Department of Anesthesiology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong 250021, China; Department of Anesthesiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China.
Department of Anesthesiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China.
Int Immunopharmacol. 2024 Oct 25;140:112838. doi: 10.1016/j.intimp.2024.112838. Epub 2024 Aug 8.
Acute lung injury (ALI) has been a hot topic in the field of critical care research in recent years. Mitochondrial dynamics consists of mitochondrial fusion and mitochondrial fission. Dynamin-related protein 1 (Drp1), a key molecule that regulates mitochondrial fission, is important in the oxidative stress and inflammatory response to ALI. Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) is a core protein that mediates mitochondrial biogenesis. G-protein pathway suppressor 2 (GPS2) acts as a transcriptional cofactor with regulatory effects on nuclear-encoded mitochondrial genes. This study aimed to investigate the mechanism of PGC-1α/Drp1-mediated mitochondrial dynamics involved in ALI and to demonstrate the protective mechanism of GPS2 in regulating mitochondrial structure and function and inflammation in ALI. The ALI model was constructed using LPS-induced wild-type mice and human pulmonary microvascular endothelial cells (HPMVECs). It was found that lung injury, oxidative stress and inflammation were exacerbated in the mice ALI model and that mitochondrial structure and function were disrupted in HPMVECs. In vitro studies revealed that LPS led to the upregulated expression of Drp1 and the downregulated expression of PGC-1α and GPS2. Mitochondrial division was reduced and respiratory function was restored in Drp1 knockdown cells, which inhibited oxidative stress and inflammatory response. In addition, the overexpression of PGC-1α and GPS2 significantly inhibited the expression of Drp1, mitochondrial function was restored, and inhibited reactive oxygen species (ROS) production and inflammatory factor release. Moreover, the overexpression of GPS2 promoted the upregulated expression of PGC-1α. This mechanism was also validated in vivo, in which the low expression of GPS2 in mice resulted in the upregulated expression of Drp1 and the downregulated expression of PGC-1α, and further exacerbated LPS-induced ALI. In the present study, we also found that LPS-induced the downregulated expression of GPS2 may be associated with its increased degradation by the proteasome. Therefore, these findings revealed that GPS2 inhibited oxidative stress and inflammation by modulating PGC-1α/Drp1-mediated mitochondrial dynamics to alleviate LPS-induced ALI, which may provide a new approach to the therapeutic orientation for LPS-induced ALI.
急性肺损伤 (ALI) 是近年来重症监护研究领域的热门话题。线粒体动力学由线粒体融合和线粒体裂变组成。动力相关蛋白 1（Drp1）是调节线粒体裂变的关键分子，在 ALI 的氧化应激和炎症反应中很重要。过氧化物酶体增殖物激活受体-γ共激活因子 1α（PGC-1α）是介导线粒体生物发生的核心蛋白。G 蛋白通路抑制因子 2（GPS2）作为一种转录共激活因子，对核编码的线粒体基因具有调节作用。本研究旨在探讨 PGC-1α/Drp1 介导的线粒体动力学在 ALI 中的作用机制，并证明 GPS2 调节线粒体结构和功能以及 ALI 中的炎症的保护机制。使用 LPS 诱导的野生型小鼠和人肺微血管内皮细胞 (HPMVEC) 构建 ALI 模型。结果发现，在小鼠 ALI 模型中，肺损伤、氧化应激和炎症加剧，HPMVEC 中线粒体结构和功能受到破坏。体外研究表明，LPS 导致 Drp1 表达上调，PGC-1α 和 GPS2 表达下调。Drp1 敲低细胞中线粒体分裂减少，呼吸功能恢复，抑制氧化应激和炎症反应。此外，PGC-1α 和 GPS2 的过表达显著抑制 Drp1 的表达，恢复线粒体功能，并抑制活性氧 (ROS) 产生和炎症因子释放。此外，GPS2 的过表达促进了 PGC-1α 的上调表达。在体内也验证了这一机制，即在小鼠中 GPS2 的低表达导致 Drp1 的上调表达和 PGC-1α 的下调表达，进一步加重 LPS 诱导的 ALI。在本研究中，我们还发现 LPS 诱导的 GPS2 下调表达可能与其通过蛋白酶体降解增加有关。因此，这些发现表明 GPS2 通过调节 PGC-1α/Drp1 介导的线粒体动力学来抑制氧化应激和炎症，从而减轻 LPS 诱导的 ALI，这可能为 LPS 诱导的 ALI 的治疗方向提供一种新方法。
