干预实验，阐明ACP5对肺纤维化肺泡上皮细胞的影响特征及其具体分子机制。本研究的实施将进一步扩展我们对于IPF发病机制的认识，并可能发现新的生物标志物及治疗靶点。

耐酒石酸酸性磷酸酶5（ACP5）是物种间高度保守的酸性磷酸酶，其通过增加蛋白去磷酸化，调控一系列病理生理过程。本项目深入的揭示ACP5在特发性肺纤维化（IPF）中的作用及临床意义。研究发现ACP5在IPF患者及博来霉素（BLM）诱导的肺纤维化中显著升高，且主要表达于肌成纤维细胞中。后续研究发现血清中ACP5的水平在重度IPF患者中明显增加。在BLM诱导的肺纤维化模型中，敲除Acp5小鼠的肺部损伤及纤维化较野生型小鼠显著减轻，同时伴随着成纤维细胞向肌成纤维细胞分化和增殖的减少。体外研究进一步发现，在成纤维细胞中，TGF-β通过TGFβR1/p-Smad3信号通路增加Acp5表达，高表达的Acp5增加p-β-catenin（S33/T41）去磷酸化，继而减少胞浆中β-catenin降解，增强胞核中β-catenin信号通路，促进成纤维细胞的分化、增殖和迁移。在此基础上，腹腔注射Acp5抑制剂或气道注射Acp5 siRNA脂质体均可有效治疗肺纤维化。本研究发现了ACP5通过β-catenin信号通路调控成纤维细胞的功能参与IPF的发病机制，并为IPF的治疗提供了新的潜在标靶。