Department of Pediatrics, Severance Hospital, Institute of Allergy, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine,134 Sinchon-Dong, Seoul 03722, Korea.
Cells. 2021 Apr 19;10(4):944. doi: 10.3390/cells10040944.
Exposure to high oxygen concentrations leads to generation of excessive reactive oxygen species, causing cellular injury and multiple organ dysfunctions and is associated with a high mortality rate. Clusterin (CLU) is a heterodimeric glycoprotein that mediates several intracellular signaling pathways, including cell death and inflammation. However, the role of CLU in the pathogenesis of hyperoxic acute lung injury (HALI) is unknown. Wild-type (WT) and CLU-deficient mice and cultured human airway epithelial cells were used. Changes in cell death- and inflammation-related molecules with or without hyperoxia exposure in cells and animals were determined. Hyperoxia induced an increase in CLU expression in mouse lungs and human airway epithelial cells. Mice lacking CLU had increased HALI and mortality rate compared with WT mice. In vitro, CLU-disrupted cells showed enhanced release of cytochrome c, Bax translocation, cell death and inflammatory cytokine expression. However, treatment with recombinant CLU attenuated hyperoxia-induced apoptosis. Moreover, the Kyoto Encyclopedia of Genes and Genomes and Gene Ontology analyses revealed metabolic pathways, hematopoietic cell lineage, response to stress and localization and regulation of immune system that were differentially regulated between WT and CLU mice. These results demonstrate that prolonged hyperoxia-induced lung injury is associated with CLU expression and that CLU replenishment may alleviate hyperoxia-induced cell death.
暴露于高浓度氧气会导致过多的活性氧产生，从而导致细胞损伤和多器官功能障碍，并与高死亡率相关。聚集蛋白（CLU）是一种异二聚体糖蛋白，可介导包括细胞死亡和炎症在内的多种细胞内信号通路。然而，CLU 在高氧急性肺损伤（HALI）发病机制中的作用尚不清楚。使用野生型（WT）和 CLU 缺陷型小鼠和培养的人气道上皮细胞。在细胞和动物中，确定有无高氧暴露时与细胞死亡和炎症相关的分子的变化。高氧诱导小鼠肺和人气道上皮细胞中 CLU 表达增加。与 WT 小鼠相比，缺乏 CLU 的小鼠 HALI 和死亡率增加。在体外，CLU 破坏的细胞显示细胞色素 c 释放增加、Bax 易位、细胞死亡和炎症细胞因子表达增加。然而，用重组 CLU 处理可减轻高氧诱导的细胞凋亡。此外，京都基因与基因组百科全书和基因本体论分析显示，WT 和 CLU 小鼠之间差异调节的代谢途径、造血细胞谱系、应激反应以及免疫系统的定位和调节。这些结果表明，长时间高氧诱导的肺损伤与 CLU 表达有关，而 CLU 补充可能减轻高氧诱导的细胞死亡。
