College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Institutes of Biomedical Sciences, Shandong Normal University, Jinan 250014, People's Republic of China.
Anal Chem. 2022 Aug 16;94(32):11272-11281. doi: 10.1021/acs.analchem.2c01866. Epub 2022 Aug 4.
Idiopathic pulmonary fibrosis (IPF) has been characterized as a chronic inflammatory disease that leads to irreversible damage to pulmonary function. However, there is no specific IPF biomarker that can be used to distinguish IPF and not pneumonia. Endoplasmic reticulum (ER) stress is prominent in IPF. To search for a specific biomarker of IPF, we developed two ER-targeting two-photon (TP) fluorescent probes, TP-ONOO and TP-Cys, for peroxynitrite (ONOO) and cysteine (Cys) imaging, respectively. A significant increase in Cys levels in the lungs was discovered only in mice with IPF, which implied that Cys might be an IPF biomarker candidate. Furthermore, we uncovered the mechanism of glutathione (GSH) deficiency in IPF, which was not due to Cys shortage but instead was attributable to impaired glutamate cysteine ligase and glutathione synthetase activities ONOO-induced post-transcriptional modification. This work has potential to provide a new method for IPF early diagnosis and drug efficacy evaluation.
特发性肺纤维化 (IPF) 已被定义为一种慢性炎症性疾病，可导致肺功能的不可逆转损伤。然而，目前尚无可用于区分 IPF 和肺炎的特定 IPF 生物标志物。内质网 (ER) 应激在 IPF 中很明显。为了寻找 IPF 的特异性生物标志物，我们开发了两种针对内质网的双光子 (TP) 荧光探针，TP-ONOO 和 TP-Cys，分别用于过氧亚硝酸盐 (ONOO) 和半胱氨酸 (Cys) 的成像。仅在患有 IPF 的小鼠中发现肺部 Cys 水平显著升高，这表明 Cys 可能是 IPF 生物标志物的候选物。此外，我们揭示了 IPF 中谷胱甘肽 (GSH) 缺乏的机制，这不是由于 Cys 短缺，而是由于谷氨酸半胱氨酸连接酶和谷胱甘肽合成酶活性受损以及 ONOO 诱导的转录后修饰所致。这项工作有可能为 IPF 的早期诊断和药物疗效评估提供一种新方法。
