Department of Geriatrics, Respiratory Medicine, Xiangya Hospital, Central South University, Changsha, 410078, Hunan, China.
Department of Physiology, School of Basic Medicine Science, Central South University, Changsha, 410078, Hunan, China.
Cell Commun Signal. 2024 Nov 26;22(1):566. doi: 10.1186/s12964-024-01946-7.
Cadmium is a ubiquitous toxic metal and environmental pollutant. More and more studies have shown that cadmium exposure can damage lung function. Alveolar epithelial cells (AECs) are structural cells that maintain the stability of lung function. The injury of AECs is an essential determinant of many lung diseases. In the lung, cadmium accumulation can cause damage to AECs. However, the specific mechanism is still unclear. This study aimed to explore the key mechanism underlying the injury of AECs caused by cadmium exposure.
The main modes of death of AECs induced by cadmium exposure were evaluated in vivo and in vitro. Transcriptomic changes of AECs induced by cadmium exposure were analyzed using RNA-sequence. Mitochondrial ROS scavengers (mitoQ), voltage-dependent anion channel 1 (VDAC1) oligomer inhibitor (VBIT4), and cyclic GMP-AMP synthase (cGAS) inhibitor (RU.521) were used to assess whether cadmium exposure triggered pyroptosis of AECs by inducing mitochondrial stress to activate the cGAS-STING-NLRP3 axis.
In this study, the expression of pyroptosis-related proteins was significantly up-regulated in the cadmium-exposed AECs, while the expression of apoptosis, necroptosis, and ferroptosis-related proteins had no significant up-regulated. The pan-caspase inhibitor ZVAD-FMK significantly reduced cell death. Thus, our research indicates that pyroptosis is the primary type of AEC death exported to cadmium. Mechanistically, RNA-seq and Western Blot results showed that cadmium exposure activated the cGAS-STING pathway in AECs and promoted pyroptosis by activating the NLRP3 inflammasome. Further investigation of the mechanism found that cadmium exposure caused mitochondrial oxidative stress, which led to mtDNA leakage into the cytoplasm and activated the cGAS-STING pathway. In addition, inhibition of the cGAS-STING pathway significantly alleviated lung injury induced by cadmium exposure in mice.
Our study confirmed that pyroptosis of AECs was a vital mechanism of lung injury after cadmium exposure in a cGAS-STING-dependent manner, which may provide a new target for the treatment of lung diseases induced by cadmium exposure.
镉是一种普遍存在的有毒金属和环境污染物。越来越多的研究表明，镉暴露会损害肺功能。肺泡上皮细胞（AECs）是维持肺功能稳定的结构细胞。AECs 的损伤是许多肺部疾病的重要决定因素。在肺部，镉积累会导致 AECs 损伤。然而，具体的机制尚不清楚。本研究旨在探讨镉暴露导致 AECs 损伤的关键机制。
在体内和体外评估镉暴露诱导的 AECs 主要死亡方式。使用 RNA-seq 分析镉暴露诱导的 AECs 的转录组变化。使用线粒体 ROS 清除剂（mitoQ）、电压依赖性阴离子通道 1（VDAC1）寡聚抑制剂（VBIT4）和环鸟苷酸-AMP 合酶（cGAS）抑制剂（RU.521）评估镉暴露是否通过诱导线粒体应激激活 cGAS-STING-NLRP3 轴来触发 AECs 的细胞焦亡。
在这项研究中，镉暴露的 AECs 中细胞焦亡相关蛋白的表达明显上调，而凋亡、坏死和铁死亡相关蛋白的表达没有明显上调。泛半胱天冬酶抑制剂 ZVAD-FMK 显著减少细胞死亡。因此，我们的研究表明，细胞焦亡是 AEC 对镉的主要死亡类型。从机制上讲，RNA-seq 和 Western Blot 结果表明，镉暴露激活了 AECs 中的 cGAS-STING 途径，并通过激活 NLRP3 炎性小体促进细胞焦亡。对机制的进一步研究发现，镉暴露导致线粒体氧化应激，导致 mtDNA 漏出线粒体并激活 cGAS-STING 途径。此外，抑制 cGAS-STING 途径可显著减轻小鼠镉暴露引起的肺损伤。
本研究证实，依赖于 cGAS-STING 的 AEC 细胞焦亡是镉暴露后肺损伤的重要机制，这可能为治疗镉暴露引起的肺部疾病提供新的靶点。
