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Bronchoalveolar Lavage Exosomes in Lipopolysaccharide-induced Septic Lung Injury
Published on: May 21, 2018
Dexmedetomidine Mitigates Sepsis-Associated Lung Injury by Suppressing Macrophage Ferroptosis via the Nrf2/HO-1
Bei Ma1,2,3, Renjie Luo2,3, Gang Kuang2,3,4
1Department of Critical Care Medicine, Liangjiang Hospital of Chongqing Medical University, 401121 Chongqing, China.
Background:
To investigate the protective role of dexmedetomidine (DEX) in sepsis-associated acute lung injury through the regulation of macrophage ferroptosis.
Methods:
In silico screening of GeneCards and FerrDb Vv3 databases was performed to identify ferroptosis-related candidate genes modulated by dexmedetomidineDEX, lung injury, and macrophage activity, prioritizing nuclear factor erythroid 2-related factor 2 (Nrf2)/Nfe2l2 for subsequent experimental validation. A murine cecal ligation and puncture model of acute lung injury (ALI) and lipopolysaccharide-stimulated macrophages were established and subjected to treatment with DEX and/or the Nrf2 inhibitor ML385. Glutathione peroxidase 4 (GPX4), Nrf2, and heme oxygenase-1 (HO-1) protein levels were analyzed using western blotting. Ferroptosis and oxidative stress markers (superoxide dismutase [SOD], glutathione [GSH], iron content, reactive oxygen species [ROS], malondialdehyde [MDA]) were measured. Samples of fresh lung tissue were observed by electron microscopy. Macrophage phenotypes and tumor necrosis factor alpha (TNF-α) expression were assessed. Macrophage-conditioned medium was used to culture non-small cell adenocarcinoma epithelial cells (A549), and cell migration was evaluated. Proliferation-related proteins (matrix metalloprotease 9 [MMP-9] and Snail-1), key tight junction proteins (zonula occludens-1 [ZO-1] and occludin) and the apoptotic status were also analyzed.
Results:
DEX significantly reduced ROS, iron content, and MDA levels while concomitantly increasing SOD activity and GSH content in both ALI model mice and LPS-treated macrophages. DEX inhibited pro-inflammatory M1 macrophage polarization with a concomitant decrease in TNF-α release through Nrf2-dependent mechanisms. DEX was found to mitigate inflammatory microenvironment-induced macrophage ferroptosis through activation of Nrf2 signaling, thereby reducing damage in A549 cells. This effect may be linked to the regulation of macrophage inflammatory phenotypes.
Conclusions:
DEX improved sepsis-associated ALI by inhibiting macrophage ferroptosis and polarization toward the M1 type by activation of the Nrf2/HO-1 pathway.
